Aim: This study aimed to establish the in vitro efficacy of chlorhexidine (CHX)-silver nanoparticles (AgNP) based preparation, against Staphylococcus aureus (S. aureus) and Pseudomonas aeruginosa (P. aeruginosa) in planktonic cultures, biofilms, and on inert stainless-steel surfaces.

Methods: The in vitro antimicrobial activity of the CHX-AgNP formulation (Dermosedan MRSA Nano AG^®) was evaluated against reference and multidrug-resistant (MDR) strains of S. aureus and P. aeruginosa by determining the minimum inhibitory and bactericidal concentrations (MIC and MBC), as well as the minimum biofilm inhibitory and eradication concentrations (MBIC and MBEC). Also, the residual bactericidal activity on inert stainless-steel surfaces was evaluated.

Results: MIC against methicillin-resistant S. aureus (MRSA) and MDR P. aeruginosa (MDR-PA) isolates ranged between 5/2.5–20/10 µg/mL, up to 8,000 times lower than the manufacturer’s recommended concentration, while MBC ranged from 500 to 2,000 times lower. MBIC matched the MBC, while higher concentrations were needed to eradicate preformed biofilms. On stainless-steel surfaces, high antimicrobial activity was observed for both pathogens. No bacterial survival was detected even after 6 hours at 4% CHX + 2% AgNP concentration. The CHX-AgNP combination demonstrated strong antimicrobial and antibiofilm activity against both S. aureus and P. aeruginosa.

Conclusions: These results support the potential application of Dermosedan MRSA Nano AG^® as a strategy for managing topical resistant infections and for environmental disinfection in both veterinary and clinical settings.

Background: The root cause of diabetes is dysregulated pathways, including those involving AMP-activated protein kinase (AMPK), GLUT-mediated glucose transport, and the PI3K/AKT pathway. There has been a notable increase in research on phytoconstituents as pathway-specific treatments for diabetes; however, the comprehensiveness of this evidence remains unclear.

Methods: This systematic review followed PRISMA guidelines and was registered on PROSPERO (CRD420251073083). Databases searched included PubMed, Scopus, Google Scholar, and Europe PMC for experimental studies (in vivo, in vitro, and in silico) published between 2015 and 2024. The final search was conducted in April 2025, and 2025 publications available as “early access” before this date were included. Only English-language studies were included. Animal studies (in vivo) were assessed for risk of bias using the SYRCLE tool, while in vitro studies were evaluated using the ToxRTool, based on test substance characterization, test system description, study design, and data reporting. Narrative synthesis was employed due to the heterogeneity of the data.

Results: Out of 3,222 articles, 177 articles met the inclusion criteria. Study types included in vitro (92; 52%), in vivo (66; 37.3%), in silico (15; 8.5%), and other experimental types (4; 2.3%). Phytoconstituents predominantly targeted PI3K/AKT (44.6%), GLUT transporters (19.8%), and AMPK (14.1%) pathways. Rodent models were most used (48.02%). Primary outcomes included improved insulin sensitivity, enhanced glucose homeostasis, and reduced oxidative stress and inflammation. The risk of bias analysis revealed 68.93% of the studies carried a moderate risk, 29.94% a low risk, and 1.13% a high risk.

Discussion: Phytoconstituent activity was consistent with the activation of diabetes-relevant signaling pathways, particularly PI3K/AKT, GLUT transporters, and AMPK cascades. However, most evidence was correlative, with limited loss-of-function validation. Methodological irregularities, moderate risk of bias, and limited translational research reduce the strength and generalizability of these findings.

Aim: The prevalence of multidrug-resistant “superbugs”, particularly Acinetobacter baumannii and Klebsiella pneumoniae, is a menacing phenomenon in society, rendering last-resort antibiotics increasingly suboptimal and ineffective. Carbapenemase enzymes play a major role in this resistance by hydrolysing carbapenem antibiotics. This study aims to identify and characterize potential non-covalent carbapenemase inhibitors using multiscale computational approaches.

Methods: A focused library of 245 compounds, comprising pharmacopeial derivatives and chemogenomic molecules, was screened using a hierarchical virtual screening workflow. Top-ranked hits were further evaluated by rescoring for thermodynamic affinity. The most promising candidate was subjected to a 100 ns molecular dynamics (MD) simulation to assess binding stability, followed by Well-Tempered Metadynamics (WTMetaD) to characterise the free energy landscape and binding behaviour. Pharmacokinetic and toxicity profiles were predicted using SwissADME and ProTox 3.0.

Results: Three compounds, daunorubicin, doxorubicin, and EUB0000226b, emerged as potential carbapenemase inhibitors. EUB0000226b demonstrated the most favourable binding affinity and structural novelty. MD simulations showed protein stability, while ligand RMSD fluctuations (2.4–5.6 Å) suggested flexible binding. WTMetaD analysis revealed a solvent-separated metastable state that increased ligand residence time within the active site. ADME and toxicity predictions indicated acceptable drug-likeness, good gastrointestinal absorption, and a generally safe profile.

Conclusions: Multiscale computational analysis identified EUB0000226b as a promising non-covalent carbapenemase inhibitor with favourable binding energetics, dynamic stability, and drug-like properties.

Immunotherapy has transformed oncology, yet has only been marginally effective in prostate cancer (PCa), which is a malignancy with a low mutational load and a highly immunosuppressive tumor microenvironment (TME). This critical review is a reflection on the changing position of the innovative immunotherapies in PCa that extends beyond the description stage to synthesize the synergies and constraints of immune checkpoint inhibitors (ICIs), chimeric antigen receptor (CAR) T-cell therapy, and next-generation modalities such as bispecific T-cell engagers (BiTEs). We assess the mechanistic reasoning of combination therapies, comprising androgen receptor signaling communicators, PARP communicators, and radioligand therapies, which seek to modulate the immunogenicity of the immune-cold PCa TME. Also, we combine new knowledge to novel resistance pathways, including the newly discovered thrombospondin-1-CD47 axis, in the process of T cell exhaustion through calcineurin-NFAT signaling. Although some preclinical data and initial clinical indicators in biomarker-selected subpopulations are promising, the vast majority of Phase III trials of ICIs in unselected populations with metastatic castration-resistant prostate cancer (mCRPC) have failed. This review reveals that the next generation of PCa immunotherapy would not be sequential monotherapies but rather rationally designed multimodal combinations guided by profound molecular and immune profiling to overcome inherent resistance mechanisms.

Background: Vascular aging is a major driver of cardiovascular, metabolic, and degenerative diseases, characterized by oxidative stress, mitochondrial dysfunction, endothelial senescence, and impaired proteostasis. Emerging data show that anti-infective drugs can influence these aging pathways beyond antimicrobial activity. However, their capacity to accelerate or slow vascular ageing has not been clearly defined. This review summarizes current evidence on how anti-infective agents modulate vascular ageing mechanisms.

Methods: A systematic review was conducted following PRISMA 2020 guidelines. Studies from 2000 to 2024 were searched in major indexed databases. Eligible studies included in vitro, animal, and human research evaluating the effects of anti-infective agents on endothelial function, vascular senescence markers (p16^INK4a, p21, SA-β-gal), oxidative stress, mitochondrial activity, inflammation, or proteostasis, key determinants of vascular ageing. Studies lacking mechanistic aging endpoints were excluded. Extracted data included drug class, model type, study design, and age-related outcomes. Risk of bias was assessed using SYRCLE, RoB-2, ROBINS-I, and narrative appraisal for in vitro studies.

Results: Ninety-eight studies were identified; after removing six duplicates, ninety-two met the criteria. Macrolides, tetracyclines, and selected antivirals exerted anti-ageing effects by suppressing senescence-associated secretory phenotype (SASP), preserving mitochondrial integrity, reducing oxidative stress, and enhancing autophagy. Aminoglycosides and fluoroquinolones accelerated vascular ageing by generating reactive oxygen species, inducing DNA damage, and disrupting proteostasis. Antiviral protease inhibitors worsened endothelial dysfunction and metabolic aging. Antifungals such as itraconazole and amphotericin B impaired mitochondrial activity and angiogenesis, contributing to ageing phenotypes. Antiparasitic drugs showed mixed aging outcomes: chloroquine promoted autophagy and longevity, whereas thiabendazole impaired vascular stability. Broad-spectrum antibiotics disrupted the gut-vascular axis, increasing trimethylamine N-oxide, a mediator of inflammatory vascular aging.

Discussion: Anti-infective drugs display diverse, class-specific effects on vascular aging. Recognizing these age-related actions is essential for safer prescribing and for repurposing anti-infective agents to target pathological vascular aging mechanisms.

Background:Antimicrobial resistance (AMR) among Gram-positive bacteria has emerged as a significant global health threat, with pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VRE) exhibiting increasing resistance to conventional antibiotics. This systematic review evaluates new advances in nanomaterial-based antimicrobial agents as innovative solutions to combat AMR in Gram-positive bacteria.

Methods: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, studies published between 2014 and 2024 were systematically screened and analysed from databases including PubMed, Scopus, Google Scholar, and HINARI. From an initial 1,405 articles, 131 experimental studies that met the inclusion criteria were systematically analysed to harness the advances in nanomaterial-based antimicrobial agents in combating AMR in Gram-positive bacteria.

Results: The included studies demonstrated that various nanomaterials, including silver nanoparticles (AgNPs), gold nanoparticles (AuNPs), zinc oxide nanoparticles (ZnO NPs), copper and copper oxide nanoparticles (Cu/CuO NPs), as well as polymeric and hybrid systems, exhibited potent antibacterial and antibiofilm activities. Key mechanisms of action included bacterial membrane disruption, reactive oxygen species (ROS) generation, intracellular interference, and targeted drug delivery. Many nanomaterials showed enhanced efficacy and synergistic effects when combined with conventional antibiotics, effectively reducing bacterial load and inhibiting biofilm formation in resistant strains like MRSA.

Discussion:Nanomaterials offer a multifaceted approach to overcome the evolving resistance mechanisms in Gram-positive pathogens, showing significant preclinical and clinical success. Despite these substantial preclinical results, challenges such as cytotoxicity, environmental impact, scalability, and the potential for resistance adaptation remain unaddressed. Furthermore, important translational barriers persist, most notably insufficient pharmacokinetic data and unclear regulatory pathways. Future efforts must focus on standardized manufacturing, comprehensive toxicity studies, and robust clinical trials to bridge the gap between laboratory innovation and practical therapeutic application.

Aim: To design, synthesize, and test small molecules and fragment-based compounds with putative selective anti-mycobacterial activity.

Methods: Standard chemosynthetic processes were used to synthesize 42 compounds. A cell-based phenotypic screen for inhibitors of mycobacterial growth was used to identify several fragments and small molecules as representatives of urea-, carbamothioate-, and α,β-unsaturated systems (Michael acceptors) chemotypes.

Results: All 42 compounds exhibited selective toxicity for mycobacteria as demonstrated by their lack of activity against various Gram-positive and Gram-negative bacteria and acid-fast Corynebacterium glutamicum. A thiadiazole compound, similar to (3-((5-(methylthio)-1,3,4-thiadiazol-2-yl)thio)pyrazine-2-carbonitrile), which activates the human lecitin: cholesterol acyltransferase (LCAT), exhibits growth-inhibitory activity [0.6 μg/mL in bovine serum albumin (BSA)-free media] against drug-susceptibleMycobacterium tuberculosis (Mtb). From the urea class, a 1,2,4-triazole-containing urea demonstrated anti-Mtb activity (4.7 μg/mL in BSA-free media). Several carbamothioate-based fragments demonstrated activity against Mycobacterium marinum [with a best minimum inhibitory concentration (MIC) of 6.25 μg/mL in minimal BSA-free media].

Conclusions: This foundational study demonstrates the utility of these newly designed and synthesized low molecular-weight compounds and fragments as potential antimycobacterials.

Type 2 diabetes mellitus (T2DM) is a global health challenge often complicated by poor treatment adherence, suboptimal lifestyle habits, and progressive metabolic deterioration. Cognitive behavioral therapy (CBT) has been shown to improve adherence and psychological outcomes, yet its integration with structured lifestyle modification and pharmacotherapy in routine clinical care remains underexplored. A descriptive case series of five patients with uncontrolled T2DM (baseline HbA1c 11–14.5%) was conducted in a primary care setting in Palestine. The intervention combined CBT-inspired behavioral counseling (goal setting, problem-solving, cognitive restructuring) with a structured two-meal low-carbohydrate diet, exercise and sleep hygiene guidance, and pharmacotherapy optimization (withdrawal of insulin/sulfonylureas, initiation of metformin, DPP-4 inhibitors, and SGLT2 inhibitors as appropriate). Patients were followed for 3–6 months. All five patients achieved clinically meaningful improvements. Mean HbA1c decreased from 12.6% at baseline to 7.4% at follow-up. Weight loss ranged from 5–17 kg (mean ~10 kg). Additional benefits included reductions in blood pressure, improvements in renal function and lipid profiles, and resolution of quality-of-life issues such as fatigue and erectile dysfunction. Several patients discontinued insulin or sulfonylurea therapy while maintaining improved glycemic control. The integration of CBT-inspired counseling with structured lifestyle intervention and pharmacotherapy adjustments was associated with short-term improvements in uncontrolled T2DM, including outcomes approaching remission. Although the small sample size and uncontrolled design limit causal interpretation, the program is being done in a low-income, limited-resources area like Palestine. Patients do not have the privilege to attend and receive care from several healthcare professionals. Hence, conducting such practice in a primary care clinic and yielding such results and improvement in diabetes status is promising and provides hope to the patients with low income.

Over the past several decades there has been a growing recognition of the role that covalent drug candidates have played in the drug development process. With this recognition, compounds that are capable of selectively and irreversibly inactivating their targets through covalent bond formation are now being specifically designed rather than being serendipitously identified. Until recently, vinyl sulfones comprised only a small fraction of the warheads under development as covalent drug candidates, but an increasing number of compounds containing this versatile functional group are now under development and consideration as drug candidates. Vinyl sulfones are generally more reactive than structurally-related acrylamides and vinyl sulfonamides, presenting a challenge for producing target-specific inactivators. The most progress in overcoming this challenge has been made in designing vinyl sulfones as selective inactivators of microbial and human cysteine proteases, incorporating these reactive warheads into peptide and peptide mimetic structures that utilize the substrate recognition motifs of these proteases. However, effective vinyl sulfones have also been produced against a growing range of phosphoryl-utilizing enzymes including kinases, phosphatases and metabolic enzymes. Here, target selection takes advantage of the capability of the sulfonyl group to act as a phosphoryl mimic. An example of this approach is presented for the targeting of a metabolic enzyme, fungal aspartate semialdehyde dehydrogenase, an essential microbial enzyme in amino acid metabolism. The studies conducted to date demonstrate the potential utility of designing vinyl sulfone drug candidates to achieve selectivity against challenging and new drug-resistant targets.

Aim: To evaluate the real-world effectiveness of prophylactic metoclopramide in preventing opioid-induced nausea and vomiting (OINV) during the initial phase of strong opioid therapy in opioid-naïve patients with cancer-related pain.

Methods: This retrospective, single-center observational cohort study included adult patients with pathologically confirmed malignancies who initiated strong opioid therapy between January 2023 and December 2024. Patients were categorized into a prophylactic metoclopramide group or a no-prophylaxis control group. Complete control (CC) of OINV during the first 7 days was defined as the absence of nausea, vomiting, and rescue antiemetic use. Univariate and multivariate logistic regression analyses were performed to identify factors associated with CC, adjusting for age, sex, body mass index, cancer subtype, cancer stage, comorbidity status, and morphine-equivalent daily dose (MEDD). Subgroup analyses were conducted based on age, sex, and cancer subtype.

Results: A total of 244 patients were included, of whom 199 received prophylactic metoclopramide, and 45 received no prophylaxis. The prophylactic group achieved significantly higher CC rates than the control group (74.9% vs. 37.8%, p < 0.001). Multivariate logistic regression confirmed that prophylactic metoclopramide was independently associated with higher odds of achieving CC (adjusted OR = 0.20, 95% CI: 0.10–0.40; p < 0.001). Similar improvements were observed for nausea and vomiting control. Subgroup analyses demonstrated consistent benefits across age and sex groups, with particularly notable effects in patients with gastrointestinal cancers.

Conclusions: Prophylactic metoclopramide significantly improves OINV control in opioid-naïve patients with cancer-related pain during the initiation of strong opioids. These findings support the rational use of early antiemetic prophylaxis in routine clinical practice. Prospective randomized trials are warranted to validate these real-world results and assess long-term safety.

The s-triazine scaffold has emerged as a privileged heterocyclic nucleus/moiety in pharmaceutical discovery and development, owing to its presence in several natural products and clinically relevant therapeutic agents, including enasidenib, gedatolisib, bimiralisib, atrazine, indaziflam, and triaziflam. s-Triazine derivatives are not only economically accessible and synthetically versatile, but they also exhibit a broad spectrum of noteworthy biological activities, encompassing anticancer, anti-inflammatory, antiviral, antidiabetic, anticonvulsant, antitubercular, and antimicrobial properties. Their widespread utility is further supported by the ease of synthesis from inexpensive precursors such as amidines or the readily available 2,4,6-trichloro-1,3,5-triazine (cyanuric chloride), which enables sequential functionalization and the rapid generation of diverse analogues. The heightened reactivity and modularity of the s-triazine core have facilitated the development of structurally rich heterocyclic hybrids with enhanced potency and improved pharmacological profiles. These multitarget-directed systems offer exciting opportunities for addressing various forms of cancer. Considering the increasing pace of innovation in this field, a comprehensive overview of recent advancements in s-triazine-based hybrid molecules is both timely and necessary. This review highlights current progress, key design strategies, and emerging perspectives to inspire continued efforts toward the identification of promising s-triazine-based lead candidates for future drug development as anticancer agents.

Aim: A seven amino acid cyclic peptide has been applied to human blood plasma treated with glucose metabolite methylglyoxal (MG) in “proof of concept” experiments to determine the peptide’s ability to counteract pathologies associated with hyperglycemia. Similar pathologies are evident during aging and in age-related disorders. In fact, elevated MG levels in the blood lead directly to diabetic complications and accelerated aging, including cognitive decline. These changes are attributed to oxidant stress and amyloidogenesis, the latter involving toxic accumulations of blood and tissue proteins.

Methods: cSKE7 was redesigned from cell survival-promoting and anti-inflammatory fragments near the N-terminus of human/primate “orphan” protein DSEP/Dermcidin and incubated at low micromolar concentrations with the MG-stressed human plasma for 24 hours. The modified design of the new compound offers several practical advantages over predecessors including cyclic stability and a marked increase in aqueous solubility.

Results: The peptide dispersed thioflavin-T-stained amyloid aggregates and reduced oxidant stress as measured by plasma levels of free thiols and of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activity. Since these N-terminal fragments of DSEP/Dermcidin have been shown to bind and influence the activity of heat shock protein 70 (HSP70), HSP70 inhibitor pifithrin-μ was added to the plasma prior to peptide treatment. The inhibitor disrupted amyloid dispersion and both peptide-induced and, in some cases, normally occurring antioxidant effects, suggesting these reparative activities are HSP70 dependent.

Conclusions: The results are discussed in terms of their potential use in new therapies for the complications of metabolic disease and disorders of aging that result from a deterioration of the quality control mechanisms of proteostasis.

The significant medicinal constituents and pharmacological potential of several botanicals suggest promising therapeutic applications. Scorzonera undulata displayed a diverse phytochemical profile, with 25 volatile and 21 phenolic compounds identified, including quinic and chlorogenic acids, along with flavonoids such as kaempferol, apigenin, luteolin derivatives, quercitrin, and naringin—mostly concentrated in the aerial parts. These extracts exhibited notable antioxidant, antimicrobial, anti-inflammatory, and cytotoxic activities, especially methanolic extracts against MCF-7 breast cancer cells, indicating therapeutic relevance.Andrographis paniculata extracts, rich in andrographolide, showed clinical potential in alleviating mild COVID-19 symptoms. However, the compound’s nonlinear pharmacokinetics highlight the need for optimized delivery strategies. Morinda citrifolia fruit extracts demonstrated considerable in vitro antimicrobial effects and moderate cytotoxicity, supported by UPLC–Orbitrap MS identification of unique bioactives. These findings reinforce the need for further pharmacological and clinical validation. The antiviral efficacy ofHouttuynia cordata against dengue virus type 2 was evident, with aqueous extracts showing strong virucidal action and inhibition of viral replication. Hyperoside was identified as the dominant active constituent, supported by a rich phytochemical profile including flavonoids, aristolactams, and triterpenoids. Genotoxicity assessments indicated a favorable safety profile, suggesting potential for phytotherapeutic development. Achillea millefolium (yarrow) contained essential oils enriched in camphor, 1,8-cineole, artemisia ketone, and azulene derivatives, alongside phenolic acids and flavonoids like chlorogenic acid, apigenin, luteolin, and quercetin. These contributed to its antioxidant, anti-inflammatory, antimicrobial, and hemostatic effects, validating traditional medicinal applications and warranting clinical standardization. Flavonoids such as luteolin and apigenin offered anticancer and cardiovascular benefits by inhibiting PD-L1 via STAT3 suppression and promoting autophagy to counter vascular calcification. Bryophyllum pinnatum demonstrated broad pharmacological activity attributed to bufadienolides, flavonoids, and phenolic acids, supporting its ethnomedicinal use while emphasizing the need for clinical safety validation.

Ageing is a gradual, multifactorial process that leads to the deterioration of physical and mental health, increasing the risk of disease and eventually death. Indicators of ageing manifest at the molecular level, including genomic instability, telomere attrition, epigenetic alterations, mitochondrial dysfunction, loss of proteostasis, and dysregulation of key signalling pathways such as the mechanistic target of rapamycin (mTOR) and insulin signalling. These molecular hallmarks of ageing are interconnected, amplifying one another over time. The resulting cellular stress triggers apoptosis or drives cells into a pathological state known as cellular senescence, in which they secrete inflammatory, pro-ageing factors. Consequently, there is a progressive decline in tissue function and regenerative capacity, accompanied by atrophy and stem cell exhaustion under a chronically inflamed microenvironment. Although functional decline with age is irreversible, research indicates it can be delayed. In this review, we discuss the hallmarks of ageing, conventional pharmacological interventions with demonstrated anti-ageing effects in cellular and animal models, and emerging therapeutic strategies being explored as ageing becomes increasingly recognized as a major risk factor for disease development.

Intranasal drug delivery exhibits therapeutic potential for the treatment of central nervous system (CNS) diseases, as it allows pharmaceuticals to bypass the blood-brain barrier (BBB) via the olfactory and trigeminal pathways. The primary advantage of this method lies in its non-invasiveness and low systemic toxicity. Nevertheless, this delivery method faces notable challenges, including limited nasal mucosal absorption and short residence time in the olfactory region. To address these limitations, intranasal nanomedicine has gained research attention. Nanomedicines can improve brain bioavailability by enhancing drug solubility, permeability, and stability. The following discussion summarizes recent advancements in nanotechnology-enabled nose-to-brain delivery systems, with the aim of synthesizing progress in the field and outlining future research directions.

Antibodies currently represent a leading segment of the biopharmaceutical market and are expected to maintain a significant presence in the therapeutic landscape. Development of therapeutic antibodies represents one of the most transformative advances in the modern medicine field, with hundreds of successful products on the market that have changed the lives of millions and the history of mankind by revolutionizing medical treatment. In its broadest context, antibody-based products consist of full-length antibodies, antibody fragments, polyvalent and polyspecific antibodies, and their conjugates (for targeted delivery of other therapeutic drugs/agents). High target specificity, tailored mechanisms of action, and broad applicability have made antibodies indispensable in a variety of diseases. With advancements in protein engineering as well as growing integration of computational biology, the field of antibody development continues to push boundaries and is expected to drive the next era of breakthroughs. This article charts the journey of therapeutic antibodies from their conceptual roots to their central role in current medicine, and offers a forward-looking perspective on what lies ahead in this dynamic field.

Aim: Bisoprolol fumarate (BF), commonly prescribed for cardiovascular conditions, is usually split to achieve specific doses. This study evaluated the effects of tablet splitting on the quality parameters of scored BF tablets from three different brands marketed in Saudi Arabia.

Methods: The products were evaluated for weight variation, content uniformity, and dissolution for intact and split tablets. A UPLC-sensitive assay was used for drug quantification.

Results: The results showed that all products lost less than 3% of its weight upon splitting, meeting the USP requirements. Content uniformity was between 85% and 115% for all products, complying with pharmacopoeial standards. Dissolution studies showed some variation between intact and split tablets. The f₂ similarity factor was calculated to compare the dissolution profiles of BF from both forms. The f₂ values showed a similar dissolution profile for the innovator product (f₂ was 62.53), but dissimilar profiles for Generic-1 and -2 (f₂ values were 48.90 and 34.43, respectively).

Conclusions: These results should be taken into consideration by healthcare professionals to avoid sub-therapeutic or toxic effects resulting from tablet splitting.

Aim: Chitosan (CHS)-based nanoparticulate systems have gained much interest due to their high drug loading capacity and the simplicity of their fabrication. The physical properties of two types of curcumin-loaded CHS nanoparticles (CHS-NPs) were determined and compared. A new in-vitro release method was developed based on mathematical modeling in which the drug is first released from the NP into the surrounding medium and subsequently diffuses through the membrane.

Methods: Curcumin-loaded CHS-NPs were fabricated by ionotropic gelation using sodium tripolyphosphate (TPP) and sodium hexametaphosphate (SHMP) crosslinking, and characterized by NP tracking analysis, loading capacity, zeta potential, Fourier transform infrared spectroscopy (FTIR), and in-vitro release rates.

Results: The data showed that compared to SHMP crosslinked CHS-NPs, TPP crosslinking demonstrated a decrease in entrapment efficiency at a relatively high concentration of the agent, probably by narrowing the space between the polymeric chains. As indicated by zeta potential measurements, TPP crosslinking at all levels was more uniformly distributed inside the NPs, whereas the higher molecular weight SHMP at a low concentration creates NPs mostly by binding onto the surface. It was found that the release rates of curcumin from CHS-NPs crosslinked by SHMP at higher concentrations were about twice as high as the release rates of curcumin from TPP-crosslinked CHS-NPs, accompanied by notable lag times.

Conclusions: This significant increase in the release rates of curcumin from SHMP-crosslinked CHS-NPs is explained by the large spatial structure of this crosslinker compared to the small TPP molecules. This study advances the literature on drug diffusion by making it possible to accurately determine its release from nanoparticulate systems.

Aim: The iridium(III) [Ir(III)] complexes exhibit anticancer properties, and along with their photoluminescence properties, they can be employed as diagnostic agents. Hence, we have tried to evaluate both properties. For this, the complexes of Ir(III) with pyridyl-based heterocyclic ligands, viz., [(TPQ)₃Ir] (1), [(TPQ)₂Ir(4-EO₂-pic)] (2), and [(ppy)₂Ir(dfpmpy)] (3) were prepared and evaluated for their cytotoxicity and emissive properties.

Methods: These complexes were authenticated by NMR (¹H and¹³C{¹H}) spectroscopy and high-resolution mass spectrometry (HRMS). Their photophysical properties were evaluated by UV-Vis spectroscopy and photoluminescence studies. Among them, [(TPQ)₃Ir] (1) and [(TPQ)₂Ir(4-EO₂-pic)] (2) complexes have exhibited red emission centred at ~600–625 nm range, which is appropriate for bio-imaging. The cellular internalization of [(TPQ)₂Ir(4-EO₂-pic)] (2) complex was investigated by confocal microscopy and flow cytometry at time intervals of 3 h and 6 h after its treatment with cancer cells. These Ir(III) complexes (1–3) were evaluated for their cytotoxicity against 4T1 mammary carcinoma cells by MTT assay. The moderately potent [(TPQ)₂Ir(4-EO₂-pic)] (2) complex was evaluated in vivo against 4T1 mammary carcinoma induced in BALB/c mice.

Results: Among these Ir(III) complexes (1–3), the [(TPQ)₂Ir(4-EO₂-pic)] (2) complex has exhibited moderate cytotoxicity (IC₅₀ ~60 µM) as observed from their evaluations against triple-negative breast cancer (TNBC), a 4T1 mammary carcinoma cell line in vitro by MTT assay. Hence, its in vivo anticancer potency was evaluated by its treatment against 4T1 mammary carcinoma induced in BALB/c mice. This study exhibited tumor-inhibitory activity.

Antimicrobial resistance (AMR) poses a growing global health threat, progressively undermining the clinical effectiveness of conventional antibiotic therapies. Despite their proven efficacy and standardized clinical frameworks, antibiotics exert strong selective pressures that accelerate resistance, disrupt host microbiota, and limit treatment options for chronic, biofilm-associated, and multidrug-resistant infections. Bacteriophage therapy has re-emerged as a potential adjunct or alternative approach, offering pathogen-specific antibacterial activity, preservation of commensal microbiota, and the capacity for co-evolution with bacterial hosts. This focused review critically compares antibiotics and bacteriophage therapy across mechanistic foundations, preclinical and clinical evidence, translational readiness, and real-world implementation challenges. While preclinical models consistently demonstrate robust antibacterial activity of bacteriophages, clinical evidence remains heterogeneous, with few randomized controlled studies available. Key system-level barriers, including regulatory inconsistency, manufacturing complexity, and lack of standardization, currently limit widespread clinical integration. Rather than positioning bacteriophages as replacements for antibiotics, this review emphasizes their potential role as complementary agents, particularly through bacteriophage-antibiotic synergy, to enhance treatment efficacy and mitigate resistance. Addressing methodological gaps, standardizing clinical trial designs, and developing integrated stewardship models will be critical to defining the future role of bacteriophage therapy in modern infectious disease management.

Aim: Two empirical methods were used to predict the absolute bioavailability (F) of medicines in adults and children following oral administration in the absence of intravenous (IV) dosing. This study systematically evaluates the predictive performance of Equation 1 to predict F in adults and children.

Methods: Equation 3 [F = Q/(Q + CL_oral)] was used for the prediction of F in adults and children. In Equation 3, clearance is the observed oral clearance following oral administration of a medicine and Q is either liver blood or plasma flow rate. The predictive performance of Equation 3 was evaluated in adults and children for three categories of medicines; medicines which are mainly metabolized in the liver, medicines which are metabolized both in the liver and the gut, and medicines which are mainly renally excreted. From the literature, oral clearance and F values for adults and children were obtained. The predictive performance of these two methods (blood or plasma flow rate) was assessed by comparing the predicted F of the medicines used in this study with the observed F (obtained from clinical studies).

Results: More than 90% predicted F values were within 0.5–2-fold prediction error in adults and children by both methods for all three categories of medicines. Plasma flow rate provided slightly better results than the blood flow rate.

Conclusions: The proposed methods indicate that the estimation of F of medicines in adults and children is possible with reasonable accuracy (within 0.5–2-fold prediction error). The method is useful to estimate F, especially in children, because it is not ethical to administer medicines by both IV and oral routes to children just for the sake of estimating F.

The global rise of antimicrobial resistance (AMR) has emerged as one of the most pressing threats to public health. This crisis calls for the urgent development of alternative therapeutic agents against antibiotic-resistant pathogens. Antimicrobial peptides (AMPs) are widely present in nature, with a broad range of effects and a low risk of causing drug resistance. Therefore, they are an ideal choice for the development of the next generation of antimicrobial drugs. To overcome the inefficiencies of traditional AMP discovery, artificial intelligence (AI) and machine learning (ML) technologies have been increasingly used to predict and design AMPs. Multiple AMP databases were used to train ML models for predicting the activity of AMPs or generating AMP sequences. This review briefly provides a comprehensive overview of AMP databases and computational tools, highlighting their capabilities and challenges. Future work should integrate larger datasets and experimental validation to accelerate clinical translation.

Advanced Therapy Medicinal Products (ATMPs) represent a transformative class of innovative therapies based on genes, cells, or engineered tissues that aim to modify, repair, or replace biological functions at a fundamental level. This review provides a foundational overview of ATMPs, addressing their scientific basis, regulatory classification, clinical translation, and key challenges for future development. The article outlines the four principal categories of ATMPs: gene therapy medicinal products, somatic cell therapy medicinal products, tissue-engineered products, and combined ATMPs, and discusses their distinct mechanisms of action and therapeutic applications. Recent clinical successes, including chimeric antigen receptor T-cell therapies, gene replacement therapies for inherited disorders, and tissue-engineered constructs for regenerative medicine, demonstrate the paradigm shift from symptomatic management towards disease modification or potential cure. However, the clinical implementation of ATMPs presents substantial challenges related to safety monitoring, long-term efficacy, complex manufacturing processes, regulatory evaluation, high treatment costs, and equitable patient access. Ethical considerations, including informed consent, long-term follow-up obligations, and global disparities in availability, further complicate their integration into routine clinical practice. Regulatory agencies have introduced adaptive pathways and accelerated approval mechanisms to facilitate timely patient access while maintaining rigorous standards of quality, safety, and efficacy. Continued technological innovation, coupled with sustainable healthcare policies and international collaboration, will be essential to realise the full therapeutic potential of ATMPs. As evidence accumulates from clinical trials and real-world use, ATMPs are expected to play an increasingly prominent role in modern medicine and the future of personalised healthcare.

Aim: This study investigated the anti-inflammatory effect of the extract and fractions of Eucalyptus camaldulensis and also profiled the secondary metabolites of its most active fraction.

Methods: The leaves of E. camaldulensis were collected, authenticated and extracted with methanol. The extract (100, 200, and 400 mg/kg), normal saline (negative control), and aspirin (positive control) were administered orally to egg-induced paw oedema rats of five groups of five rats each. The extract was partitioned, and each of the solvent fractions was assayed for its anti-inflammatory activity. The results obtained were subjected to one-way analysis of variance (ANOVA) followed by Bonferroni post hoc tests, and p < 0.05 was considered significant. Also, the most active fraction was subjected to gas chromatography-mass spectrometry (GC-MS) analysis.

Results: The extract at 100 mg/kg demonstrated the best anti-inflammatory effect at 29%, while the n-hexane (N-HEX) fraction gave the highest inflammatory inhibition at 43%. α-Phellandrene, o-cymene, n-hexadecanoic acid, and beta-sitosterol were identified as the most abundant compounds in the N-HEX fraction.

Conclusions: The study concluded that the methanol extract of E. camaldulensis possesses good anti-inflammatory properties, and its non-polar fraction was responsible for the observed activity. Bioassay-guided purification of anti-inflammatory constituents of the N-HEX fraction is recommended for future studies.

Brazil harbors remarkable biological and cultural diversity, reflected in a rich body of traditional knowledge regarding the medicinal use of plants. This study synthesized ethnobotanical evidence on plants traditionally used for skin and wound healing in Brazil and examined their convergence with available antibacterial data. An integrative literature review identified twenty ethnobotanical studies, mainly involving rural populations and local residents, reporting 51 plant species traditionally used for skin and wound healing across 22 genera, predominantly native and mainly documented in the Northeastern and Northern regions. The most frequently cited species included Aloe vera (L.) Burm.f. and Anacardium occidentale L., followed by Stryphnodendron adstringens (Mart.) Coville. Fabaceae and Anacardiaceae concentrated the highest number of species with confirmed antibacterial activity, followed by Piperaceae and Euphorbiaceae, which also showed a high proportional representation of active species. A meaningful convergence between ethnobotanical use and experimental antibacterial evidence was observed for more than half of the plants, frequently againstStaphylococcus aureus, a key pathogen in wound infections. Antibacterial data were predominantly derived from in vitro assays using non-standardized extracts, and only a limited number of studies reported possible mechanisms of action, such as membrane disruption and biofilm inhibition. Furthermore, few investigations evaluated antibacterial activity in infected wound models or quantified bacterial load reduction in vivo. Future studies should prioritize chemically standardized extracts, testing against resistant clinical strains and mature biofilm models, and validation of safety and therapeutic efficacy in clinical investigations. These findings reveal a gap between traditional use and clinically validated applications, underscoring the urgent need for standardized research approaches and reinforcing Brazil’s potential as a strategic reservoir of bioactive plant resources for primary health care. Addressing these limitations is essential to strengthening the translational basis for the rational use of medicinal plants in primary health care and public health contexts.

Schizophrenia affects approximately 24 million people worldwide, representing 0.3–0.7% of the global population, and remains a leading cause of years lived with disability. The disorder contributes to over 13 million disability-adjusted life years, underscoring its substantial global health and socioeconomic burden. This review critically examines the convergence of artificial intelligence (AI) and advanced oral drug delivery systems as an emerging strategy in schizophrenia management. Conventional diagnostic frameworks, reliant on subjective symptom assessment, often result in delayed or inaccurate diagnosis, while standard oral antipsychotics are limited by poor bioavailability, extensive first-pass metabolism, and inadequate brain targeting. Recent advances in AI, including natural language processing (NLP), neuroimaging analytics, electrophysiological modeling, and multi-omics integration, support diagnostic classification, risk prediction, symptom monitoring, and patient stratification. Simultaneously, nanotechnology-driven oral delivery platforms such as lipid nanoparticles, dendrimers, and proliposomes enhance pharmacokinetics, central nervous system targeting, and therapeutic adherence. The integration of AI with pharmacogenomics, wearable monitoring, and digital twin models further facilitates real-time dose optimization and personalized therapy. Despite promising preclinical and clinical outcomes, challenges related to data privacy, algorithmic bias, scalability, and regulatory translation persist. This review highlights a shift toward precision psychiatry, where AI-enabled diagnostics and smart oral therapeutics may support predictive, personalized, and adaptive care in schizophrenia.

Today, researchers have already made great progress in finding drug-based clinical solutions against microbial infections. It has become an essential part of a healthy human lifestyle. High antibiotic consumption has accelerated antibiotic resistance in microbial species (multi-drug-resistant microbial strains, like Staphylococcus aureus and Mycobacterium tuberculosis, have already been reported). Loss of microflora is also associated with the heavy and unnecessary use of drugs. This review presents bacteriophage as an alternative to antibiotics. The supporting bacteriophage characteristics include bacteriophage lytic mode of replication, specificity towards its host, bacteriophage mass production, and bacteriophage genetic modification (BRED and CRISPR) to make it capable of degrading microbial biofilm. The author has also tried to inculcate previous work that has already been done with bacteriophages for some clinical therapies. Potential administration routes (oral, intravenous, and intraoperative) used in clinical therapies are discussed.

PKPDindex() is a free and open-source R package for analysing pharmacokinetic/pharmacodynamic (PK/PD) indices, including AUC/MIC, Cmax/MIC, and T>MIC. Development was motivated by previously identified inconsistencies in PK/PD index modelling and reporting practices. The package fits eight variations of the Emax model to data and compares model performance using the Akaike information criterion (AIC) andR² values. As input, the package requires a dataset containing PK/PD indices and a response variable. As output, it generates tables summarising all fitted models, identifies the best-fitting model for each index, and produces customisable plots of model fits with parameter estimates. PKPDindex() is freely available on CRAN (https://CRAN.R-project.org/package=PKPDindex).

A diabetic foot ulcer (DFU) is an open sore or wound, usually on the bottom of the foot, affecting about 15% of people with diabetes. Caused by nerve damage, poor circulation, and high pressure, these ulcers often present as swelling, drainage, redness, or foot deformities. Treatment focuses on infection control, debridement, and offloading pressure, often taking weeks to months to heal. Despite treatment, recurrence and amputation remain major clinical concerns. Gene therapy for DFUs is an emerging, promising field aiming to accelerate healing in chronic, non-healing wounds by delivering therapeutics (e.g., growth factors) directly to the site to promote angiogenesis and tissue regeneration. Key approaches include topically applied, multi-target gene therapies (e.g., AUP1602-C reporting 83% healing rate) and plasmid-based therapies (e.g., VM202/Engensis). This narrative review aims to describe the molecular aspects of wound healing, pathogenesis and management of DFU, followed by evolving gene therapies including AUP-16, VM202, and gene targets like SCUBE1, RNF103-CHMP3 and PGI1. We have also discussed emerging targets such as C-X-C motif chemokine receptor 4 (CXCR4), thrombospondin 1 (TSP1), yes-associated protein-transcriptional co-activator with PDZ binding motif (YAP-TAZ) pathway, and others as potential targets for gene therapy to promote healing in chronic non-healing DFUs.

Hepatitis C virus (HCV) remains a major global health burden, causing significant morbidity, mortality, and economic costs. Direct-acting antivirals (DAAs) have become the primary treatment for patients with hepatitis C. Since the first approval in 2011, more effective agents have entered the market. Different guidelines for hepatitis treatment are implemented worldwide. The American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL) recommend using DAAs in combination to achieve better outcomes and reduce resistance. The guidelines include regimens for treatment-naive and -experienced patients. They also include treatment recommendations for cirrhotic patients and unique populations. With mass screening, treatment over the last few years, and possible vaccination, eradication is attainable.

Aim: To address the limitations of current metabolomics analysis, including the neglect of metabolite interdependencies, poor interpretability of black-box models, and incomplete utilization of biological information due to pathway annotation limitations. This study aims to develop and validate a dual-branch biologically informed neural network (Dual-BINN) that integrates metabolic pathway hierarchy and molecular structural hierarchy for improved prediction and interpretability in metabolomics.

Methods: We developed a Dual-BINN, which explicitly incorporates metabolic pathway hierarchy and molecular structural category hierarchy into the model architecture. Pathway and structure subnetworks were constructed and integrated via an adaptive fusion mechanism. SHAP was employed for interpretability analysis. The model was evaluated using multi-center plasma metabolomics data for gastric cancer and a breast cancer dataset.

Results: On the independent gastric cancer test set, Dual-BINN achieved a recall of 0.937, which compares favorably with the recall of 0.905 reported by the 10-DM model on the same dataset split. Key metabolites were enriched in the tricarboxylic acid cycle, one-carbon metabolism, and energy metabolism pathways, while structurally concentrated in organic acids, amino acids, and nucleoside-related compounds. The model also demonstrated excellent classification performance on the breast cancer dataset, confirming strong cross-disease generalization ability.

Conclusions: The proposed framework enhances predictive performance while providing biologically meaningful structured interpretations, offering a robust computational approach for metabolomic mechanism analysis and biomarker discovery in complex diseases.

Aim: Squamous cell carcinoma (SCC) is one of the most common types of cancer affecting the oral cavity and the upper aerodigestive tract. In many cases, misdiagnosis leads to the progression of the disease to life-threatening stages, highlighting the importance of advancing anti-oral cancer therapeutics. In this study, we evaluated the cytotoxic activity against SCC of a series of synthetic peptides derived from bovine lactoferricin (bLFcin). To enhance the cationic and amphiphilic properties of lactoferricin-derived peptides, we designed branched and palindromic sequences from bLFcin(20-25) (i.e., 20RRWQWR25).

Methods: A total of 14 peptides were synthesized using solid support synthesis. More than 90% peptide purity was obtained by solid-phase extraction, and the final products were characterized using reversed-phase liquid chromatography and mass spectrometry. The in vitro cytotoxic activity of the peptides was assessed in cancer cell lines SCC9 and FaDu; HEK001 keratinocytes were used as a non-cancerous control cell line. Additionally, scanning electron microscopy and flow cytometry provided further insights into the peptide-cell interaction. Finally, the dimeric peptide bLFcin(20-25)₂ was evaluated in a chemically-induced carcinoma in vivo model.

Results: Tetrameric and dimeric peptides with higher cationic charge and improved amphiphilic properties were cytotoxic to the oral carcinoma cell line FaDu. Scanning electron microscopy revealed membrane disruption and pore formation. In addition, flow cytometric analyses of cells treated with fluorescently tagged bLFcin(20-25)₂ confirmed the interaction of the cationic peptide with the anionic cancer cells. Furthermore, the dimeric peptide bLFcin(20-25)₂ inhibited tumor growth of chemically induced oral carcinoma in hamsters, demonstrating its in vivo efficacy.

Conclusions: Branched peptides with a higher cationic charge were cytotoxic to the cancer cell line FaDu; they induced cell membrane lysis, as evidenced by electron microscopy, and inhibited tumor progression in hamsters. These preliminary results support further design and mechanistic evaluation of branched cationic peptides as potential oral cancer therapeutics.

Aim: Antimicrobial resistance (AMR) among vaginal bacterial pathogens is an increasing clinical concern, particularly where empirical therapy is common and local susceptibility data are limited. This study investigated the prevalence, resistance patterns, and multidrug resistance (MDR) burden of bacterial isolates recovered from human high vaginal swabs (HVSs).

Methods: A retrospective laboratory-based analysis was performed on 220 bacterial isolates recovered from HVS specimens. Organism distribution, antibiotic resistance prevalence, MDR status, MRSA/ESBL phenotypes, MDR scores, hierarchical clustering, heatmap patterns, and principal component analysis were evaluated using R-based statistical and multivariate methods.

Results: Staphylococcus aureus was the most frequent isolate (50.0%), followed by Escherichia coli (38.6%). The highest overall resistance was observed against ceftazidime (89.1%), clarithromycin (83.6%), erythromycin (80.9%), cefoxitin (79.1%), levofloxacin (77.7%), and penicillin (77.3%). In contrast, vancomycin (10.9%), chloramphenicol (11.4%), imipenem (11.8%), linezolid (15.5%), and amikacin (20.0%) retained comparatively better activity. MDR was detected in 95.0% of isolates, with a mean MDR score of 5.19. Clustering, heatmap, and PCA analyses demonstrated distinct resistance groupings and strong co-resistance patterns among the major pathogens.

Conclusions: The study demonstrates a high burden of AMR and MDR among HVS-derived bacterial isolates, especially amongS. aureus and E. coli. These findings support routine culture-based susceptibility testing and stronger antimicrobial stewardship in women with vaginal infections.

Human milk is widely recognized as the biological standard for early-life nutrition, providing both essential nutrients and bioactive components that support immune development. However, breastfeeding is not always feasible, and infant formula remains a necessary alternative in specific clinical and social contexts. Despite advances in formulation, significant immunological differences persist between breastfed and formula-fed infants, contributing to the so-called “immunological gap.” This review critically examines the potential of human milk-derived antimicrobial peptides (HM-AMPs) as functional ingredients to partially address this gap. Current evidence indicates that these peptides, derived from proteins such as lactoferrin, caseins, and α-lactalbumin, exhibit antimicrobial and immunomodulatory activities through mechanisms including membrane disruption and modulation of inflammatory pathways. However, most available data are derived from in vitro and preclinical models, limiting direct translation to clinical outcomes. In addition, significant challenges remain, including peptide instability during industrial processing, uncertain bioavailability in the gastrointestinal tract, and limited clinical validation. While emerging computational and bioengineering strategies offer opportunities to optimize peptide functionality, their large-scale implementation remains constrained by technological and regulatory factors. Overall, HM-AMPs represent a promising but still developing approach to improving infant formula functionality. Their contribution should be interpreted as partial and context-dependent, rather than as a complete replication of the immunological properties of human milk.

Background: Acid-hydrolyzed nanocrystalline starch has attracted interest as a sustainable pharmaceutical excipient because of its crystallinity, compactibility, and potential suitability for direct compression tableting. However, the available evidence on its fabrication methods, material attributes, and performance as a direct compression tablet excipient remains scattered.

Methods: A systematic review was conducted using MEDLINE, Scopus, PubMed, Embase^®, and Google Scholar to identify studies published from 2000 to 2025. Search terms included starch nanocrystals, acid-modified starch, hydrolyzed starch, acid-hydrolyzed starch, nanostarch, and direct compression fillers. Forward and backward snowballing were also performed. Studies were screened using predefined eligibility criteria, excluding reviews, conference abstracts, non-pharmaceutical applications, low crystallinity products, and studies lacking adequate characterization, particularly X-ray diffraction.

Results: The search identified 651 records; after removal of 3 duplicate records, 648 records were screened, 51 underwent full text assessment, and 34 were included in the review. Acid hydrolysis was the most widely reported method for preparing nanocrystalline starch, while pretreatment strategies such as enzymatic treatment, ultrasonication, ball milling, heat moisture treatment, organic acid treatment, and mixed acid hydrolysis were reported to reduce preparation time or improve yield and crystallinity. Across tablet related studies, acid modified nanocrystalline starch generally showed improved crystallinity, compactibility, and tablet hardness compared with native starch. Spray drying and agglomeration further improved flow and direct compression performance in several studies.

Discussion:Acid modified nanocrystalline starch shows promise as a sustainable direct compression tablet excipient. However, broader pharmaceutical adoption remains limited by low or variable yield, long processing time, botanical source variability, inconsistent powder flow, limited standardization, and unclear scale up pathways. Future studies should connect preparation methods, material characterization, powder flow engineering, and tablet performance testing to support industrial development.

The therapeutic landscape for obesity is changing rapidly, driven by the recognition of obesity as a chronic, biologically heterogeneous disease, with clinically relevant organ consequences. In this context, the phase 3 SYNCHRONIZE™-1 trial of survodutide, a once-weekly dual agonist of glucagon receptor and glucagon-like peptide 1 (GLP-1) receptor, is notable not simply because it adds another effective incretin-based therapy, but because it tests a broader metabolic concept. By pairing GLP-1-mediated appetite suppression with glucagon-mediated effects on energy expenditure and hepatic lipid handling, survodutide aims to extend treatment beyond appetite control towards coordinated modulation of adiposity, cardiometabolic risk and steatotic liver disease. In adults with obesity without diabetes, SYNCHRONIZE™-1 showed sustained body-weight reductions of approximately 12–13% over 76 weeks, compared with 5.4% with placebo, and increased the proportion of participants achieving clinically ambitious weight-loss thresholds, including at least 20% weight loss. Improvements in waist circumference, glycemic and lipid measures, together with reductions in visceral and liver fat content (LFC) in imaging analyses, support the possibility of benefits that are metabolically broader than scale weight alone. Yet the trial also illustrates familiar tensions in obesity pharmacotherapy: gastrointestinal tolerability, treatment discontinuation, the absence of an active comparator, unexpectedly high placebo-associated weight loss and limited outcome data. Thus, SYNCHRONIZE™-1 should be read as an important proof of principle for dual glucagon-GLP-1 receptor agonism rather than as a definitive positioning of the therapy within the treatment landscape. The next challenge is to determine whether this mechanism delivers durable cardiovascular, renal, and hepatic benefits, and in which patient populations.

Cancer treatment faces severe challenges such as drug resistance, side effects, and high costs. The “repurposing old drugs” strategy, which involves repositioning approved drugs for non-oncology indications for cancer treatment, has opened up new avenues for developing efficient, low-toxicity, and rapidly translatable combination therapies. This strategy can not only accelerate clinical translation by leveraging known pharmacological and safety data but also generate synergistic effects with standard chemotherapy, targeted therapy, or immunotherapy by targeting non-classical pathways such as the tumor microenvironment, metabolic reprogramming, and epigenetic regulation. This paper aims to systematically review the repositioning strategies of non-oncology drugs in cancer combination therapies, focusing on their mechanisms of action, synergistic principles, high-throughput screening and computational prediction methods, as well as pre-clinical and clinical research progress based on models such as patient-derived organoids. The paper systematically analyzes the synergistic effects and potential of representative drugs such as metformin, statins, antimalarials, antipsychotics, non-steroidal anti-inflammatory drugs, β-blockers, antihistamines, and cardiovascular drugs. It also summarizes the current challenges in drug screening, mechanism validation, commercial incentives, clinical trial design, and safety re-evaluation, aiming to provide a theoretical basis and future research directions for optimizing cancer combination treatment strategies.

Cannabis sativa has a long history in ethnomedicine, but advances in molecular biology and regulatory shifts have reignited global interest in its therapeutic potential. Cannabinoid research in the 21st century spans molecular pharmacology, clinical applications, and public health integration. This study provides a comprehensive synthesis of the current state of knowledge. This narrative review synthesizes evidence from Scopus, PubMed, and Google Scholar using Medical Subject Headings-based search strategies. Only articles published in English were included, without restrictions on publication year; however, greater

Plant metabolites are an invaluable source of bioactive molecules, and a high percentage of them can react covalently with their targets. Lipid-derived α,β-unsaturated systems (Michael acceptors), which are present in all plants, regulate signaling pathways in cells. In addition, they potentially represent novel molecular targets and mechanisms of action in drug development. The irreversible covalent binding of the majority of these electrophilic molecules to their corresponding molecular targets, combined with, in certain cases, unfavorable pharmacokinetic properties, i.e., absorption, distribution, metabolism, and excretion (ADME), has shifted their use predominantly to that of molecular probes for target identification. In this review, we present examples of structural modification of the original naturally occurring Michael acceptor-containing compounds, as well as examples of incorporating naturally occurring functionalities in the design of reversible covalent probes and drug candidates in order to improve ADME and increase target selectivity.

Aim: Kinetoplastids are flagellated protozoa encompassing multiple parasitic species responsible for severe neglected diseases. Although treatments exist, therapeutic failure and toxic side effects underscore the need for innovative drug development. Recent advances in protein design have accelerated the creation of small protein modules with specific functions, known as miniproteins, with broad pharmacological applications. However, their intrinsic inability to cross biological membranes limits their use against intracellular targets. This work aims to propose and computationally explore a modular delivery strategy that exploits the flagellar pocket (FP) as an entry route to deliver protein-based therapeutics into the parasites.

Methods: Using experimentally determined structures of three FP receptors, we applied a motif-scaffolding pipeline combining RFdiffusion, ProteinMPNN, and AlphaFold2-multimer to design de novo miniprotein modules capable of mimicking the natural cargo recognized by each receptor. Candidate designs were evaluated using a scoring function integrating minimum interaction predicted aligned error (miPAE) and backbone root mean square deviation (RMSD) across five predicted models per design.

Results: The design campaign yielded different outcomes depending on the target. For the transferrin receptor, 67 candidates surpassed the established in silico success thresholds, a pool expected to contain multiple experimentally validated binders. For the invariable surface glycoprotein 65, 17 candidates met the criteria, constituting a tractable experimental panel. Lastly, the haptoglobin-hemoglobin receptor proved a challenging target, with no candidates clearly surpassing both thresholds, likely due to the hydrophilic nature of its binding interfaces and the requirement for direct heme coordination.

Conclusions: This work provides a structural rationale for a novel receptor-mediated intracellular delivery paradigm in kinetoplastid parasites, offering a computational pipeline for generating miniprotein modules ready for experimental validation. We further outline how these delivery modules could be integrated into modular protein-based drugs incorporating protease recognition sequences, cell-penetrating peptides, and subcellular localization signals, laying the conceptual ground for a new therapeutic approach against these neglected diseases.