Matrine is the main component extracted from legumes and has extensive anti-cancer effects; however, its molecular mechanism is unclear. In our study, we found that matrine induced vacuolation in leukemia cells is closely related to cell proliferation inhibition. Vacuolization was reversed after matrine removal. The neutral red staining assay indicated that the matrine-induced vacuoles were acidic, and the vacuoles originated mostly from the lysosome or endosome, as observed by transmission electron microscope (TEM) and fluorescence microscopy localization of LAMP-GFP. Furthermore, single-cell RNA sequencing (RNA-seq) demonstrated that the expression of vacuolation- and lysosomal-related genes were up-regulated after matrine treatment, and western blot (WB) and flow cytometry (FCM) analysis confirmed that matrine inhibits intracellular proteolytic enzyme expression and activity, suggesting that matrine may inhibit lysosomal function. In addition, we identified that matrine significantly up-regulated the expression levels of vacuolar ATPase (V-ATPase) subunits in cells, and the V-ATPase inhibitor effectively reversed the occurrence of cell vacuoles, suggesting that V-ATPase plays an important role in matrine-induced vacuoles. The molecular structure of matrine was further analyzed, and the protonation of matrine in lysosomes to activate V-ATPase may be a direct cause of vacuole formation. Our results revealed a new molecular mechanism by which matrine inhibit leukemia cell proliferation.
This study aimed to investigate the use of Sucrose acetate isobutyrate (SAIB) and Glyceryl monooleate (GMO) as co-formers for creating Cubosomes and SAIB-based nanodispersions of Rivaroxaban (RXB). The process utilized a modified melt dispersion technique with varying polymer: drug ratios (0.5:1, 0.75:1, and 1:1) and a fixed polymer: poloxamer 407 ratio (0.1:1). Particle size (PS), polydispersity index (PDI), zeta potential (ZP), and entrapment efficiency (EE) were measured to determine the optimal formulas. The best-lyophilized formulas were then analyzed using Fourier transform infrared spectroscopy (FT-IR), powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), dissolution testing, and Pharmacokinetic (PK) studies. The results revealed significant correlations between polymer concentrations and various variables in cubosomal and SAIB-based nanodispersions. An increase in GMO concentration led to a decrease in PS, PDI, and ZP but an increase in EE and yield. Maintaining optimal GMO concentration is crucial for consistent nanoparticle formulations. In contrast, increasing SAIB concentration led to a decrease in PS and PDI but an increase in EE and yield. The drug release rates of different preparations were measured during the dissolution test. The best-lyophilized cubosome (L4) and the best-lyophilized SAIB-based nanodispersions (L8) showed significantly improved drug release compared to XARELTO®. L4 displayed the best dissolution rate, and L8 also had a reasonable rate. A PK study demonstrated that L4 and L8 had significantly better bioavailability than XARELTO®, possibly due to their improved solubility. This study suggests that SAIB and GMO can significantly enhance the solubility and bioavailability of RXB in nano preparations, leading to more efficient drug delivery. This new approach can also reduce the required dosage for the desired therapeutic effect. However, further research is needed to fully understand these polymers' potential benefits and limitations.
Anxiety and depression are the most prevalent psychiatric disorders in the world, and they are highly comorbid with each other. Ziziphi Spinosae Semen (ZSS) is a traditional Chinese herbal medicine widely used in the treatment of insomnia and anxiety in clinical practice. To explore the effects of ZSS in alleviating anxiety in a sleep deprivation (SD) zebrafish model, the locomotor activity performance and anxiety behavior of these experimental fish were evaluated, and the underlying mechanisms of its anti-anxiety effect were examined by analyzing the transcriptomics of brain tissues. Results indicated that ZSS could significantly reduce the freezing duration and alleviate anxiety-like behavior. Moreover, ZSS was effective in promoting melatonin biosynthesis and synaptic transmission, modulating circadian rhythm, and preventing inflammatory response and oxidative stress, as evidenced by the expression alterations of the key anti-oxidation genes (GCLC, GPX1A, GSR, NRF2A and PRDX1) and pro-inflammatory cytokine (IL2RGA, IL6 and IL17A/F1). These findings will contribute to the understanding of how ZSS alleviates SD-induced anxiety, and provide a theoretical basis for the clinical application of ZSS.
Biowaiver allows for the waiver of bioequivalence studies for regulatory approval of certain drug products with saving of time, and money. Before approval of the application for biowaivers, studies based on the Biopharmaceutical Classification System (BCS) are required to satisfy regulators in the US, Europe, and other developing markets. Only pharmaceutical products that meet the regulatory requirements for solubility, diffusion, and permeability will be granted a biowaiver. Due to high solubility and considerable permeability, BCS class I and class III drugs are highly preferred for biowaiver by regulatory agencies. The World Health Organization recently expanded the scope of the biowaiver acceptance by considering all BCS classes. These techniques can cut down on time and money spent on ineffective bioequivalence studies. In the present article, an attempt has been made to cover the prerequisites and guidelines for biowaiver approval of a generic product, a topical system, oral films, and BCS class II and IV drugs.
Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by memory loss, cognitive decline, impairment in activities of daily living, and loss of independent function. Cognitive decline and brain shrinkage, particularly hippocampal atrophy, are associated with the accumulation of tau proteins. They cause inflammation, amyloid plaque deposition, neuronal loss, temporofrontal cortex atrophy, aberrant protein fragment clusters, and twisted fiber bundles. Given the significant role of oxidative processes in neurodegeneration, it is logical to consider the potential of antioxidants in the treatment of AD. Several antioxidants, including glutathione, astaxanthin, ascorbyl palmitate, catalase, and molecular hydrogen, play important roles in AD. Antioxidants interact with free radicals to neutralize them. Several studies have suggested that oxidative stress or damage is involved in the development of AD via different mechanisms and pathways. Thus, new approaches are needed to reduce the extent of oxidative damage that may be therapeutically effective against AD. Although certain antioxidants have exhibited notable benefits in animal models, their efficacy in human clinical trials has been limited, casting doubt regarding the efficacy of antioxidant treatments for AD. Therefore, a more focused and precise strategy that incorporates antioxidants is essential for slowing or stopping AD progression. The integrated role of antioxidants in reducing inflammation must be considered, because the link between inflammation and AD is undeniable. Therefore, the present study aimed to elucidate the role of antioxidants in AD, with the goal of aiding researchers in developing effective and potentially enhanced antioxidant-based therapeutic strategies.
Ionically cross-linked hydrogel serves as an excellent matrix material for the sustained delivery of drugs. Tablets prepared with tamarind kernel polysaccharide (TKP) as the sole matrix material could not provide sustained release of the incorporated drugs. The purpose of the work was to modify TKP and development of ionically cross-linked hydrogel matrix tablets for sustained drug delivery. Grafting of TKP was performed with methacrylic acid (MAA) following the free radical polymerization technique. Hydrogel matrix tablets using Al3+ ion cross-linked grafted TKP were prepared by direct compression method. Al3+ ions were found to considerably influence the erosion, swelling, and paracetamol release from the matrix tablet. Retardation of the erosion, swelling, and paracetamol release was observed with increasing the concentration of Al3+ ions. The hydrogel matrix tablets showed a slow release of drugs in an acidic medium and a relatively faster drug release in an alkaline medium. The optimized formulation having a co-polymer/aluminium hydroxide (Al(OH)3) ratio of 1:1, exhibited sustained drug release action for more than 10 h with lower swelling and erosion of the gel matrix. We conclude that Al3+ ion cross-linked grafted TKP is an excellent matrix material for sustained delivery of drugs in the gastrointestinal milieu.
Ferulic acid and p-coumaric acid, cinnamic derivatives of phenolic acid, have antibacterial, prooxidant, and antioxidant effects. In this study ferulic acid and p-coumaric acid amide derivatives were investigated for their antibacterial and antioxidant properties are described in this communication. The most effective conjugates against B subtilis were 5b (IC50: 215 ± 1.3 μM) and 4d (IC50: 336 ± 2.7 μM) and against P. aeruginosa were 4b (IC50: 365 ± 2.8 μM) and 5b (IC50: 341 ± 3.6 μM), whereas the none of conjugates were more effective against E. coli than reference Kanamycin. Conjugates 5b was the most effective against B subtilis of all the synthesized conjugates, with IC50 values of (IC50: 215 ± 1.3 μM). The free radical scavenging capacity of each compound was determined using the DPPH and ABTS assays. Conjugates 4b (IC50: 53 ± 3.6 μM), 4c (IC50: 58 ± 1.3 μM), 4d (IC50: 57 ± 2.5 μM), 5b (IC50: 29 ± 1.5 μM) and 4a (IC50: 56 ± 4.3 μM) have greater antioxidant capacity than ferulic acid and ascorbic acid in the DPPH assay. Whereas in the ABTS assay, compounds 4b (IC50: 7 ± 1.8 μM), 5b (IC50: 5 ± 0.7 μM), 4a (IC50: 9 ± 3.2 μM), 4g (IC50: 7 ± 2.3 μM), and 5a (IC50: 8 ± 4.3 μM) showed more antioxidant activity than ferulic acid, p-coumaric acid and ascorbic acid. Thus, a large library of compounds derived from bile acid can be easily synthesized for extensive structure-activity relationship studies in order to identify the most appropriate antibacterial and antioxidant agents.
Chronic and severe inflammation results in many diseases and disorders in humans. Currently, available conventional anti-inflammatory drugs have numerous mild-to-severe side effects. Thus, there is a need for safe, effective, affordable, and alternative anti-inflammatory drugs. This study aimed to evaluate the anti-inflammatory effect of sclareol (SCL), a diterpene alcohol that is the principal ingredient in the refined oil of Salvia sclarea (L.), through in vivo and in silico studies. First, we examined the individual and combined effects of SCL (5, 10, and 20 mg/kg) and standard drugs celecoxib (CXB) or ketoprofen (KPN) at 42 mg/kg (p.o.) on the formalin-induced inflammatory Swiss mice. Additionally, an in silico analysis was conducted to evaluate the potential anti-inflammatory mechanism of this study. For this, we examined the potentiality of SCL and standards to interact with cyclooxygenase (COX) -1 and COX-2 receptors. Our findings suggest that SCL exhibits a dose-dependent anti-inflammatory effect in mice. SCL-20 mg/kg significantly reduced the number of paw licks and paw edema diameters. Moreover, SCL-20 combined with CXB-42 and KPN-42 demonstrated better anti-inflammatory effects. In comparison to the standards, SCL revealed a comparable binding interaction with COX-1 and COX-2 receptors in the molecular docking study. Furthermore, SCL displayed remarkable pharmacokinetic characteristics. In conclusion, SCL significantly and dose-dependently reduced the number of paw licks and edema diameters in animals. Thus, SCL may be responsible for producing an anti-inflammatory effect by interacting with COX-1 and COX-2 receptors.
Idiopathic pulmonary fibrosis (IPF), a progressive lung disease characterized by irreversible lung dysfunction caused by fibroblast proliferation and excessive collagen deposition, is the result of persistent chronic inflammation of the lung parenchyma. Although the pathogenesis is not fully understood, the role of immune mechanisms such as innate immune response, adaptive immunity and immune regulation, and cytokines in the pathophysiological mechanism of pulmonary fibrosis have been gradually recognized. There are currently limited drugs available to treat IPF, and long-term use of these drugs may have many adverse effects. With the elucidation of the underlying immunological pathogenesis, the development of more valuable drugs targeting the immune system becomes possible. This review introduces the immunological pathogenesis of pulmonary fibrosis and the emerging drugs targeting the immune system in recent years, aiming to provide insights into the mechanism and treatment direction of pulmonary fibrosis.
Multiple mechanisms are involved in driving the efficacy of drug delivery. Drug particle size is one of the challenges as particles need to be delivered from the external environment, into the circulation or interstitial fluid and transiting the cell membranes for cellular internalisation. Small particles are presumably easier to be internalised, yet they are not easy to retain as they are subject to fast clearance. Big particles do not cross biological barriers as easily, but their size distribution is easier to be controlled. Because of the various routes of administration, the size range of these particles will also need to be catered for the anatomical, biological, and dynamic barriers involved. This review hopes to provide an insight into the range of particle size that has been engineered for drug delivery via various routes of administration of the body, such as to cross the epithelium of gastrointestinal tract, lungs, skin, blood-brain barrier, kidney and liver, the eye, nose, and ear, the cancer tumour matrix and into the muscles. While successful drug delivery also depends on the material properties of the delivery systems and the bio/nano interface related properties, this review focuses on the importance of particle size for enhancing bioavailability at the various organs of the body.
Natural products (NPs), especially antibiotics, exhibit diverse bioactivities and often play critically important roles in dictating and/or driving medical, health, agricultural, animal husbandry, and cosmetic industry initiatives. An important realization in the field of NP applications is that both targeted pathogens and the antibiotic-producing hosts themselves have usually evolved a host of resistance strategies by which to protect themselves. Although the former class of microbes (pathogens) has come to be associated with the global antibiotic resistance crisis, mechanisms by which producing organisms become resistant or tolerant to the ill effects of their bioactive metabolites have begun to attract a great deal of attention. Studies aimed at understanding antibiotic resistance have shown that producer-bourne mechanisms of self-resistance are possible prototypes by which to understand corresponding resistance elements in antibiotic-resistant bacteria. Historically speaking, the most efficient and potent chemistries employed by pathogens to evade harm from antimicrobial NPs have evoked enzymatically-driven transformations. We summarize herein the primary chemical modifications known to impart upon bioactive NP-producing microbes a means of self-defense against their own antimicrobial secondary metabolites; in understanding these chemistries we expect to gain new insights into how antibiotic resistance mechanisms in targeted pathogens might be circumvented or prevented. Such a translation of knowledge has a high likelihood of advancing humanity's ability to counter drug-resistant pathogens.
Premature ejaculation (PE) is the most common male sexual dysfunction. Selective serotonin reuptake inhibitors (SSRIs) are currently recommended for PE. However, the side effects of SSRIs, such as nausea, vomiting, and xerostomia, pose challenges to clinicians. Simultaneously, evidence indicates that psychological and behavioral treatments are often insufficient. LibidUp-PE is a nutraceutical designed to enhance sexual wellness and contains a combination of essential amino acids to boost stamina and vigor, addressing concerns like erectile dysfunction (ED). This study aimed to assess the safety and efficacy of LibidUp-PE in the treatment of PE. In this crossover, double-blind, placebo-controlled trial, 76 patients with PE were randomly divided into two groups. Group A received LibidUp-PE, whereas Group B received a placebo for 12 weeks. Following a 2-week wash-out period, the groups switched treatments for another 12 weeks. Intravaginal ejaculatory latency time (IELT) and post-ejaculatory refractory time (PERT) were measured as the primary outcomes to evaluate PE improvement. Plasma serotonin levels were measured as secondary parameters using enzyme-linked immunosorbent assay. The results showed that LibidUp-PE significantly improved the IELT score, increasing from 0.8 ± 0.2 min to 2.9 ± 1.1 min (p < 0.01). PERT scores also significantly decreased from 15.8 ± 1.7 min to 5.6 ± 0.6 min after 12 weeks of LibidUp-PE treatment. Plasma serotonin levels significant increased from 93.6 ± 7.8 ng/mL to 168.4 ± 12.8 ng/mL (p < 0.001) with LibidUp-PE treatment. In contrast, no significant improvements were observed in the placebo group. Notably, none of the participants withdrew their consent due to adverse reactions, which is indicative of the safety and tolerability of LibidUp-PE. In conclusion, 12-week treatment with LibidUp-PE demonstrated a beneficial effect in reducing PE symptoms, as reflected by improved IELT, reduced PERT, and increased plasma serotonin levels. Therefore, LibidUp-PE could be a promising solution for individuals with PE.
Despite years of research, technological advancements, and the widespread use of vaccines and antibiotics as tools to combat microbial threats to humans, methicillin-resistant Staphylococcus aureus (MRSA) infections remain a serious threat to global healthcare systems. The challenge of MRSA is a result of the bacteria's remarkably rapid evolution and adaptation, building up a collection of resistance genes that defeat the mechanism of traditional antibiotics. Conventional antibiotics, including the most notable beta-lactam antibiotics, such as penicillin and cephalosporin, are increasingly inadequate against the rapid adaptability and resistance of MRSA. Consequently, the scientific community's therapeutic arsenal for battling MRSA infections is becoming increasingly limited, necessitating innovative interventions. Antimicrobial peptides (AMPs), with their precise targeting mechanisms and innate modifiability, have emerged as promising therapeutic agents. By selectively interrupting bacterial processes and boosting innate immunological responses, AMPs offer a multifaceted strategy. Modern biotechnological and bioinformatics advancements have enabled the refinement of AMPs for improved efficacy. This comprehensive review delves into the intricate facets of MRSA pathogenicity, determinants of resistance, foundational tenets of peptide-based therapeutics, and recent scientific breakthroughs. A comprehensive analysis of the current research landscape, clinical implications, and persistent challenges underscores the potential of precisely tailored peptides as formidable weapons for counteracting the enduring threat of MRSA infections.
Diabetic nephropathy (DN) poses a significant risk to individuals with diabetes. Inflammation plays a crucial role in DN pathogenesis. Lycorine hydrochloride (LH) is derived from Lycoris radiata (L'Hér.). This herb has been identified as a potent anti-inflammatory molecule. Further studies indicated that LH displayed therapeutic potential against metabolic disorders, renal dysfunction, and fibrosis in a high-fat diet and streptozotocin-induced (HFD/STZ)-induced DN mouse model. Mechanistically, LH mitigated renal inflammation in DN mice by targeting NF-κB pathways and the NLRP3 inflammasome verified by in vivo study. In vitro, LH inhibited NLRP3 inflammasome activation induced by nigericin (Ng), monosodium urate (MSU), and ATP, reduced caspase-1 activation, and IL-1β release. Additionally, LH suppressed the NF-κB IS-induced activation, prevented nuclear translocation of NF-κB, and subsequently reduced the expression of downstream proteins COX2 and iNOS. Collectively, these results indicated that LH primarily improved hyperglycemia-induced renal function by reducing inflammation by targeting NF-κB and NLRP3 inflammasome, implying it is a promising therapeutic agent for DN.
The adoption of innovative mixing and fabrication technologies in the pharmaceutical industry has inspired research on nano-drugs and expanded the scope of study in the field. Researchers' interest in the recently discovered drug delivery nanoparticles has increased significantly. This interest is especially seen in the specific preparation of nanoparticles as drug carriers through the use of three-dimensional (3D) printing, a modern additive manufacturing (AM) technology. The benefits of 3D printing, especially at the nanoscale, make it an innovative technology that could revolutionize the pharmaceutical and regenerative medicine industries. The laborious creation of intricate structures made possible by nanoscale 3D printing brings up the possibility of developing nanomedicine and producing functioning tissues and organs. The uses of AM in nano drug delivery systems (NDDS) are highlighted in this study, with a focus on how it can improve drug release kinetics, enhance therapeutic efficacy, and minimize side effects. A new era of personalized medicine has begun with the development of patient-specific formulations made possible by the customization capabilities of 3D printing. This review discusses the various uses of AM in NDDS while addressing issues including scalability, biocompatibility, and regulatory concerns. This review highlights the developing integration between AM and nanotechnology in medicine delivery and discusses ongoing research activities and possible solutions. As this innovative technology develops further, it has the potential to completely change the pharmaceutical development field by providing fresh approaches to the complex problems of contemporary healthcare and advancing the ideas behind drug delivery.
Oncolytic viruses (OVs) are natural or genetically recombinant viruses that selectively infect and kill tumor cells without affecting normal cell growth. As a novel type of immunotherapy, OVs have been shown to activate antitumor immune responses, regulate the tumor microenvironment, and enhance the efficacy of immune checkpoint inhibitors. In this review article, we discuss the latest research on the characteristics, antitumor mechanisms, and status of OV research. In terms of mechanism of action, after targeting tumor cells, OVs not only directly lyse tumor cells but also exert antitumor effects through indirect approaches. As an emerging cancer treatment, OVs face challenges that need to be overcome. Finally, we summarize the challenges and prospects for the future application of OVs.
Hydrophobic drugs exhibit altered bioavailability and pose other challenges at an industrial level due to their poor solubility and dissolution rates. In addition, poor flowability, compressibility, complex dosing schedules, and light-sensitivity problems associated with hydrophobic drugs have led to poor patient compliance. To overcome these problems at an industrial level, the liquid-solid technique is a promising approach for tackling such challenges. This study outlines the prementioned challenges related to hydrophobic drug candidates and introduces the liquisolid technique as a potential alternative using non-volatile water-miscible solvents, carrier agents, coating substances, and their subsequent applications in the pharmaceutical industry. Furthermore, this study highlights the role of liquisolid technology in achieving sustained-release kinetics, emphasizing its benefits in minimizing pH changes in drug release and enhancing photostability. The study aimed to explore the liquisolid technique as an important tool for improving drug delivery, overcoming solubility issues, and optimizing therapeutic outcomes. In addition, this manuscript holds significant importance by highlighting the applications and recent advances in liquisolid technology, focusing on industrial-level applications. Moreover, it is impressive that such a technique offers improved formulation options to enhance the safety and efficacy of therapy. Overall, this study serves as a valuable resource for researchers to overcome formulation challenges and optimize drug delivery in the pharmaceutical industry.
We previously synthesized the xanthine oxidoreductase (XOR) inhibitor WN1703. In addition to showing XOR inhibitory effects, WN1703 also showed anti-inflammatory effects in a rat hyperuricemia model. Here, we studied WN1703's anti-inflammatory effects on gout and explored the underlying mechanisms. Tohoku Hospital Pediatrics-1 (THP-1) cells were stimulated by lipopolysaccharide/interferon-γ/monosodium urate (MSU). The levels of inflammatory cytokines in the supernatant and protein expression in THP-1 cells were detected using enzyme-linked immunosorbent assay (ELISA) kits and western blotting, respectively, to verify the inhibitory effects of WN1703 and its mechanism. Potassium oxonate, hypoxanthine, and MSU were administered to establish a hyperuricemia rat model complicated by acute gouty arthritis. At 1-24 h after MSU injection, the degree of ankle swelling was recorded to compare the anti-inflammatory effects at each time point. The potential mechanism was further explored using immunohistochemistry and ELISA. WN1703 significantly downregulated expression of nucleotide-binding oligomerization domain-like receptor thermal protein domain associated protein 3 (NLRP3), apoptosis-associated speck-like protein containing a CARD (ASC), caspase-1, toll-like receptor-4 (TLR4), myeloid differentiation primary response protein 88 (MyD88), nuclear factor-kappa B (NF-κB), and relevant cytokine levels in THP-1 cells. Identical doses of WN1703 and febuxostat had comparable effects on these proteins and cytokines. In the gout rats, the same dose of WN1703 and febuxostat showed equivalent inhibitory effects on NLRP3, ASC, and NF-κB; however, WN1703 showed weaker impacts on alleviating ankle swelling than febuxostat showed. In conclusion, WN1703 showed significant anti-inflammatory effects in hyperuricemic rats with acute gout. Such effects were related to the inhibition of the NLRP3/ASC/Caspase-1 and TLR4/MyD88/NF-κB signaling pathways, thereby downregulating inflammation-related protein expression and decreasing inflammatory cytokine secretion.
Surgical resection, radiotherapy, and chemotherapy are traditional methods for cancer treatment. With the development of materials science, photodynamic, photothermal, and sonodynamic therapies have been established over the past few years. Despite these advances, the development of novel and efficient cancer treatment protocols remains highly desirable. Recently, combination therapy has emerged as a powerful tool for achieving this goal. In this context, cyanine-nanoparticles have attracted considerable interest. Cyanine dyes have high molar absorptivity, narrow absorption/emission bands, and also excellent biocompatibility. This has meant that they have been widely used in biomedical imaging and therapy. Cyanine nanoparticles assembled from cyanine dyes and amphiphilic polymers or liposomes are endowed with high biocompatibility and long-term circulation for cancer combination therapy. A plethora of cyanine-nanoparticle-based combination therapy systems have been reported, and research in this discipline continues to expand. In this review, we aim to summarize recent advances in the combination therapy of cancers using cyanine nanoparticles over the last five years (i.e., from 2018 to 2023), with an emphasis on the structures of cyanine dyes, design concepts, and combination strategies. Personal insights and challenges in this field are also discussed. We expect that this review will inspire creative progress in combination therapies based on cyanine nanoparticles and facilitate the investigation of future clinical applications.
Effective clinical methods are urgently required to treat brain diseases. Small interfering RNAs (siRNAs) are promising in the treatment of brain diseases because of their ability to target and specifically silence genes associated with disease progression. However, their effectiveness is hindered by physiological barriers such as enzymatic degradation, the blood-brain barrier, and the blood-brain tumor barrier, severely restricting them from reaching the desired target sites. The development of nanotechnology has made the effective delivery of siRNAs to the brain possible. This is accomplished by encapsulating siRNAs in cationic polymers, liposomes, or micelles to improve their stability and targeting efficiency. In this review, we first analyzed the limitations of siRNA delivery in brain diseases such as brain tumors, stroke, and neurodegenerative diseases. Next, we summarized how nanotechnology can offer a solution by enabling effective siRNA delivery to the brain and improving the intracellular transfection efficiency of siRNA. Finally, we discussed the challenges and future advances of siRNA-based delivery systems to facilitate their clinical translation. This review emphasizes the importance of overcoming physiological barriers associated with siRNA delivery and highlights recent advances in the rational design of siRNA-based delivery systems for the effective treatment of brain diseases.
The global antibiotic resistance crisis highlights the inappropriate use of medicines by the population and the lack of development of new antimicrobial agents. According to various studies, natural products are promising alternatives for combating bacterial resistance and treating infectious diseases. Accordingly, the present study aimed to analyze the chemical composition and evaluate the antibacterial and antibiotic potential of an aqueous extract of Cordia oncocalyx Allemão (AECO). Phytochemical analyses were performed using high-performance liquid chromatography equipped with a diode array detector (HPLC-DAD). The minimum inhibitory concentration (MIC) was used to evaluate the antibacterial activity of C. oncocalyx against conventional and multidrug-resistant (MDR) bacterial strains (Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus). According to HPLC-DAD analysis, the following compounds could be identified in the aqueous extract of C. oncocalyx: luteolin (3.07 ± 0.04 mg/g), caffeic acid (1.05 ± 0.03 mg/g), ellagic acid (0.62 ± 0.05 mg/g), and quercetin (0.58 ± 0.01). AECO did not exhibit antibacterial activity when administered alone (MIC >512 μg/mL). However, when combined with gentamicin, ampicillin, and norfloxacin, AECO potentiated the action of these antibiotics against the multi-resistant strains of P. aeruginosa and S. aureus. Although clinical relevance was not revealed by the in vitro tests against pathogenic bacteria, AECO can combined with commercial antibiotics to improve their antibacterial effects. Future studies focusing on the mechanisms of action of the compounds isolated from C. oncocalyx and toxicological tests are fundamental.
The diterpenoid phytol is evidently acting against anemia in experimental animals. However, the molecular mechanisms behind this issue are yet to be discovered. This study aimed to evaluate phytol's effect on methotrexate-induced folate-deficient animals through in vivo and in silico studies. For this, a total of thirty adult male Swiss albino mice were randomly divided into six different groups, namely the normal control (vehicle), the negative control (folate deficiency inducer, methotrexate 3 mg/kg), the standard (folic acid 1.5 mg/kg), two test groups comprising phytol 25 and 50 mg/kg, and a combined group composed of the standard and highest test doses of phytol. Except for the vehicle, all groups were treated with methotrexate for the first 3 days (once/day) to induce folate deficiency. Then followed by the respective treatment once a day for 3 days. Hemoglobin (Hb) level was measured from the peripheral blood (by tail cutting) on days 1st (before treatment), 4th (after methotrexate treatment), and 7th (after treatment). On the other hand, the computational studies were performed by PyMol, PyRex, Discovery Studio, and other complementary tools. Findings suggest that phytol significantly (p < 0.05) augmented Hb levels that are altered by methotrexate-induced reduction of Hb levels in animals dose-dependently. The combination also augmented Hb levels in animals; however, its effect was slightly lower than the individual groups (standard and test). In the in silico study, phytol showed good binding capacity (binding energy: −7.0 kcal/mol) with dihydrofolate reductase (DHFR). In conclusion, phytol may act against folate deficiency by altering methotrexate's impacts in animals, possibly through interacting with DHFR. Further validated research is necessary to develop phytol as an anti-anemia drug in the near future.
Acute kidney injury (AKI) is characterized by a rapid loss of renal metabolic function and a high mortality rate. Although significant progress has been made in developing targeted drugs for AKI treatment, issues such as inadequate antioxidant effects and poor renal enrichment efficiency remain. Nanomotors can enhance drug delivery efficiency in AKI treatments through self-propulsion in the microenvironment or via external stimuli. We reviewed recent progress in the targeted treatment of AKI with nanomotors, focusing on their contribution to targeted drug delivery at different stages and combined treatments. Current limitations and future development directions are also discussed.
Medicinal plants from the Asclepiadaceae family, such as Luo Mo (Metaplexis japonica Makino), Xu Changqing (Cynanchum paniculatum), and Bai Wei (Cynanchum atratum Bge.), have long been staples in Traditional Chinese Medicine (TCM) due to their wide range of pharmacological activities (Su et al., 2021) [1]. These beneficial properties are largely attributed to compounds like saponins, alkaloids, and polysaccharides. Polysaccharides, in particular, are vital components in TCM and have garnered increasing attention for their diverse therapeutic effects. Polysaccharides from Asclepiadaceae plants are reported to exhibit a variety of pharmacological activities, including anti-radiation, anti-tumor, anti-fatigue, antioxidant, anti-hyperlipidemic, immune-boosting, and liver-protective effects. These polysaccharides have complex structures made up of different monosaccharides, contributing to their wide range of activities. In this review, we provide a comprehensive summary of the isolation, purification, structural characterization, and pharmacological activities of polysaccharides from medicinal plants in the Asclepiadaceae family. We begin by outlining the methods used for the extraction, isolation, and purification of these polysaccharides. Next, we delve into the pharmacological activities of the isolated polysaccharides. Finally, we discuss the potential clinical applications of these polysaccharides in treating various diseases and highlight areas that require further investigation.
Patients with advanced hepatocellular carcinoma (HCC) are not sensitive to sorafenib (SOR), therefore, combination therapy is required. In this study, an improved thin-film dispersion and post-insertion anchoring technique was utilized to construct a dual-targeted co-delivery SOR and docetaxel (DTX) liposome drug delivery system, folate/chondroitin sulfate with SOR/DTX-modified liposomes (FA/CS@SDLP), to jointly enhance the anti-recurrence and metastasis of HCC. FA/CS@SDLP can establish the gradual release of the two drugs because of successful lysosomal escape in the condensed hyaluronidase environment. The results indicated that modification with folate (FA) and chondroitin sulfate (CS) significantly enhanced the cellular uptake of FA/CS@SDLP and the internalization of SOR/DTX in HepG2 cells through FA and CD44 receptor-mediated endocytosis. Compared to free drugs or the mono-targeted liposomal system (FA@SDLP), FA/CS@SDLP presented higher potency against HepG2 cells regarding pro-apoptosis, anti-proliferation, and anti-metastasis (migration and invasion). Moreover, a more satisfactory antitumor efficacy was observed for FA/CS@SDLP in the pulmonary metastasis of HCC in a mouse model. In summary, dual-targeted co-delivery of liposomes can synergistically treat HCC recurrence and metastasis, providing a new approach for the clinically accurate treatment of HCC.
Activating mutations in RAS genes, notably KRASG12C, are pervasive in numerous cancers, presenting formidable challenges to therapy due to their elusive druggability. The landmark discovery of KRASG12C allosteric inhibitors marked a transformative milestone in cancer treatment, resulting in the approval of sotorasib and adagrasib. However, limitations in the depth and duration of response prompted the quest for alternative strategies. Recently, Holderfield et al., Wasko et al., and Jiang et al. reported on tri-complex inhibitors, namely RMC-7977 and RMC-6236, targeting activated RAS variants, demonstrating promising preclinical efficacy surpassing adagrasib. These advancments signify a paradigm shift in RAS oncology, promising enduring therapeutic benefits and warranting further clinical exploration.
Traditional chemotherapy is often accompanied by off-target toxicity, resulting in adverse side effects and driving the development of targeted therapies. Targeted drug conjugates (TDCs) typically comprise targeting ligands, such as specific antibodies, peptides, or small molecules, attached to a cytotoxic agent via a chemical linker. In this study, we briefly discussed the molecular aspects of the key components of TDCs and the mechanisms by which these key factors exert their activity. Moreover, we reviewed FDA-approved TDCs and promising candidates in clinical trials and discussed current challenges and future directions for TDC development, providing insights for the research and development of novel cancer therapeutics using TDCs. TDCs combine the advantages of highly specific targeting and a potent killing effect, enabling accurate and efficient cancer cell elimination. Food and Drug Administration (FDA)-approved antibody-drug conjugates (ADCs) have shown good efficacy in treating various cancers; however, they still present limitations such as immunogenicity, hematotoxicity, and complex pharmacokinetics. Smaller peptide-drug conjugates (PDCs) and small molecule-drug conjugates (SMDCs) may combine the advantages of ADCs while overcoming some of their limitations, thereby presenting more efficacious and safer alternatives. TDCs enhance the therapeutic effects of cytotoxic agents and reduce their adverse effects. However, tumor heterogeneity, limited transmembrane permeability, and drug resistance pose significant challenges for TDCs, potentially affecting their therapeutic efficacy. Nevertheless, TDCs are a promising therapeutic approach for cancer treatment, achieving precise drug delivery while minimizing toxicity and side effects on normal cells.
The use of N-acetylcysteine against acetaminophen(APAP)-induced hepatotoxicity, a leading cause of liver injury, has several drawbacks, including short therapeutic windows. Khaya grandifoliola (Meliaceae) has been traditionally used to manage liver-related diseases, and many reports have confirmed its hepatoprotective properties. However, its therapeutic potential as an antidote against APAP-induced hepatotoxicity has yet to be proven in a clinically relevant model. This study aimed to verify the efficacy of delayed treatment with the hydroethanolic extract of K. grandifoliola (KgE) in suppressing the early injury phase of APAP pathophysiology. KgE was analyzed using HPLC/UV. Acute oral toxicity tests were conducted in mice to determine the therapeutic dose of KgE. Mice were treated with 300 mg/kg APAP; 1h and 12h later, they were treated with either predetermined doses of KgE or 20 mg/kg c-Jun N-Terminal Kinase (JNK) inhibitor SP600125, which served as a reference antidote. At 6h and 24h after APAP treatment, the parameters of liver damage and mitochondrial dysfunction, phosphorylation of JNK, and mitochondrial translocation were assessed. KgE at a dose of 5000 mg/kg was safe for mice. Accordingly, 100, 200, and 400 mg/kg were selected as curative treatments. Delayed administration of KgE reversed the histopathological changes in the liver, inhibited serum levels of alanine aminotransferase, reduced the liver content of nitric oxide and malondialdehyde, and restored hepatic glutathione pools and superoxide dismutase and catalase activities in APAP-intoxicated mice. Moreover, KgE prevented APAP-induced JNK phosphorylation and p-JNK mitochondrial translocation and rescued the activities of mitochondrial enzyme complexes II and V. HPLC/UV analysis revealed the presence of gallic acid, Quercetin and Silibinin, with retention times of 3.77, 11.63 and 11.95 min as the major active ingredients present in KgE. Our findings demonstrate that post-treatment with KgE protects the mouse liver from APAP-hepatotoxicity through the inhibition of JNK activation and mitochondrial dysfunction.
Natural products (NPs) exhibit diverse chemical structures and biological activities that make them valuable sources for drug discovery. With advancements in computational technology, computation-enabled natural drug discovery is gaining increasing significance, with NP databases playing a pivotal role. In light of this, we first summarize the key features of NP databases, including structural data, property annotations, biological sources, biosynthetic pathways, and web interfaces. Subsequently, the wide applications of these databases in drug discovery, such as virtual screening, knowledge graph construction, and molecular generation, are reviewed. We further discuss the puzzle of database development, focusing on data quality and updating. Finally, we emphasize the pivotal role of team collaboration and toolkit innovation in harnessing the immense potential of NP-related databases to accelerate bioactivity mining, structure modification, and manufacturing. This review aims to elucidate the key features and applications of NP databases, with the goal of aiding researchers in developing and maintaining high-quality NP databases for drug discovery.
Fructus Cannabis (hemp seed) is important in food and traditional Chinese medicinal applications. Several studies have shown it has antioxidant, antiaging, anti-inflammatory, and neuroprotective properties. Studies have reported its anti-Alzheimer's disease effects. However, its active substances have not been defined, and little is known about the chemical constituents of the aqueous extract. The chemical profile of the aqueous extract of Fructus Cannabis (EFC) was obtained via isolation, structural identification, and qualitative and quantitative analyses. Twenty-seven compounds were identified, including seven nucleosides (1-7), five phenylpropanamides (8-11, and 24), three alkaloids (15, 16, and 26), two cyclic dipeptides (17 and 25), and one pyrimidine (19). Compounds 1, 3-7, 12, 14-19, and 21-27 were not reported previously in the Cannabis genus. Therefore, their chemotaxonomic significance is discussed. Neuroprotective activity screening revealed that EFC and the isolated compounds, particularly 9, 11, and 17, showed significant neuroprotective effects in PC12 cells (rat pheochromocytoma cells). The novel object recognition experiment and Nissl staining showed that EFC improved cognitive impairment in APP/PS1 mice and that EFC intervention reduced the number of senile plaques. These findings will contribute to the utility of Fructus Cannabis.
Chronic myeloid leukemia (CML) is the chronic proliferation of myeloid-lineage cells in hematopoietic stem cells driven by the BCR-ABL1 fusion oncoprotein. The development of tyrosine kinase inhibitors (TKIs) has revolutionized CML treatment; however, resistance and intolerance to these drugs remain key challenges. CML stem cells (CMLSCs) are the root cause of CML relapse and resistance to TKIs. This review discusses novel targeted therapeutic options targeting CMLSCs to address the abovementioned challenges. Numerous novel TKIs, such as flumatinib, vodobatinib, and olverembatinib, have shown remarkable potential against BCR-ABL1, but few, including AT9283, MK0457, and DCC-2036, are still undergoing clinical trials. Targeting CMLSCs is a fundamental therapeutic approach for the treatment of CML progression, relapse, and TKI resistance. In this review, novel agents targeting core signaling pathways and novel molecular targets in CMLSCs are highlighted. Currently, multiple approaches, such as targeting epigenetic modifications or microRNAs and altering metabolism in leukemic cells, have shown desirable effects in treating CML. Immunotherapy, autophagy inhibitors, and protein synthesis inhibitors are novel and effective therapies for the treatment of CML. Although various therapeutic strategies have provided exceptional results in the treatment of CML, the challenges of TKI resistance and CML remission or relapse remain. Therefore, current therapeutic approaches and targeted therapies have practical and clinical implications for achieving desirable outcomes.
Constitutive KRAS activating mutations are prevalent in hematopoietic malignancies. Our previous study showed that the deficiency of Sos1 prolongs the survival of KrasG12D/+ mice. However, whether Sos1 deletion ameliorates oncogenic Kras-mediated hematopoietic defects remains unknown. Here, we found that Sos1 deletion restored KrasG12D-mediated hematopoietic stem cell (HSC) and multipotent progenitor (MPP) exhaustion by maintaining quiescent HSC and MPP pools. Sos1 knockout attenuates hyperactivation of ERK signaling in KrasG12D/+ HSCs and MPPs. Additionally, the loss of Sos1 reduced the frequency and colony-forming capability of myeloid progenitors in KrasG12D/+ mice, resulting in a less severe myeloproliferative neoplasm phenotype. Moreover, Sos1 knockout prolonged the survival of KrasG12D/+ mice in a cell-autonomous manner. In general, cells with Sos1 deletion remained sensitive to MEK and JAK inhibition, suggesting that combined Sos1 inhibition and other therapies could be a promising strategy for the treatment of oncogenic KRAS-driven leukemia.
Nanoparticles (NPs) have significantly advanced medical applications, including drug delivery, immunotherapy, vaccines, and diagnostics. This versatility is partly due to the potential of tailoring NPs from multiple sources. Notably, saponins, amphiphilic plant metabolites, have shown great promise in NP formulation. This study explored the development of micellar NPs using saponin crude fractions (SCFs) extracted from five Congolese plant species: Millettia laurentii, Penthaclethra eetveldeana, Schwenckia americana, Musa paradisiaca, and Musa sapientum. Plant materials were subjected to histological examination through optical microscopy, while phytochemical analyses by thin-layer chromatography confirmed the presence and predominance of saponins in the SCFs. We used a phthalocyanine-isoniazid hybrid (Pc-INH) as a hydrophobic probe to determine the critical micellar concentrations of SCFs and explore the feasibility of developing cost-effective saponin-based micelles (SBMs). Phytochemical screenings indicated saponins in the extracted SCF and other metabolites like flavonoids, phenolic acids, and anthocyanins. Dynamic light scattering and transmission electron microscopy analyses revealed the formation of nano-sized particles, particularly noting SBMs from P. eetveldeana with notable dimensions (157 nm, PDI of 0.27, and ZP of −4.01 mV) and spherical shape. The micelles from M. laurentii exhibited superior encapsulation efficiency for Pc-INH (55%) compared to control micelles formulated from pure saponin (33%). In vitro tests showed that M. paradisiaca SBMs have the best safety profile for red blood cells, with a 10% hemolysis rate compared to a 150% rate for bulk SCFs. However, there is a significant difference between SCFs and SBMs (p < 0.0001). The release profiles of M. paradisiaca SBMs show a pH-dependent relationship, suggesting potential for stimuli-responsive drug delivery. This work lays the foundation for leveraging plant-derived crude saponins in nanotechnology, emphazising their encapsulation efficiency, controlled release potential, and biocompatibility, paving the way for the cost-effective production of high-value biomedical NPs.
Hedyotis diffusa Willd., a herbal remedy for cancer, has a complex chemical profile that is difficult to analyze in detail. Here, we introduce an optimized sample preparation method coupled with two-dimensional gas chromatography-time-of-flight mass spectrometry (GC × GC-TOF/MS) to enhance the chemical profiling of H. diffusa. By employing dichloromethane extraction for nonpolar compounds, aqueous extraction, and solid-phase extraction fractionation into moderately polar and polar fractions, we extracted and analyzed a comprehensive range of chemicals from H. diffusa. GC × GC-TOF/MS analysis revealed a rich chemical landscape, identifying 185, 325, and 483 peaks in the dichloromethane extract, solid-phase extraction elution, and unretained fractions, respectively. Library matching against known compounds confirmed 155, 178, and 184 hits with a similarity of 80% or greater. Notably, this method also involves group-type elution of steroids and anthraquinones, facilitating the identification and screening of similar compounds. This comprehensive approach to herbal chemical analysis offers a high-dimensional perspective and greatly advances our understanding of the chemical constituents of H. diffusa.
Advanced metastatic colon cancer is difficult to treat with existing chemotherapy medicines, and hypoxic microenvironment is closely related to angiogenesis and distant metastasis of colon cancer. Quercetin, a natural flavonoid, has been shown anti-tumor effects. The aim of this study is to investigate the effect of quercetin alone or combined with 5-FU on the invasion and metastasis of advanced metastatic or primary colorectal cancer in hypoxic environment. The cytotoxicity of quercetin or/and 5-FU on colon cancer cells using CCK8 assay, Hoechst 33342, flow cytometry and AO staining. The effects of quercetin or/and 5-FU on the migration and invasion were determined by transwell, cell scratching method and murine xenograft models. The potential mechanism was explored by Western blot and immunofluorescent assay. The results revealed quercetin effectively inhibited the invasion and migration of high metastatic advanced colon cancer LOVO cells under hypoxia through the inhibition of ROS and the expression of HIF-1α and PI3K/AKT pathway. Combination of quercetin and 5-FU could promote the inhibition of 5-FU on the invasion and migration of LOVO cells. Moreover, quercetin also significantly inhibited the proliferation of either LOVO cells or HT-29 cells under hypoxia by inducing apoptosis and autophagy, particularly, showing stronger inhibition on HT-29 cells than LOVO cells. In conclusion, quercetin inhibited the invasion and migration of advanced metastatic colon cancer LOVO cells under hypoxia through inhibition of ROS and HIF-1α expression and the downregulation of PI3K/AKT pathway. Moreover, quercetin alone or in combination with 5-FU can effectively inhibit the invasion and migration of high metastatic advanced colon cancer. Quercetin has the potential to be used as an effective anti-colon cancer drug alone or in combination for the clinical treatment of advanced colon cancer.