Search Results (363)

The protein p53, often referred to as the “guardian of the genome,” is essential for preserving cellular balance and preventing cancerous transformations. As one of the most commonly altered genes in human cancers, its impaired function is associated with tumor initiation, development, and resistance to treatment. Exploring the diverse roles of p53, which include regulating the cell cycle, repairing DNA, inducing apoptosis, reprogramming metabolism, and modulating immunity, provides valuable insights into cancer mechanisms and potential treatments. This review integrates recent findings on p53′s dual nature, functioning as both a tumor suppressor and an oncogenic promoter, depending on the context. Wild-type p53 suppresses tumors by inducing cell cycle arrest or apoptosis in response to genotoxic stress, while mutated variants often lose these functions or gain novel pro-oncogenic activities. Emerging evidence highlights p53′s involvement in non-canonical pathways, such as regulating tumor microenvironment interactions, metabolic flexibility, and immune evasion mechanisms. For instance, p53 modulates immune checkpoint expression and influences the efficacy of immunotherapies, including PD-1/PD-L1 blockade. Furthermore, advancements in precision diagnostics, such as liquid biopsy-based detection of p53 mutations and AI-driven bioinformatics tools, enable early cancer identification and stratification of patients likely to benefit from targeted therapies. Therapeutic strategies targeting p53 pathways are rapidly evolving. Small molecules restoring wild-type p53 activity or disrupting mutant p53 interactions, such as APR-246 and MDM2 inhibitors, show promise in clinical trials. Combination approaches integrating gene editing with synthetic lethal strategies aim to exploit p53-dependent vulnerabilities. Additionally, leveraging p53′s immunomodulatory effects through vaccine development or adjuvants may enhance immunotherapy responses. In conclusion, deciphering p53′s complex biology underscores its unparalleled potential as a biomarker and therapeutic target. Integrating multi-omics analyses, functional genomic screens, and real-world clinical data will accelerate the translation of p53-focused research into precision oncology breakthroughs, ultimately improving patient outcomes. Full article

Wax deposition, driven by the crystallization of long-chain n-alkanes, poses severe challenges across industries such as petroleum, oil and natural gas, food processing, and chemical manufacturing. This phenomenon compromises flow efficiency, increases energy demands, and necessitates costly maintenance interventions. Wax inhibitors, designed to mitigate these issues, operate by altering wax crystallization, aggregation, and adhesion over the pipelines. Classic wax inhibitors, comprising synthetic polymers and natural compounds, have been widely utilized due to their established efficiency and scalability. However, synthetic inhibitors face environmental concerns, while natural inhibitors exhibit reduced performance under extreme conditions. The advent of nano-based wax inhibitors has revolutionized wax management strategies. These advanced materials, including nanoparticles, nanoemulsions, and nanocomposites, leverage their high surface area and tunable interfacial properties to enhance efficiency, particularly in harsh environments. While offering superior performance, nano-based inhibitors are constrained by high production costs, scalability challenges, and potential environmental risks. In parallel, the development of “green” wax inhibitors derived from renewable resources such as vegetable oils addresses sustainability demands. These eco-friendly formulations introduce functionalities that reinforce inhibitory interactions with wax crystals, enabling effective deposition control while reducing reliance on synthetic components. This review provides a comprehensive analysis of the mechanisms, applications, and comparative performance of classic and nano-based wax inhibitors. It highlights the growing integration of sustainable and hybrid approaches that combine the reliability of classic inhibitors with the advanced capabilities of nano-based systems. Future directions emphasize the need for cost-effective, eco-friendly solutions through innovations in material science, computational modeling, and biotechnology. Full article

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

The distinctive nature of ferroptosis is that it is induced chemically and signifies a regulated cell death dependent on iron-dependent lipid peroxidation. The mechanism of ferroptosis involves oxidative damage to the membrane lipids. It differs from apoptosis and necroptosis, triggering metabolic changes in the iron-lipid homeostasis and antioxidant defense, such as glutathione (GSH) and glutathione peroxidase 4 (GPX4). Herein, the molecular mechanisms of ferroptosis and its role in the tumorigenesis process and infection-related diseases are presented. It also discusses metabolic reprogramming as a factor that modifies the levels of cell-sensitizing polyunsaturated fatty acids (PUFAs), iron dysregulation, and oxidative stress in aggressive cancers and inflammatory diseases such as sepsis, tuberculosis, and COVID-19. Particular attention is given to chemical modulators of ferroptosis, including synthetic inducers and inhibitors, as well as bioactive natural compounds. Our focus is on the significance of analytical tools, such as lipidomics and metabolomics, in understanding the phenomenon of ferroptosis. Finally, we explore novel therapeutic approaches targeting ferroptosis in cancer and infectious diseases, while navigating both the opportunities and challenges in drug development. The review then draws on chemical biology and disease pathology to propose promising areas of study for ferroptosis-related therapies. Full article

L-asparaginase (L-ASNase) remains a vital chemotherapeutic agent for acute lymphoblastic leukemia (ALL), primarily due to its mechanism of depleting circulating asparagine essential for leukemic cell proliferation. However, existing ASNases (including pegylated ones) face limitations including immunogenicity, rapid clearance, and off-target toxicities. Earlier, we have shown that the conjugation of L-ASNase with the polyamines and their copolymers results in significant enhancement of the antiproliferative activity due to accumulation in tumor cells. We suggested that this effect is probably mediated by polyamine transport system (PTS) receptors that are overexpressed in ALL cells. Here, we investigated the effect of competitive inhibitors of PTS receptors to the L-ASNase interaction with cancer cells (L5178Y, K562 and A549). L-ASNase from Rhodospirillum rubrum (RrA), Erwinia carotovora (EwA), and Escherichia coli (EcA) were conjugated with natural polyamines (spermine—spm, spermidine—spd, putrescine—put) and a synthetic branched polymer, polyethyleneimine 2 kDa (PEI2 ), using carbodiimide chemistry. Polyamine conjugation with L-ASNase significantly increased enzyme binding and cellular uptake, as quantified by fluorimetry and confocal microscopy. This increased cellular uptake translated into increased cytotoxicity of L-ASNase conjugates. The presence of competitive ligands to PTS receptors decreased the uptake of polyamine-conjugated enzymes-fatty acid derivatives of polyamines produced the strongest suppression. Simultaneously with this suppression, in some cases, competitive ligands to PTS significantly promoted the uptake of the native unconjugated enzymes, “equalizing” the cellular access for native vs conjugated ASNase. The screening for competing inhibitors of PTS receptor-mediated endocytosis revealed spermine and caproate/lipoate derivatives as the most potent inhibitors or antagonists, significantly reducing the cytostatic efficacy of polyamine-conjugated ASNases. The results obtained emphasize the complex, cell-type-dependent and inhibitor-specific nature of these interactions, which highlights the profound involvement of PTS in L-ASNase internalization and cytotoxic activity. These findings support the viability of polyamine conjugation as a strategy to enhance L-ASNase delivery and therapeutic efficacy by targeting the PTS. Full article

Microbial extracellular polymeric substances (EPSs) are emerging as sustainable alternatives to conventional corrosion inhibitors due to their eco-friendly nature, biodegradability, and functional versatility. Secreted by diverse microorganisms including bacteria, fungi, archaea, and algae, EPSs are composed mainly of polysaccharides, proteins, lipids, and nucleic acids. These biopolymers, chiefly polysaccharides and proteins, are accountable for surface corrosion prevention through biofilm formation, allowing microbial survival and promoting their environmental adaptation. Usually, EPS-mediated corrosion inhibitions can take place via different mechanisms: protective film formation, metal ions chelation, electrochemical property alteration, and synergy with inorganic inhibitors. Even though efficacious EPS corrosion prevention has been demonstrated in several former studies, the application of such microbial inhibitors remains, so far, a controversial topic due to the variability in their composition and compatibility toward diverse metal surfaces. Thus, this review outlines the microbial origins, biochemical properties, and inhibition mechanisms of EPSs, emphasizing their advantages and challenges in industrial applications. Advances in synthetic biology, nanotechnology, and machine learning are also highlighted and could provide new opportunities to enhance EPS production and functionality. Therefore, the adoption of EPS-based corrosion inhibitors represents a promising strategy for environmentally sustainable corrosion control. Full article

Background: Cyclin-dependent kinases 4 and 6 (CDK4/6) are pivotal regulators of the cell cycle, whose dysregulation is closely linked to cancer progression. While synthetic CDK4/6 inhibitors such as Palbociclib and Ribociclib are clinically effective, their use is limited by significant adverse effects. Methods: In this study, the aqueous root extract of Thottea siliquosa, a traditionally used medicinal plant, was evaluated for its potential as a natural CDK4/6 inhibitor. Phytochemical profiling using GC-MS identified bioactive compounds, which were subsequently subjected to molecular docking, ADME prediction, and in vitro cell-based assays using HCT116 and L929 cells. Results: The docking results revealed that Isocorydine (−7.4 kcal/mol for CDK4 and −7.2 kcal/mol for CDK6) and Thunbergol (−6.5 kcal/mol for CDK4 and −7.0 kcal/mol for CDK6) exhibited promising binding affinities comparable to standard CDK inhibitors, Palbociclib (−7.2, −8.3 kcal/mol) and Ribociclib (−7.1, −8.1 kcal/mol). Among the other tested natural compounds, Squalene (−7.1 kcal/mol for CDK4) and 2-palmitoylglycerol (−5.2 kcal/mol for CDK4, −4.9 kcal/mol for CDK6) demonstrated moderate binding affinities. ADME analysis confirmed favorable drug-like properties with minimal toxicity alerts. The extract displayed dose-dependent cytotoxicity with an IC₅₀ of 140 μg/mL and reduced cell migration in HCT116 cells, indicating potential anti-proliferative effects. These findings suggest that T. siliquosa root extract, through synergistic phytochemical interactions, holds promise as a multi-targeted, plant-based therapeutic candidate for CDK4/6-associated cancers, warranting further in vitro and in vivo validation. Full article

The growth of tumor cells is accompanied by an increased rate of endoplasmic reticulum stress (ERS), the accumulation of misfolded proteins, and the activation of a network of adaptive signaling pathways known as the unfolded protein response (UPR). Although the UPR is an adaptive reaction aiming to restore ER proteostasis, prolonged and severe ERS leads to cell death. Taking into account that the components of the ERS/UPR machinery in cancers of different types can be overexpressed or downregulated, both the induction of excessive ERS and suppression of UPR have been proposed as therapeutic strategies to sensitize cells to conventional chemotherapy. This narrative review presents a several examples of using natural and synthetic compounds that can either induce persistent ERS by selectively blocking ER Ca²⁺ pumps (SERCA) to disrupt ER Ca²⁺ homeostasis, or altering the activity of UPR chaperones and sensors (GRP78, PERK, IRE1α, and ATF6) to impair protein degradation signaling. The molecular alterations induced by miscellaneous inhibitors of ERS/UPR effectors are described as well. These agents showed promising therapeutic effects as a part of combination therapy in preclinical experimental settings; however, the number of clinical trials is still limited, while their results are inconsistent. Multiple side effects, high toxicity to normal cells, or poor bioavailability also hampers their clinical application. Since the pharmacological modulation of ERS/UPR is a valuable approach to sensitize cancer cells to standard chemotherapy, the search for more selective agents with better stability and low toxicity, as well as the development of more efficient delivery systems that can increase their therapeutic specificity, are highly required goals for future studies. Full article

This study explores the identification, characterization, and biological evaluation of angiotensin I-converting enzyme (ACE)-inhibitory peptides derived from enzymatic hydrolysates of crucian carp swim bladders. Following sequential purification by size-exclusion and reversed-phase chromatography, two bioactive peptides—Hyp-Gly-Ala-Arg (Hyp-GAR) and Gly-Ala-Hyp-Gly-Ala-Arg (GA-Hyp-GAR)—were identified using ultra-high-performance liquid chromatography coupled with linear ion trap–Orbitrap tandem mass spectrometry. The synthetic peptides demonstrated potent ACE-inhibitory activity in vitro, with IC₅₀ values of 12.2 μM (Hyp-GAR) and 4.00 μM (GA-Hyp-GAR). Molecular docking and enzyme kinetics confirmed competitive inhibition through key interactions with ACE active site residues and zinc coordination. In vivo antihypertensive activity was evaluated in spontaneously hypertensive rats, revealing that GA-Hyp-GAR significantly reduced systolic blood pressure in a dose-dependent manner. At a dose of 36 mg/kg, GA-Hyp-GAR reduced systolic blood pressure by 60 mmHg—an effect comparable in magnitude and timing to that of captopril. Mechanistically, GA-Hyp-GAR modulated levels of angiotensin II, bradykinin, endothelial nitric oxide synthase, and nitric oxide. A 90-day subchronic oral toxicity study in mice indicated no significant hematological, biochemical, or histopathological alterations, supporting the peptide’s safety profile. These findings suggest that GA-Hyp-GAR is a promising natural ACE inhibitor with potential application in functional foods or as a nutraceutical for hypertension management. Full article

Glioblastoma (GBM) is the most aggressive primary brain tumor in adults, characterized by a dismal prognosis and limited therapeutic options. Its highly invasive nature and pronounced intratumoral heterogeneity underscores the urgent need for innovative and targeted therapeutic strategies. One promising approach is synthetic lethality, which exploits cancer-specific genetic vulnerabilities to selectively eliminate tumor cells. A well-characterized example involves the deletion of methylthioadenosine phosphorylase (MTAP), commonly observed in GBM and other malignancies. This review focuses on synthetic lethality targeting protein arginine methyltransferase 5 (PRMT5) in MTAP-deleted GBM. Loss of MTAP leads to the accumulation of methylthioadenosine (MTA), a metabolite that partially inhibits PRMT5, thereby creating a selective vulnerability to PRMT5 inhibition which is used to inhibit the residual function of PRMT5. We critically evaluate preclinical and clinical data on both first- and second-generation PRMT5 inhibitors, with particular emphasis on MTA-cooperative compounds that selectively exploit MTAP deficiency. Despite promising anti-tumor activity in vitro, the clinical efficacy of PRMT5 inhibitors is often limited by the tumor microenvironment, particularly the impact of non-malignant cells that attenuate drug activity. Finally, we explore rational combination strategies that integrate PRMT5 inhibition with existing therapies to enhance clinical outcomes in GBM. Full article

The present study was designed to evaluate the effect of supplementation with papaya seeds (PSM), fish testes powder (FTP), and 17α-methyltestosterone (MT) on the reproductive parameters, growth performance, digestive enzymes, and histology of Cyprinus carpio. In the present study, fries (2–3 days old) were acclimatized for 2 days and then equally distributed into one control and six treatment groups and fed with one control and six experimental diets for 30 days, followed by a control diet for 60 days in each group with triplicates. These diets included control (T0), different levels of 17α-methyltestosterone (T1: 60 mg/kg; T2: 70 mg/kg), papaya seed powder (T3: 6 g/kg; T4: 7 g/kg), and fish (tilapia) testes powder (T5: 70%; T6: 80%). The treatment groups receiving papaya seed meal (PSM) showed significant improvements in growth performance, with a significant increase in final body weight. The best zootechnical performances (PER, SGR, and CF) were observed in fish fed with papaya seed compared to the control group. Reproductive analysis showed significant variations between treatment groups, with a large number of female C. carpio observed in the control group. Fish treated with T4 increased the sex percentage in favor of male fish by achieving 90% male phenotype followed by T6 with 88% male. Diets based on papaya seeds and fish testes powder significantly reduced the reproductive performance by reducing GSI, which affected the gonadal histology. The results revealed a visible effect of 17 α-MT and PSM feeding on the gonad structure. There were significant elevations in protease enzyme activity in T6 compared to the control (p < 0.05), and the highest amylase activity was observed in T3. Natural resources are not only more cost-effective but also environmentally friendly and readily available; they are a superior choice over synthetic alternatives for controlling the prolific breeding of C. carpio. Full article

Cancer remains one of the leading causes of morbidity and mortality worldwide, driving the search for innovative and selective therapeutic agents. Topoisomerases I and II are essential enzymes involved in key cellular processes such as DNA replication and transcription. They have emerged as valuable anticancer targets; thus, many inhibitors of topoisomerases have been designed and some of them are considered to be major anticancer agents such as anthracyclines, etoposide or irinotecan. A great deal of attention is currently being paid to chalcones, a class of naturally occurring compounds, since they exhibit a wide range of biological activities, including anticancer properties. These compounds are characterized by an open-chain structure and an α,β-unsaturated carbonyl moiety that enables interaction with cellular targets. Recent studies aiming to design anti-topoisomerase agents have identified both natural and synthetic chalcones, including chalcone-based hybrids. This review highlights the structural diversity of chalcones as topoisomerase inhibitors and particular attention is given to structure–activity relationship studies and molecular hybridization strategies aimed at optimizing the pharmacological profile of chalcones. These findings underline the potential of chalcones as promising scaffolds in the design of next-generation anticancer agents. Full article

Dipeptidyl peptidase-4 (DPP-4) inhibitors play a critical role in the management of type 2 diabetes; however, some synthetic drugs may cause adverse effects. Natural peptides derived from rice offer a promising alternative due to their favorable biocompatibility and development potential. In this study, an AI-assisted virtual screening pipeline integrating machine learning, molecular docking, and molecular dynamics (MD) simulations was established to identify and evaluate rice-derived DPP-4 inhibitory peptides. A random forest classification model achieved 85.37% accuracy in predicting inhibitory activity. Peptides generated by simulated enzymatic hydrolysis were screened based on machine learning and docking scores, and four proline-rich peptides (PPPPPPPPA, PPPSPPPV, PPPPPY, and CPPPPAAY) were selected for MD analysis. The simulation results showed that PPPSPPPV formed a stable complex with the DPP-4 catalytic triad (Ser592–Asp670–His702) through electrostatic and hydrophobic interactions, with low structural fluctuation (RMSF < 1.75 Å). In vitro assays revealed that PPPPPY exhibited the strongest DPP-4 inhibitory activity (IC₅₀ = 153.2 ± 5.7 μM), followed by PPPPPPPPA (177.0 ± 6.0 μM) and PPPSPPPV (216.3 ± 4.5 μM). This study presents an efficient approach combining virtual screening and experimental validation, offering a structural and mechanistic foundation for the development of natural DPP-4 inhibitory peptides as candidates for functional foods or adjunct diabetes therapies. Full article

Endometriosis is a chronic gynecological disorder characterized by the presence of endometrial-like tissue outside the uterus, leading to inflammation, pain, and infertility. Emerging evidence indicates that endometriotic lesions exhibit cancer-like properties, including metabolic reprogramming marked by increased glucose uptake, enhanced Warburg’s effect, and altered mitochondrial function. These metabolic adaptations support cell survival under hypoxic conditions and contribute to immune evasion and sustained proliferation. This review summarizes current findings on the molecular mechanisms driving metabolic reprogramming in endometriosis, including the roles of mitochondrial dysfunction, hypoxia-inducible factor (HIF) signaling, the PI3K/AKT/mTOR pathway, inflammatory cytokines, and genetic and epigenetic regulators. In addition, we discuss therapeutic strategies targeting glycolytic pathways using both synthetic inhibitors and natural compounds, which represent promising non-hormonal options. Finally, we highlight the need for further preclinical and clinical studies to validate metabolic interventions and improve outcomes for patients with endometriosis. Full article

Acetazolamide (AZA) is a validated carbonic anhydrase inhibitor (CAI) that has the potential for use in various therapeutic applications. Herein, we report a novel AZA-loaded biodegradable nanodelivery system that was proven to enhance the antibacterial efficacy of the drug against Gram-negative bacteria, such as Escherichia coli. Carbonic anhydrases (CA, EC 4.2.1.1) in E. coli play a crucial role in bacterial metabolism and CO₂/HCO₃⁻ balance; therefore, they represent a suitable target for antimicrobial strategies. The nanoparticles were obtained using a green synthetic protocol that allowed conjugation of a natural fatty acid to hyaluronic acid (HA) under solvent-free conditions. Full characterization of the micellar aggregates was performed (diameter of the micelles, zeta potential, and drug release study). In vitro studies demonstrated that AZA loaded in HA-based nanoparticles significantly inhibited E. coli growth at concentrations as low as 0.5 µg/mL, whereas higher concentrations of free AZA were required, as previously reported. Additionally, encapsulated AZA disrupted glucose consumption in E. coli, indicating its profound impact on bacterial metabolism. These findings suggest that the HA–palmitate nanoparticle not only enhances the delivery and efficacy of AZA but also offers a strategy to affect bacterial metabolism. Full article