DARU Journal of Pharmaceutical Sciences最新文献

Background: A recent body of evidence has suggested regular exercise as a promising complementary therapeutic strategy in the management of epilepsy and its related cognitive impairments.

Objectives: To put it to the test, our study aimed to comparatively examine the effects of physical exercise, low and high doses of levetiracetam, or the combination of both on amygdala electrical kindling-induced epilepsy in rats, as well as the consequent learning and memory impairments.

Methods: Male Wistar rats were randomly divided into ten groups (n = 7 per group) as the following: (I) Control (without kindling and exercise), (II) Lev (rats were received 54 mg/kg of levetiracetam without kindling and exercise), (III) Ex (rats were subjected to exercise without kindling), (IV) Ex-K (rats were subjected to preventive exercise before kindling), (V) K (rats were subjected to kindling without any intervention), (VI) K-Ex (rats were subjected to exercise after kindling), (VII) K-L lev (rats were received 27 mg/kg levetiracetam after kindling), (VIII) K-H lev (rats were received 54 mg/kg levetiracetam after kindling), (IX) K-Ex-L lev (subjected to exercise and receiving a low dose of levetiracetam after kindling), and (X) K-Ex-H lev (rats were subjected to exercise and receiving a high dose of levetiracetam after kindling). After the kindling procedure and interventions, the seizure parameters, including dADD, S₁L, S₂L, S₃L, S₄L, S₅L, Max S5D, and Max ADD, were recorded, and seizure-related behavioral changes were evaluated using the MWM test.

Results: Our findings showed that in all therapeutic interventional groups, including Ex, L lev, H lev, and their combination (Ex-L lev and Ex-H lev), there was a substantial reduction in parameters, including seizure stages, seizure duration, and dADD. In contrast, there was a significant increase in the mean delay time or latency from electrical stimulation to the onset of stages 1, 2, and 3 of seizure (S₁L, S₂L, and S₃L), and all groups were significantly different from the kindling group. Moreover, the kindling-induced spatial memory and learning deficit was remarkably ameliorated by preventive exercise, Ex, L lev, H lev, and their combination.

Conclusion: Our study reveals that, in conjunction with levetiracetam, regular exercise can ameliorate the intensity and frequency of amygdala electrical kindling-induced epileptic seizures, as well as the consequent spatial memory and learning impairments.

Background: Falcarindiol, a bioactive polyacetylene, has shown cytotoxic effects in several cancers including breast, colorectal, and oral squamous carcinoma, but its pharmacological actions in cervical cancer are not well defined.

Objectives: This study aims to integrate in silico approaches to define the multi-target pharmacological mechanisms of falcarindiol in cervical cancer, including ADMET profiling, network pharmacology, target prioritization, and molecular docking especially of EGFR/mTOR associated signaling pathways. Simultaneously, the study aims to experimentally verify the anticancer activity of falcarindiol in cervical cancer cells by examining its impacts on cell viability, apoptosis, mitochondrial dysfunction, reactive oxygen species generation, senescence induction, and cell cycle regulation.

Methods: Pharmacokinetic and toxicity properties were evaluated using in silico ADMET profiling. Potential molecular targets and signaling pathways were identified from integrated databases, with hub genes prioritized by protein-protein interaction analysis. Protein-ligand binding was assessed through docking. Gene expression and prognostic significance were analyzed using public cancer datasets. Functional effects of falcarindiol were validated in HeLa and SiHa cervical cancer cells by MTT assay, Annexin V/PI, and AO/PI staining, mitotracker intensity, H₂DCFDA fluorescence, β-galactosidase staining, and cell cycle analysis.

Results: Falcarindiol demonstrated favorable ADMET properties and low predicted toxicity. Target prioritization identified EGFR, ERBB2, mTOR, MMP9, and CASP3 as central nodes, with strong interactions confirmed for EGFR and mTOR. Expression analyses revealed upregulation and hypomethylation of these genes in cervical cancer. Falcarindiol reduced viability (IC50 ~ 125-150µM), induced apoptosis, disrupted mitochondrial membrane potential, increased ROS production, and caused G₀/G₁ arrest in vitro. Senescence was also enhanced in treated cells.

Conclusion: Falcarindiol exerts multi-targeted pharmacological actions in cervical cancer by modulating EGFR/mTOR signaling and apoptotic pathways, supporting its potential as a therapeutic lead compound.

Background: Cholesteryl ester transfer protein (CETP) inhibitors, specifically anacetrapib and obicetrapib, have shown strong lipid-modifying effects by lowering low-density lipoprotein cholesterol (LDL-C) and altering other lipid parameters. However, comparative evidence on their relative efficacy and safety is limited.

Objectives: To compare the efficacy and safety of anacetrapib and obicetrapib.

Methods: We systematically searched PubMed, Scopus, Web of Science, Cochrane Central Register, and ClinicalTrials.gov. The protocol was registered at OSF ( https://doi.org/10.17605/OSF.IO/VRP8Y ). The primary outcome was change in LDL-C; secondary outcomes included high-density lipoprotein cholesterol (HDL-C), non-HDL-C, total cholesterol, triglycerides, lipoprotein (a), apolipoprotein B (ApoB), apolipoprotein AI (ApoAI), apolipoprotein E (ApoE), incidence of adverse events, serious adverse events, and discontinuation. A frequentist random-effects network meta-analysis was performed using the netmeta package in R, with placebo as reference.

Results: Ten randomized controlled trials (2,937 patients) were included. Obicetrapib showed the most significant reduction in LDL-C (MD -33.63 mg/dL; 95% CI [-44.10, -23.16]) and the most significant increase in HDL-C (MD 154.33 mg/dL; 95% CI [132.73, 175.93]), outperforming anacetrapib. Both drugs comparably reduced non-HDL-C, ApoB, and Lp(a). Obicetrapib was associated with greater increases in ApoA1 and ApoE, while anacetrapib lowered triglycerides more effectively. Obicetrapib had the lowest risk of overall adverse events (RR 0.69; 95% CI [0.49, 0.99]) and ranked favorably for serious adverse events and discontinuation.

Conclusion: Both agents effectively reduced LDL-C levels, with obicetrapib demonstrating superior efficacy compared to anacetrapib. Additionally, both treatments demonstrated favorable safety profiles. These findings underscore the potential of CETP inhibitors as promising therapeutic options for patients with dyslipidemia.

Background: Cochlospermum religiosum (CR) is a traditionally valued medicinal plant, but its anticancer constituents and mechanisms remain poorly understood.

Objective: This study aimed to investigate the anticancer potential of CR by integrating phytochemical profiling, molecular docking, and in vitro/in vivo evaluations.

Methods: GC-MS and LC-MS analyses were performed to identify bioactive compounds in CR. Molecular docking was carried out against key cancer targets (CDK-2, CDK-6, IGF-1R, Bcl-2, and VEGFR-2). In vitro cytotoxicity was tested on MCF-7 (breast) and HT29 (colon) cancer cell lines, and in vivo efficacy was evaluated in an Ehrlich Ascites Carcinoma (EAC) mouse model. Haematological and hepatic parameters were also assessed.

Results: Several bioactive compounds were identified, including euphornin (reported for the first time in CR), lupeol, and stigmasterol, all with known anticancer activity. Docking studies suggested strong multitarget inhibitory potential. CR extract showed selective cytotoxicity against MCF-7 and HT29 cells with IC₅₀ values of ~ 33-42 µg/mL, while sparing normal cells. In the EAC mouse model, a 400 mg/kg dose of CR significantly reduced tumor burden, improved survival, and restored haematological (↑hemoglobin, ↑lymphocytes) and hepatic (↓SGOT, ↓SGPT, ↓bilirubin) parameters.

Conclusions: Cochlospermum religiosum exhibits promising multitarget anticancer potential, coupled with immunomodulatory and hepatoprotective effects. These findings provide a strong foundation for further mechanistic and clinical investigations.

Background: Irritable bowel syndrome (IBS) requires long-term, site-specific therapy. Mebeverine hydrochloride is effective but limited by rapid metabolism and frequent dosing. This study aimed to develop colon-targeted, controlled-release nanoparticles to improve therapeutic efficacy and compliance.

Methods: Nanoparticles were prepared via chitosan-xanthan gum polyelectrolyte complexation and optimized using a Box-Behnken design. Molecular docking predicted strong binding of mebeverine to the muscarinic acetylcholine receptor (-7.4 kcal/mol). Optimized nanoparticles were enteric-coated with Eudragit S100 for pH-dependent colonic release and evaluated through in vitro dissolution and in vivo efficacy in an acetic acid-induced IBS-D rat model.

Results: Optimized nanoparticles showed a mean size of ~ 380 nm, zeta potential + 25 mV, and entrapment efficiency of 95%. In vitro, the enteric-coated formulation resisted gastric pH and released > 95% drug under colonic conditions within 12 h. In vivo, treated rats demonstrated significantly reduced visceral hypersensitivity (AWR score, p < 0.05), normalized intestinal motility (p < 0.05), and improved behavioral outcomes compared to the IBS group. High-dose nanoparticles performed better than the marketed sustained-release capsule.

Conclusion: The chitosan-xanthan gum nanoparticle system enabled sustained, colon-specific delivery of mebeverine hydrochloride with superior therapeutic efficacy in vivo, offering a promising strategy for long-term IBS management.

Background: Bromelain is a proteolytic enzyme obtained from pineapple stems, possessing diverse pharmacological properties such as antioxidant, antidiabetic, anticancer, anti-inflammatory, anthelmintic, cardioprotective, nephroprotective, and antiaging effects. However, its therapeutic potential has been limited due to poor bioavailability and low blood-brain barrier (BBB) permeability.

Objectives: This review aims to summarize the therapeutic effects of bromelain, highlight its pharmacological importance, and discuss novel drug delivery system (NDDS)-based nanoformulations developed to enhance its bioavailability and clinical applicability.

Methods: Relevant literature was reviewed to collect data on bromelain's pharmacological activities, limitations in clinical use, and recent advancements in nanoformulation-based delivery approaches. Additionally, available clinical trial data involving bromelain were examined.

Results: NDDS-based formulations, including solid lipid nanoparticles, gold nanoparticles, silver nanoparticles, nanoemulsions, and nanostructured lipid carriers, have been shown to improve bromelain's bioavailability and BBB permeability, thereby enhancing its therapeutic efficacy. Several clinical studies further support its pharmacological potential, though broader investigations remain limited.

Conclusion: Bromelain exhibits wide-ranging therapeutic benefits, and NDDS-based nanoformulations provide a promising strategy to overcome its pharmacokinetic limitations. Further clinical research is needed to validate its efficacy and establish its role in pharmaceutical and nutraceutical applications. Our evaluation emphasizes that nano-enabled delivery is the most credible route to consistent pharmacokinetics and effect sizes across indications; however, dose-exposure-response data remain sparse and should be prioritized in upcoming trials.

Obesity is a health problem with an economic burden. This study examined the anti-obesogenic impact of caffeic acid (Caf) or resveratrol (Res) and their effect on lipogenic enzymes. Wister albino rats received high-fat diet (HFD) for 16 weeks then were randomly allocated into three groups and treated orally with either drug vehicle, Caf (50 mg/kg/day) or Res (120 mg/kg/day) for further 6 weeks. Rats in control group received normal chow diet for 22 weeks. Treatment of obese rats with either Caf or Res attenuated body weight gain and fat pad mass, and improved hyperglycemia and dyslipidemia. Both drugs promoted adiponectin expression, while decreased tumor necrosis factor-alpha (TNF-α) levels in white adipose tissue (WAT) of obese rats. Res down-regulated the expression of sterol regulatory element binding protein-1 (SREBP-1) mRNA and protein levels of ATP citrate lyase (ACLY) and fatty acid synthase (FAS), to a greater extent than Caf. Conversely, both drugs promoted adipose triglyceride lipase (ATGL)-mediated lipolysis in obese rats and the effect of Res was superior to that of Caf. These findings suggest that Caf and Res have certain regulatory effects regarding obesity-related metabolic disorders, more likely through modulating lipogenesis and lipolysis-related proteins.

Background: Resistance to docetaxel (DTX), a frontline chemotherapeutic agent for prostate cancer (PC), remains a major therapeutic challenge, often driven by impaired apoptosis and enhanced metastatic potential. Calebin A (CA), a natural polyphenol derived from turmeric, has demonstrated anticancer properties in various malignancies. This study investigated the individual and combined effects of CA and DTX on proliferation, apoptosis, cell cycle progression, migration, and gene expression in human PC3 prostate cancer cells.

Methods: PC3 cells were treated with varying concentrations of CA and DTX, alone or in combination. Cell viability was assessed using the MTT assay, and drug interactions were evaluated using the combination index (CI) analysis. Flow cytometry was employed to analyze apoptosis and cell cycle distribution. Gene expression of Bax, Bcl-2, MMP-2, and MMP-9 was quantified using qRT-PCR, while gelatin zymography and wound healing assays evaluated protease activity and migratory behavior, respectively.

Results: Both CA and DTX exhibited time- and dose-dependent cytotoxicity, with combination treatment producing synergistic effects (CI < 1). Co-treatment significantly increased apoptotic cell populations and induced marked sub-G1 and G2/M cell cycle arrest. The combination therapy upregulated the pro-apoptotic Bax/Bcl-2 ratio and downregulated MMP-2 expression, with modest reductions in MMP-2 and MMP-9 enzymatic activities. Furthermore, migratory capacity was significantly diminished under combinatorial treatment compared to monotherapies.

Conclusion: CA enhances the antitumor efficacy of DTX by potentiating apoptosis, inhibiting migration, and modulating gene expression associated with metastasis and survival. These findings suggest CA as a promising adjuvant to overcome chemoresistance and improve therapeutic outcomes in prostate cancer.

Background: Cardiovascular diseases (CVDs) remain the leading cause of death globally, necessitating innovative therapeutic strategies. Nanoparticles have emerged as a promising tool due to their unique properties, including tunable size, high surface area, drug-loading capacity, and the ability to be functionalized for targeted delivery. Their potential in early detection, precise drug delivery, and localized therapy positions them as a transformative approach in CVD management.

Objectives: This review explores the latest advancements in nanoparticle-based interventions for CVDs, focusing on their role in targeted drug delivery, diagnostic applications, and therapeutic efficacy. We highlight how engineered nanoparticles can improve specificity, reduce systemic side effects, and enhance treatment outcomes.

Methods: We examine preclinical and clinical studies on lipid-based, polymeric, and inorganic nanoparticles optimized for CVD treatment. Their surface modifications, drug-release mechanisms, and targeting capabilities are analyzed, with particular attention to their applications in atherosclerosis, myocardial repair, and inflammation modulation.

Results: Functionalized nanoparticles demonstrate significant potential in CVD therapy by enabling site-specific drug delivery to atherosclerotic plaques, damaged cardiac tissue, and inflamed vasculature. Chemical and natural-based nanoparticles show enhanced therapeutic precision, with improved outcomes in drug bioavailability and reduced off-target effects.

Conclusion: Nanotechnology is reshaping CVD treatment through advanced drug delivery systems that enhance precision and efficacy. By leveraging nanoparticle engineering, future therapies can achieve targeted, personalized interventions, offering new hope in combating CVDs.

While traditional peer review offers advantages in academic publishing, it is often hampered by significant weaknesses, leading to frustration among many authors. Scientific discoveries after publication depend on thorough discussions and critiques, making post-publication peer review (PPPR) an essential tool for identifying errors and encouraging authors to make necessary corrections. PPPR is defined as a critical, ongoing, and public review conducted by the broader scientific community once research findings are formally published. Its goal is to enable more academic experts to continuously examine, question, and validate the work, identifying potential flaws or strengths that might have been missed during the initial review. This ongoing dialogue promotes transparency and motivates authors to make necessary corrections. Although the goal of PPPR is to enhance scientific integrity, the open nature of PPPR platforms makes them vulnerable to misuse. It can also be exploited to undermine colleagues, suppress differing viewpoints, or further personal or organizational interests. We also observe an increase in "hyper-skepticism," which differs from constructive criticism, reflecting an overly critical mindset that focuses on doubt rather than fostering understanding. To fully realize the benefits of PPPR and prevent misuse, the scientific community must build a more equitable and more responsible framework. Addressing these challenges requires a thoughtful strategy that integrates technological advancements, strengthens editorial policies, enhances transparency measures, and provides robust protections for good-faith scientific debate.