5’ Adenosine monophosphate-activated protein kinase (AMPK) is a metabolic sensor responsible for maintaining homeostasis, regulating metabolic control, monitoring energy status, and balancing energy production with consumption. The most important protein kinases that activate AMPK are liver kinase B1 and calcium-calmodulin-dependent protein kinase. AMPK significantly impacts physical performance by accelerating recovery periods and restoring energy stores through several key mechanisms. It regulates muscle glycogen content, ensuring readily available energy during physical exertion. In addition, a high number of mitochondria enable the utilization of fatty acids as an energy source, thereby improving endurance efforts. Furthermore, rich vascularization in the muscles enhances the delivery of nutrients and oxygen, optimizing performance and speeding up recovery. AMPK is also important for maintaining muscle homeostasis. It decreases insulin resistance, stimulates mitochondrial biogenesis, and exerts an antioxidant effect. As a regulator of energy homeostasis, AMPK plays a key role in linking cellular energy levels with the aging process. It acts as a modulator of cellular senescence and has the potential to extend life expectancy, particularly in the context of caloric restriction. By activating AMPK, caloric restriction (activated with a 30 - 70% reduction in nutrient intake) helps to maintain energy balance in cells, which may slow down aging and support healthier cellular function over time. In conclusion, the involvement of AMPK in metabolic regulation and maintenance makes it an important therapeutic target for the treatment and prevention of several diseases, both age-related and otherwise.

Light has been used for medical purposes for centuries, but the first steps toward photodynamic therapy (PDT) were taken in the early 20th century. PDT is an innovative therapeutic approach that involves three key components: A photosensitizer (PS), molecular oxygen, and visible light. The destruction of diseased tissues and cells in PDT occurs through the activation of a PS by near-infrared or visible radiation. This activation, in the presence of molecular oxygen, generates singlet oxygen and other reactive oxygen species. PDT has been successfully applied to treat various types of cancer, particularly superficial ones. This review outlines the principles of PDT and discusses its application in cancer treatment, specifically in the context of pancreatic and esophageal cancer. While PDT is effective, it can also have adverse effects on the human body, such as changes to cell and organelle membranes. PDT is a modern, non-invasive treatment modality utilized for both non-malignant conditions and also various types of tumors in diverse locations. Enhancing the efficacy of PDT and reducing its side effects may be possible by combining PSs with nanomaterials, which would also allow for targeted therapy to specific receptors. PDT is continuously being developed to improve its effectiveness, and ongoing studies aim to minimize unwanted side effects and identify contraindications for its use.

Recent advancements in biomarker research for the diagnosis, prognosis, and treatment strategies of major depressive disorder (MDD) have yielded significant findings that warrant documentation. The clinical demand for biomarkers persists due to the limited accuracy and efficiency of subjective diagnostic approaches. This review scrutinized research papers related to MDD biomarkers published between January 2011 and till July 2024, focusing exclusively on human studies with statistically significant results. The compiled biomarkers encompass cellular membrane receptors, cytoplasmic organelles, and genomic and epigenomic intranuclear markers. Cell surface molecular receptors implicated in MDD pathogenesis include brain-derived neurotrophic factor (BDNF) receptors, N-methyl D-aspartate receptors (NMDAR), and interleukin (IL) receptors. Endogenous compounds with diagnostic and prognostic potential, such as L-carnitine and alpha-L-carnitine, have also been identified. Transcriptomic biomarkers, including mRNA expression levels of the BDNF, IL-1β, macrophage migration inhibitory factor, and tumor necrosis factor-alpha (TNF-α), have demonstrated utility in MDD management. MicroRNAs (miRNAs), the endogenous molecules that alter the structure of mRNA, show potential for diagnosis and treatment outcome prediction, with miR-221-3p, miR-129-5p, miR-134, and miR-184 emerging as key candidates for MDD monitoring. Long non-coding RNAs (lncRNAs), such as GSK3βAS1, GSK3βAS2, and GSK3βAS3 have been investigated for the evaluation of disease severity and treatment response. Most recently, the pathological role of circular (circRNA) and DNA methylation in MDD has also been documented. The rs155979 polymorphism in the lncRNA NOTHSAT102891 was significantly associated with depression and risk of suicide. The data compiled in this review aim to guide further research in the quest for biomarkers that will improve the management of MDD.

Heart failure (HF) is categorized by left ventricular ejection fraction (LVEF) into three groups. HF with reduced ejection fraction (HFrEF) is one of these groups characterized by the heart’s inability to pump sufficient blood to meet the body’s needs, resulting from the left ventricle’s impaired ability to contract effectively. The Canadian Cardiovascular Society (CCS) guidelines recommend vericiguat for hospitalized patients experiencing worsening symptoms of HFrEF. This article reviews vericiguat’s efficacy and potential benefits in Pakistani patients with HFrEF. A literature search from 2013 to 2024 was conducted using PubMed, ScienceDirect, and Google Scholar, employing keywords such as guidelines, heart failure, Pakistan, and reduced ejection fraction. Soluble guanylate cyclase (sGC) stimulators, like vericiguat, have shown benefits in patients with left ventricular hypertrophy and fibrosis by reducing afterload through vasodilation. Vericiguat (2.5 - 10 mg taken orally once daily) shows promise in reducing cardiovascular mortality and hospitalization in adults with LVEF ≤45%. Vericiguat may alleviate Pakistan’s growing cardiovascular disease burden. Expedited access to this innovative therapy can be achieved through collaborative efforts among policymakers, healthcare authorities, and international research centers, potentially reducing hospitalization rates in Pakistani HFrEF patients.

Erythropoietin (EPO) is an essential growth factor for erythropoiesis. We report the results of the preclinical safety evaluation of GBpoietin®, a recombinant human EPO (rhEPO), through a comparative acute toxicity study with the reference product, Eprex®. The products were administered subcutaneously into Wistar rats for both the single-dose and repeated-dose toxicity studies. Hematological and biochemical parameters were measured for all test subjects before the first dose and the day after the last dose in both studies. Necropsy and histopathology of representative subjects from each group were also performed to find any pathological changes, such as degeneration or cellular necrosis in internal organs such as the kidney, liver, lung, and spleen. Both GBpoietin® and Eprex® comparative toxicology studies, which were not significantly different (P > 0.05), revealed similar pharmacologically driven mechanisms of toxicity. Although hematological parameters stayed within the normal range throughout the study, improved profiles of hemoglobin and hematocrit (P < 0.05) confirmed the therapeutic effect of rhEPO in both studies. Moreover, the initial and final values of aspartate aminotransferase, alanine aminotransferase, and blood urea nitrogen were comparable (P > 0.05) for both experimental products. The study established that the toxicological profiles of GBpoietin® and Eprex® were similar and aligned with the known pharmacology of EPO alfa, demonstrating proof of “totality” and “no residual uncertainty.”

This study evaluated behavioral phenotypes and superoxide dismutase (SOD) enzymatic activity in a repeated sub-anesthetic dose of ketamine (KET) administered to model schizophrenia in an animal study. The animals were divided into three (3) experimental groups. The KET alone group received sub-anesthetic dose of KET (20 mg/kg) for 14 consecutive days. The control group vehicle (VEH) received distilled water (10 mL/kg) as a VEH, while the KET and risperidone (RISP) group (KET + RISP) received a sub-anesthetic dose of KET (20 mg/kg) alone for 7 consecutive days, followed by RISP (0.5 mg/kg) administered 1-h post-KET treatment from days 8 to 14. All treatments were administered intraperitoneally (i.p.). Twenty-four hours after the last treatment, behavioral phenotypes (locomotor activity and cognition) were assessed using the locomotor activity cage and the elevated plus maze (EPM). Thereafter, SOD enzymatic activity was evaluated in homogenized brain tissue from each mouse using spectrophotometric analysis. Animals that received KET (20 mg/kg i.p) alone showed a significant (P < 0.05) increase in movement counts and rearing events in the locomotor activity test. It also prolonged the latency to enter the open arms during the anxiety-induced cognitive assessment in the EPM, compared to animals that received distilled water or those that received KET and RISP. SOD enzymatic activity was significantly elevated in the KET group compared to the VEH and KET + RISP groups. The elevated SOD enzymatic activity may represent a compensatory response to the oxidative stress induced by repeated sub-anesthetic doses of KET.

Inflammatory responses and oxidative stress (OS) play a significant role in the development of spinal cord injury (SCI), as evidenced by both pre-clinical and clinical studies. This research aimed to assess the potential antioxidant and anti-inflammatory properties of curcumin (CuC) as a therapeutic approach in a unilateral SCI model using male rats. We used 40 adult male Wistar rats (each weighing 220 - 250 g) that were randomly assigned to one of the five experimental groups: (1) Control (Con), (2) Model (SCI animals), (3) Model+CuC20, (4) Model+CuC40, and (5) Model+CuC80. Accordingly, the SCI animals in Model+CuC20, Model+CuC40, and Model+CuC80 groups received 20, 40, and 80 mg/kg/day of CuC through the intraperitoneal route, respectively. We assessed functional recovery, measured OS indicators, including malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), and total antioxidant capacity (TAC) in the blood, and evaluated protein levels of caspase 1, NOD-like receptor family pyrin domain-containing 3 (NLRP3), and apoptosis-associated speck-like protein containing a CARD (ASC) in the spinal cord tissue. The CuC treatment groups showed a significant enhancement in functional recovery, a marked decrease in MDA levels, and a notable elevation in SOD activity relative to the SCI animals. Model+CuC40 and Model+CuC80 animals exhibited a significant improvement in GSH activity and TAC level as compared to the SCI animals. The results also showed a dramatic decrease in the protein concentration of NLRP3, ASC, and Casp1 in the Model+CuC40 and Model+CuC80 groups relative to the Model group (P < 0.0001). In conclusion, the treatment with CuC significantly enhanced functional recovery in SCI rats by effectively mitigating OS and reducing inflammatory markers.

This review explores the development, modification, and optimization of potent active compounds using combinatorial synthetic methods that incorporate phytoconstituents from plant extracts, aiming to enhance efficacy and mitigate resistance. Attenuated total reflectance-Fourier transform infrared spectroscopy, gas chromatography-mass spectrometry (GC-MS), and antibacterial data from the literature were employed to validate these strategies. The methodology emphasized precise harvesting, pre-treatment, and extraction processes to ensure the quality and efficacy of the plant extracts. Various extraction methods and solvents were used to isolate specific phytoconstituents, followed by further purification through chromatography. The review proposes three strategies: (i) reacting single or multiple plant extracts with reagents such as acids or catalysts, (ii) combining plant extracts with ineffective drugs to induce structural changes that enhance antibacterial efficacy, and (iii) integrating plant extracts with drugs not originally intended for the target disease to explore new structural functionalities. Significant findings include synergistic effects observed when Psidium guajava and Calotropis procera extracts were combined with antibiotics, leading to substantially increased zones of inhibition against resistant bacteria. GC-MS analysis identified numerous bioactive compounds, some of which with known anticancer properties, suggesting potential applications beyond antibacterial effects. These innovative combinatorial approaches demonstrate the potential to yield new compounds with enhanced pharmacological properties, highlighting the critical role of plant extracts in drug discovery and development. This review underscores the promise of harnessing natural products to combat multi-drug resistance, paving the way for advanced research and development in pharmaceutical applications.

Fungal infections of the central nervous system have dramatically surged over the past decade, particularly in semitropical regions such as Karachi. Herein, we retrospectively evaluated the diagnostic potential of galactomannan (GM) and 1,3-β-d-glucan (BDG) assays for intracranial fungal infections (IFI) at a tertiary care facility in Karachi. A total of 12 patients (3 immunocompromised and 9 immunocompetent) aged 18 - 60 years underwent serum fungal biomarker testing, imaging studies, and cerebrospinal fluid (CSF) analysis. Suboptimal GM and high BDG titers indicated invasive mycoses. Computed tomography scan revealed fungal sinusitis, and magnetic resonance imaging revealed brain parenchyma involvement. Fungal biomarkers helped rule out a neoplastic etiology. Normal GM and high BDG titers negated the probability of aspergillosis. Further, culture tests helped identify the causative organisms and tailor the treatment. Our findings emphasize the diagnostic value of GM and BDG assays in IFIs. Furthermore, we recommend the use of CSF specimens for fungal biomarker assays in future diagnostic protocols.

Hypoglycemia is a serious adverse effect in the pharmacological treatment of Type 2 diabetes mellitus (T2DM), exacerbated by comorbidities that affect drug metabolism and clearance. This report describes a case involving a 61-year-old man with hypertension and T2DM. The patient experienced hypoglycemia while taking a combination of voglibose and metformin hydrochloride. His condition was further complicated by urosepsis, acute-on-chronic kidney disease, and hydroureteronephrosis calculi, which likely altered drug clearance and pharmacokinetics. This condition increased his risk of hypoglycemia. Effective management required close monitoring of blood glucose levels and adjustments to the treatment regimen, considering his renal impairment. This case highlights the risks associated with combination therapy in patients with renal issues and underscores the importance of personalized treatment plans, vigilant glucose monitoring, and consideration of renal function to reduce the risk of drug-induced hypoglycemia in patients with T2DM and comorbidities.