Search Results (217)

Background: Sodium–glucose cotransporter 2 (SGLT2) inhibitors have transformed type 2 diabetes mellitus (T2DM) management by promoting glucosuria, lowering glycated hemoglobin (HbA1c), blood pressure, and weight; however, their use is limited by genitourinary infections and ketoacidosis. Phytocannabinoids—bioactive compounds from Cannabis sativa—exhibit multi-target pharmacology, including interactions with cannabinoid receptors, Peroxisome Proliferator-Activated Receptors (PPARs), Transient Receptor Potential (TRP) channels, and potentially SGLT2. Objective: To evaluate the potential of phytocannabinoids as novel modulators of renal glucose reabsorption via SGLT2 and to compare their efficacy, safety, and pharmacological profiles with synthetic SGLT2 inhibitors. Methods: We performed a narrative review encompassing the following: (1) the molecular and physiological roles of SGLT2; (2) chemical classification, natural sources, and pharmacokinetics/pharmacodynamics of major phytocannabinoids (Δ⁹-Tetrahydrocannabinol or Δ⁹-THC, Cannabidiol or CBD, Cannabigerol or CBG, Cannabichromene or CBC, Tetrahydrocannabivarin or THCV, and β-caryophyllene); (3) in silico docking and drug-likeness assessments; (4) in vitro assays of receptor binding, TRP channel modulation, and glucose transport; (5) in vivo rodent models evaluating glycemic control, weight change, and organ protection; (6) pilot clinical studies of THCV and case reports of CBD/BCP; (7) comparative analysis with established synthetic inhibitors. Results: In silico studies identify high-affinity binding of several phytocannabinoids within the SGLT2 substrate pocket. In vitro, CBG and THCV modulate SGLT2-related pathways indirectly via TRP channels and CB receptors; direct IC₅₀ values for SGLT2 remain to be determined. In vivo, THCV and CBD demonstrate glucose-lowering, insulin-sensitizing, weight-reducing, anti-inflammatory, and organ-protective effects. Pilot clinical data (n = 62) show that THCV decreases fasting glucose, enhances β-cell function, and lacks psychoactive side effects. Compared to synthetic inhibitors, phytocannabinoids offer pleiotropic benefits but face challenges of low oral bioavailability, polypharmacology, inter-individual variability, and limited large-scale trials. Discussion: While preclinical and early clinical data highlight phytocannabinoids’ potential in SGLT2 modulation and broader metabolic improvement, their translation is impeded by significant challenges. These include low oral bioavailability, inconsistent pharmacokinetic profiles, and the absence of standardized formulations, necessitating advanced delivery system development. Furthermore, the inherent polypharmacology of these compounds, while beneficial, demands comprehensive safety assessments for potential off-target effects and drug interactions. The scarcity of large-scale, well-controlled clinical trials and the need for clear regulatory frameworks remain critical hurdles. Addressing these aspects is paramount to fully realize the therapeutic utility of phytocannabinoids as a comprehensive approach to T2DM management. Conclusion: Phytocannabinoids represent promising multi-target agents for T2DM through potential SGLT2 modulation and complementary metabolic effects. Future work should focus on pharmacokinetic optimization, precise quantification of SGLT2 inhibition, and robust clinical trials to establish efficacy and safety profiles relative to synthetic inhibitors. Full article

Menopause is characterized by a decline in estrogen levels, leading to symptoms such as vasomotor instability, osteoporosis, and increased cardiovascular and cognitive risk. Hormone replacement therapy (HRT) remains the gold standard for managing menopausal symptoms; however, concerns regarding its long-term safety, including elevated risks of cancer and cardiovascular events, have prompted interest in alternative therapies. Phytoestrogens, particularly the isoflavones daidzein and genistein, are plant-derived compounds structurally similar to 17β-estradiol (E2) and capable of binding estrogen receptors. Found abundantly in soybeans and red clover, these compounds exhibit selective estrogen receptor modulator (SERM)-like activity, favoring ERβ over ERα, which underlies their tissue-specific effects. In vitro, in silico, and in vivo studies demonstrate their ability to modulate estrogenic pathways, inhibit oxidative stress, and influence reproductive and neurological function. Clinical trials show that daidzein and genistein, especially in equol-producing individuals, can reduce vasomotor symptoms such as hot flashes and night sweats. While results across studies vary, consistent findings support their safety and modest efficacy, particularly for women unable or unwilling to use HRT. Pharmacokinetic studies reveal moderate bioavailability and interindividual variability due to gut microbiota metabolism. At dietary levels, these compounds are generally safe, although high-dose supplementation is discouraged in individuals with hormone-sensitive cancers. Emerging evidence suggests lifelong consumption of soy-based foods may reduce cancer risk. In conclusion, daidzein and genistein represent promising, well-tolerated natural alternatives to conventional HRT, offering symptom relief and additional health benefits. Further research is warranted to optimize dosing, improve clinical outcomes, and clarify long-term safety in diverse populations, particularly with genetic variations in isoflavone metabolism. Full article

Soybeans are a primary source of plant-based protein, with seeds containing approximately 40% protein—a key quality trait. Selecting superior hybrid combinations and managing progeny effectively are crucial for developing high-protein soybean varieties. Using a recombinant inbred line population (RIL3613) derived from Dongnong L13 × Heihe 36 and its previously constructed high-density genetic linkage map, QTLs and QTL × environment interactions (QEIs) associated with seed protein content (SPC) were identified through the bi-parental population (BIP) model and multi-environment trials (MET) model in QTL IciMapping v4.2. Candidate genes were then predicted via sequence alignment and haplotype analysis between the parents. Finally, simulated breeding was conducted using the B4L function in the In Silico Breeding (ISB) module of the Blib platform to determine optimal breeding strategies across diverse environments. The analysis identified 19 QTLs associated with SPC and 97 QEIs linked to SPC. These QTLs collectively explained 84.442% of the phenotypic variance, with four QTLs exhibiting significant contributions. A key candidate gene, Glyma.12G231400, associated with soybean SPC, was predicted within the 38,995,090–39,293,825 bp interval on chromosome 12. Across 11 environments, three to six optimal breeding schemes were selected, all employing modified pedigree selection. These findings enhance our understanding of the genetic basis of soybean protein formation and provide technological support for molecular breeding for seed quality improvement. Full article

Milk quality has a growing importance for farmers as component-based pricing becomes more widespread. Food quality and precision manufacturing techniques demand consistent milk composition. Udder health, general cow condition, environmental factors, and especially feed composition all influence milk quality. The large volume of routinely collected milk data can be used to build prediction models that estimate valuable constituents from other measured parameters. In this study, casein was chosen as the target variable because of its high economic value. We developed a multiple linear-regression model and a feed-forward neural network model to estimate casein content from twelve commonly recorded milk traits. Evaluated on an independent test set, the regression model achieved R² = 0.86 and RMSE = 0.018%, with mean bias = +0.003% and slope bias = −0.10, whereas the neural network improved performance to R² = 0.924 and RMSE = 0.084%. In silico microgreen inclusion from 0% to 100% of dietary dry matter raised the predicted casein concentration from 2.662% to 3.398%, a relative increase of 27.6%. To extend practical applicability, a simulation module was created to explore how microgreen supplementation might modify milk casein levels, enabling virtual testing of dietary strategies before in vivo trials. Together, the predictive models and the microgreen simulation form a cost-effective, non-invasive decision-support tool that can accelerate diet optimization and improve casein management in precision dairy production. Full article

Human topoisomerase III beta (hTOP3B) is a unique and important enzyme in human cells that plays a role in maintaining genome stability, affecting cellular aging, and potentially impacting viral replication. Its dual activity on both DNA and RNA makes it a valuable target for therapeutic interventions. hTOP3B has been shown to be required for the efficient replication of certain positive-sense ssRNA viruses including Dengue. We performed in silico screening of a library comprising drugs that are FDA-approved or undergoing clinical trials as potential drugs to identify potential inhibitors of hTOP3B. The topoisomerase activity assay of the identified virtual hits showed that bemcentinib, a compound known to target the AXL receptor tyrosine kinase, can inhibit hTOP3B relaxation activity. This is the first small molecule shown to inhibit the complete catalytic cycle of hTOP3B for the potential interference of the function of hTOP3B in antiviral application. Additional small molecules that share the N⁵,N³-1H-1,2,4-triazole-3,5-diamine moiety of bemcentinib were synthesized and tested for the inhibition of hTOP3B relaxation activity. Five compounds with comparable IC₅₀ to that of bemcentinib for the inhibition of hTOP3B were identified. These results suggest that the exploration of tyrosine kinase inhibitors and their analogs may allow the identification of novel potential topoisomerase inhibitors. Full article

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Long COVID are complex multisystem conditions that pose significant challenges in healthcare. Accumulated research evidence suggests that ME/CFS and Long COVID exhibit overlapping metabolic symptoms, indicating potential shared metabolic dysfunctions. This study aims to systematically explore shared metabolic disturbances in the muscle tissue of patients. Utilizing genome-wide metabolic modeling, we identified key metabolic irregularities in the muscle of patients with ME/CFS, notably the downregulation of the alanine and aspartate metabolism pathway and the arginine and proline metabolism pathway. Further, in silico knockout analyses suggested that supplementation with aspartate (ASP) or asparagine (ASN) could potentially ameliorate these metabolic deficiencies. In addition, assessments of metabolomic levels in Long COVID patients also showed the significant downregulation of ASP during post-exertional malaise (PEM) in both muscle and blood. Consequently, we propose that a combination of l-ornithine and l-aspartate (LOLA) is a potential candidate to alleviate metabolic symptoms in ME/CFS and Long COVID for future clinical trials. Full article

Postbiotics, defined as a preparation of inanimate microorganisms and/or their components, including metabolic byproducts, have gained recognition as promising modulators of gut health and disease, offering advantages over probiotics in terms of safety, stability, and formulation. This systematic review investigates the therapeutic potential of postbiotics derived from functional foods in the context of colorectal cancer (CRC), a leading cause of cancer-related mortality worldwide. Despite encouraging preclinical findings, translation into clinical practice remains limited due to a paucity of robust human trials, revealing a significant gap and the need for further translational research. Key bioactive categories of postbiotics are described, alongside their anti-inflammatory, immunomodulatory, and chemopreventive mechanisms. Through comprehensive literature mapping, this review uniquely categorizes research according to the experimental models employed, i.e., in vitro, in silico, in vivo, and ex vivo, and advanced models such as organoids and organ-on-chip platforms. The latter offers greater physiological relevance by closely mimicking human tissue architecture and microenvironment. These models help demonstrate how postbiotics may influence tumorigenesis through mechanisms involving inflammation, apoptosis, epigenetic regulation, and the maintenance of gut barrier integrity. Finally, the review summarizes recent innovations in their delivery strategies and calls for comprehensive mechanistic studies and high-quality clinical trials to validate postbiotics as safe and effective adjuncts in CRC prevention, therapy, and management. Full article

Background: Fatigue failure of artificial leaflets significantly limits the durability of prosthetic valves. However, the costs and complexities associated with in vitro testing and conventional clinical trials to investigate the fatigue life of leaflets are progressively escalating. In silico trials offer an alternative solution and validation pathway. This study presents in silico trials of prosthetic valves, along with methodologies incorporating nonlinear behaviors to evaluate the fatigue life of artificial leaflets. Methods: Three virtual patient models were established based on in vitro test and clinical trial data, and virtual surgeries and physiological homeostasis maintenance simulations were performed. These simulations modeled the hemodynamics of three virtual patients following transcatheter valve therapy to predict the service life and crack propagation of leaflets based on the fatigue damage assessment. Results and Conclusions: Compared to traditional trials, in silico trials enable a broader and more rapid investigation into factors related to leaflet damage. The fatigue life of the leaflets in two virtual patients with good implantation morphology exceeded 400 million cycles, meeting the requirements, while the fatigue life of a virtual patient with a shape fold in the leaflet was only 440,000 cycles. The fatigue life of the leaflets varied considerably with different implant morphologies. Postoperative balloon dilation positively enhanced fatigue life. Importantly, in silico trials yielded insights that are difficult or impossible to uncover through conventional experiments, such as the increased susceptibility of leaflets to fatigue damage under compressive loading. Full article

Chemotherapy resistance, particularly multidrug resistance (MDR), remains a significant barrier to effective cancer treatment, leading to high mortality rates. The development of novel therapeutic strategies targeting key molecular mechanisms to counteract drug resistance is thus an urgent clinical need. In this study, we evaluated the potential of the small molecule SCO-101 to restore chemotherapy sensitivity in drug-resistant cancer cells. Using in silico and in vitro models such as molecular docking, cell viability, colony formation, dye efflux, transporter assays and chemotherapy retention, we assessed the impact of SCO-101 on drug retention and response in several drug-resistant cancer cells. SCO-101 was found to inhibit the activity of breast cancer resistance protein (BCRP/ABCG2) and UDP Glucuronosyltransferase Family 1 Member A1 (UGT1A1), two key proteins involved in drug resistance by cellular drug excretion and drug metabolism. Our results demonstrate that inhibition of these proteins by SCO-101 leads to increased intracellular drug accumulation, enhancing the cytotoxic effects of chemotherapy agents. Additionally, we identified a strong correlation between high ABCG2 expression and MDR in non-drug-resistant models, where cells exhibiting elevated ABCG2 levels displayed chemotherapy resistance, which was effectively reversed by SCO-101 co-treatment. These findings highlight the therapeutic potential of SCO-101 in overcoming MDR by inhibiting drug efflux mechanisms and metabolism, thereby enhancing chemotherapy efficacy. SCO-101 is currently undergoing clinical trials as an orally administered drug and is considered a promising strategy for improving cancer treatment outcomes in patients with drug-resistant tumors. Full article

Mycobacterium tuberculosis (Mtb) vaccines are designed to prevent infection, prevent reactivation of latent infection, and/or provide adjuvant therapy to standard TB treatment for active Mtb. Emerging vaccine technologies include reverse vaccinology, DNA and RNA vaccines, subunit vaccines, and multi-epitope vaccines. Currently, many different types of vaccine candidates are in clinical trials, though, to date, BCG remains the only approved Mtb vaccine. Mtb has a complex genome with numerous antigens, but not all are equally effective in eliciting immunity, so a critical challenge is the selection of antigens and epitopes that are most likely to induce a long-term, broad-spectrum protective immune response. Multi-epitope vaccines (MEVs) represent a new event horizon in vaccine development. Bioinformatic computer modeling is being used to maximize efficacy and minimalize adverse effects. Although no multi-epitope vaccines have proceeded to in vivo clinical trials, three candidate MEVs have made it through in silico tests. Multi-epitope vaccine candidate PP13138R, containing 13 HTL epitopes, 13 CTL epitopes, and 8 B cell epitopes in addition to both TLR2 and TLR4 agonists, aims to elicit a broad immune response that could address both active and latent Mtb infection. Similarly, immunoinformatic data were used to design and validate another MEV candidate based on the biomarker PE_PGRS17 with four B cell, nine HTL, and six CTL linked epitopes, with a griselimycin sequence as the adjuvant. A third novel prophylactic and therapeutic MEV was developed that targets Ag85A, AG85B, ESAT-6, and CFP-10 proteins with 12 CTL, 25 HTL, and 21 LBL epitopes with a CpG adjuvant. Full article

Background: Monoclonal antibodies against the sodium-dependent phosphate transporter NaPi2b (SLC34A2) represent a promising approach in the treatment of ovarian and lung cancer. Of particular interest is the potential cancer-specific MX35 epitope of NaPi2b, as it serves as a target for monoclonal antibodies studied at various stages of preclinical and clinical trials. However, variations in the NaPi2b protein structure may limit the efficacy of therapeutic antibodies by affecting the accessibility of the MX35 epitope. Methods: An in silico analysis was performed using data from 101,562 tumor samples. Genomic DNA sequencing was conducted on blood samples from patients with ovarian carcinoma, breast cancer, and renal carcinoma to access the frequency of germline mutations in the SLC34A2 gene region encoding the MX35 epitope. To assess the impact of the selected mutation, we generated a model cell line through site-directed mutagenesis carrying the mutant NaPi2b variant. Results: Using in silico analysis, we identified 17 unique variants in the SLC34A2 gene leading to amino acid substitutions within the MX35 epitope of the NaPi2b. Among these, the most prevalent mutation, c.989C>T, resulting in p.T330M substitution, was detected in 5 out of 64 patients through genomic DNA sequencing. Using site-directed mutagenesis, we created the OVCAR-8/NaPi2b^p.T330M model cell line. L3 (28/1) monoclonal antibodies specific to the MX35 epitope failed to recognize the mutant NaPi2b^p.T330M variant compared to the wild-type of the NaPi2b in both Western blot and confocal microscopy experiments. Conclusions: The obtained data may serve as a basis for predicting the efficacy of monoclonal antibody-based targeted therapy binding to the MX35 epitope of NaPi2b in the treatment of oncological diseases. Full article

Double-stranded RNA (dsRNA) biopesticides offer the potential for highly targeted pest control with minimal off-target impacts. Varroa mites (Varroa destructor) are an important pest of honey bees (Apis mellifera) that are primarily managed by synthetic pesticides. A next-generation treatment using a varroa-active dsRNA, vadescana, has been developed to target calmodulin expression in varroa. We evaluated the potential exposure of non-target species to vadescana. First, we assessed potential gene silencing effects on 39 arthropods with known genomes via bioinformatics. Three mite species, monarch butterflies (Danaus plexippus), fruit flies (Drosophila melanogaster), and European earwigs (Forficula auricularia) showed theoretical potential for off-target effects. These in silico results could be used to help inform risk assessments. Second, we conducted vadescana feeding trials on the greater wax moth (Galleria mellonella), a common beehive associate. There were no significant differences in wax moth reproduction, survival, or adult F2 wing length between vadescana-fed and control groups. Male F2 body weight was slightly but significantly lower in wax moths exposed to the highest vadescana dose, with no such effect observed in female moths. Calmodulin gene expression was unaffected in wax moths. Our hazard assessment of vadescana’s lethal and sublethal effects on wax moths indicates minimal impact following continuous dietary exposure far greater than any exposure that might be expected in the field, in line with the bioinformatics findings. This biopesticide appears highly varroa-specific and likely has fewer non-target effects than many current varroa control methods. Full article

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a positive-sense RNA virus with an unusually large genome of approximately 30 kb. It is highly transmissible and exhibits broad tissue tropism. The third most pathogenic of all known coronaviruses, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is responsible for the clinical manifestation known as coronavirus disease 2019 (COVID-19), which has resulted in the loss of millions of lives on a global scale. This pandemic has prompted significant efforts to develop therapeutic strategies that target the virus and/or human proteins to control viral infection. These efforts include the testing of hundreds of potential drugs and thousands of patients in clinical trials. Although the global pandemic caused by the SARS-CoV-2 virus is approaching its end, the emergence of new variants and drug-resistant mutants highlights the need for additional oral antivirals. The appearance of variants and the declining effectiveness of booster shots are resulting in breakthrough infections, which continue to impose a significant burden on healthcare systems. Computer-aided drug design (CADD) has been widely utilized for predicting drug–target interactions and evaluating drug safety; it is regarded as an effective tool for identifying promising drug candidates to combat SARS-CoV-2. The CADD approach aids in the discovery of new drugs or the repurposing of United States Food and Drug Administration (FDA)-approved drugs, whose safety and side effects are already well established, thus making the process more viable. This review summarizes potential therapeutic agents that target SARS-CoV-2 or host proteins critical for viral pathogenesis, as identified using CADD approaches. Additionally, this study provides insights into the common in silico methods used in CADD and their current applications in the SARS-CoV-2 drug discovery process. Full article

The development of new drugs is a lengthy and complex process regarding its conception and ideation, passing through in silico studies, synthesis, in vivo studies, clinical trials, approval, and commercialization, with an exceptionally low success rate. The lack of efficacy, safety, and suboptimal pharmacokinetic parameters are commonly identified as significant challenges in the discovery of new drugs. To help address these challenges, various approaches have been explored in medicinal chemistry, including the use of prodrug strategies. As a well-established approach, prodrug design remains the best option for improving physicochemical properties, reducing toxicity, and increasing selectivity, all while minimizing costs and saving on biological studies. This review article aims to analyze the current advances using the prodrug approach that has allowed the advance of drug candidates to clinical trials in the last 10 years. The approaches presented here aim to inspire further molecular optimization processes and highlight the potential of this strategy to facilitate the advancement of new compounds to clinical study phases. Full article

Human immunodeficiency virus (HIV) and hepatitis B virus (HBV) continue to be global public health issues. Globally, about 39.9 million persons live with HIV in 2023, according to the Joint United Nations Programme on HIV/AIDS (UNAIDS) 2024 Fact Sheet. Consequently, the World Health Organisation (WHO) reported that about 1.5 million new cases of HBV occur, with approximately 820 thousand mortalities yearly. Conversely, the lower percentage of HBV (30%) cases that receive a diagnosis is a setback in achieving the WHO 2030 target for zero HBV globally. This has necessitated a public health concern to repurpose antiretroviral (ARV) drugs for the treatment of HBV diseases. This review provides an introductory background, including the pros and cons of repurposing antiretrovirals (ARVs) for HBV treatment. We examine the similarities in replication mechanisms between HIV and HBV. We further investigate some clinical studies and trials of co-infected and mono-infected patients with HIV–HBV. The topical keywords including repurposing ARV drugs, repurposing antiretroviral therapy, Hepatitis B drugs, HBV therapy, title, and abstracts are searched in PubMed, Web of Science, and Google Scholar. The advanced search includes the search period 2014–2024, full text, clinical trials, randomized control trials, and review. The search results filtered from 361 to 51 relevant articles. The investigations revealed that HIV and HBV replicate via a common route known as ‘reverse transcription’. Clinical trial results indicate that an early initiation of ARVs, particularly with tenofovir disoproxil fumarate (TDF) as part of a regimen, significantly reduced the HBV viral load in co-infected patients. In mono-infected HBV, timely and correct precise medication is essential for HBV viral load reduction. Therefore, genetic profiling is pivotal for successful ARV drug repurposing in HBV treatment. Pharmacogenetics enables the prediction of the right dosages, specific individual responses, and reactions. This study uniquely explores the intersection of pharmacogenetics and drug repurposing for optimized HBV therapy. Additional in vivo, clinical trials, and in silico research are important for validation of the potency, optimum dosage, and safety of repurposed antiretrovirals in HBV therapy. Furthermore, a prioritization of research collaborations comprising of regulators and funders to foster clinically adopting and incorporating repurposed ARVs for HBV therapy is recommended. Full article