The synthesis of psychopharmaceuticals in the twentieth century marked the beginning of modern psychopharmacology, replacing earlier first-line psychiatric management that relied on psychosurgery, physical restraint, or administering narcotics and sedatives, e.g., morphine and chloral, which suppressed psychotic outbreaks temporarily without addressing the origin. Chlorpromazine's effective management of psychosis in the early 1950s opened the door for non-surgical therapies, making psychopharmaceuticals the current first-line treatment. While modern psychopharmacology began in the 1950s, the history of psychopharmacology may extend back many years. The concept of treating patients by understanding the cause and healing the mind was also evident during the Islamic Golden Age (ninth to thirteenth century CE). One of the physicians in the field was Rhazes (865-925 CE), also known as Abu Bakr Muhammad ibn Zakariyya Al-Razi. Rhazes' contributions to both psychiatry and pharmacology make his work a subject for examining the roots of psychopharmacology. This study aims to explore Rhazes' pharmacological approaches for patients with mental illnesses, focusing on the conditions under which he prescribed herbs for neurological, psychological, and psychiatric issues. An analytical approach has been utilized to systematically extract data from Al-Hawi and Liber Almansoris concerning neurological, psychological, psychiatric, and behavioral conditions. For the next phase, another table was created to list each condition alongside its treatment and psychopharmacological classification based on the works of Rhazes. Based on the collected information from Rhazes' Al-Hawi and Liber Almansoris, each of the mentioned neurological, psychological, psychiatric, and behavioral conditions was categorized. Rhazes distinguished between different psychological conditions and avoided using a universal prescription. He also differentiated between conditions that necessitated pharmacological interventions and those that could be effectively addressed through lifestyle modifications, nutritional adjustments, or manual therapy (hands-on therapy techniques like massage for managing musculoskeletal problems). The current historical study indicates that the roots of psychopharmacology can be traced back to the ninth century, during which the physician Rhazes documented various psychological and psychiatric diseases in his works Al-Hawi and Liber Almansoris, along with their natural pharmacological treatments. This historical perspective can enhance our understanding of psychopharmacology and provide new insights for expanding the range of psychopharmacological agents. Clinical trial number: Not applicable.
Ulcerative colitis (UC) is a chronic, relapsing, immune-mediated inflammatory disease of the colonic mucosa that imposes a substantial and growing global health burden. The pathophysiological basis of UC encompasses a multifactorial interplay among genetic predisposition, dysregulated innate and adaptive immune responses, gut microbiome dysbiosis, epithelial barrier dysfunction, and environmental triggers. Despite considerable advances in therapeutic strategies over the past two decades ranging from aminosalicylates and corticosteroids to biologic agents targeting TNF-α, integrins, and the IL-12/23 axis, as well as small molecule modulators such as JAK inhibitors and sphingosine-1-phosphate receptor agonists-a substantial proportion of patients either fail to achieve remission or experience loss of response over time, underscoring the continued need for novel therapeutic approaches. This comprehensive review systematically addresses the definition, epidemiology, socioeconomic burden, and unmet clinical needs in UC. The molecular and cellular underpinnings of the disease are discussed in depth, including the roles of key signaling pathways, pattern recognition receptors, cytokine networks, and the gut-immune interface. Clinical features, diagnostic criteria, endoscopic and histological scoring systems, and validated disease activity indices are also described. Current pharmacological therapies are reviewed with regard to mechanisms of action, pivotal clinical trial data, and safety profiles. Emerging investigational strategies including precision biologic agents, next-generation small molecules, microbiome-based therapeutics, and cell and gene therapy approaches are evaluated within a translational framework. A curated synthesis of experimental models of UC induction in rodents is presented, followed by structured tabular summaries of selected naturally derived bioactive compounds and pharmacological drug candidates that have demonstrated protective efficacy in preclinical models of UC. Compounds were selected for tabular inclusion on the basis of three prespecified criteria: (i) availability of at least one peer-reviewed in vivo study conducted in a validated experimental colitis model (DSS, TNBS, and acetic acid); (ii) a clearly described and mechanistically plausible basis of action relevant to UC pathophysiology; and (iii) representation across the principal mechanistic clusters identified in this review. Application of these criteria to the studies included in the final review yielded 29 naturally derived bioactive compounds (Table 1) and 26 pharmacological drug candidates (Table 2) for structured synthesis.
Recurrent pregnancy loss (RPL) is a complex disorder fundamentally linked to immune dysregulation at the maternal-fetal interface. While endometrial immune profiling provides critical diagnostic insights for managing RPL, its clinical application is limited by the invasive nature of endometrial biopsies. This study aimed to identify non-invasive, serum-based immunological and metabolic markers that accurately reflect local endometrial immune profiles, facilitating a less-invasive risk assessment and patient categorization. The study enrolled 106 participants, including 81 women with RPL and 25 fertile controls. The specimens of endometrium by doing biopsy of IL-15/Fn-14, IL-18/TWEAK, and CD56 expression were analyzed to categorize patients as having balanced, highly dysregulated (over-activated) and lowly dysregulated immune profiles. For each patient, blood samples from the same time frame were processed for immune profile (Th1/Th2 ratio), non-specific immune cell populations (NK), a metabolic profile containing autoantibody levels, and a metabolic screening of adiponectin, prostaglandin E2 (PGE-2), insulin-like growth factor-1 (IGF-1), and total phospholipids. All control subjects exhibited a balanced endometrial immune profile. In contrast, approximately 71% of RPL patients demonstrated immune dysregulation, with 46.9% showing an over-activated profile and 24.7% a low-activated profile. Systemically, the high immune dysregulation group exhibited significantly elevated peripheral NK cell frequencies and Th1/Th2 ratios compared to the balanced group. Furthermore, this over-activated group demonstrated a substantially higher prevalence of serum autoantibodies. Metabolically, high immune dysregulation was associated with significantly decreased serum adiponectin and IGF-1 levels, alongside markedly elevated PGE-2 and total phospholipid concentrations. These findings suggest that systemic metabolic and immune biomarkers may potentially reflect local endometrial immune status in women with RPL. Although these serum markers demonstrate promise as minimally invasive tools for immune profiling, further large-scale validation and predictive studies are required before they can be introduced as reliable alternatives to endometrial biopsy in clinical practice.
Few conditions in reproductive medicine rival polycystic ovary syndrome (PCOS) in terms of clinical breadth and global impact. Affecting roughly 6-21% of women of childbearing age depending on which diagnostic criteria are applied PCOS sits at the intersection of endocrinology, metabolism, and gynecology, making it difficult to capture within any single disciplinary lens. Its hallmarks are well rehearsed: excess androgens, disrupted ovulation, and the characteristic follicular architecture seen on pelvic ultrasound. Yet what makes PCOS genuinely challenging is the degree to which these reproductive features overlap with far-reaching metabolic consequences, including insulin resistance, type 2 diabetes, lipid abnormalities, and a meaningfully elevated cardiovascular risk profile that persists well beyond the fertile years. Despite several decades of sustained investigation, the origins of PCOS remain imperfectly understood. Genetic susceptibility, epigenetic programming, environmental chemical exposures, and modern dietary habits all appear to play contributory roles, though no single culprit has emerged. The molecular picture is equally layered: aberrant insulin signaling feeds androgen overproduction, gonadotropin secretion goes out of balance, inflammatory cytokines accumulate, oxidative injury mounts, and more recently the gut microbial community has been implicated as an additional participant in this cascade. Diagnosis is further complicated by the phenotypic variability of the syndrome, with different criteria yielding meaningfully different patient populations. Treatment, in turn, requires individualization; lifestyle change, hormonal therapies, insulin sensitizers, and an expanding repertoire of repurposed drugs and plant-based agents each address different facets of a fundamentally heterogeneous disorder. This review provides a comprehensive and integrated account of PCOS across its full biological and clinical spectrum. It covers epidemiology, clinical presentation, risk factors, and current diagnostic frameworks. Pathophysiological mechanisms are examined in depth. A central and distinctive focus of this review is the experimental preclinical landscape. Established animal induction models, letrozole, dehydroepiandrosterone (DHEA), testosterone/dihydrotestosterone propionate, and high-fat diet protocols are critically evaluated for their translational relevance. Drawing on these models, we comprehensively catalogue protective agents across four systematic tables, encompassing both repurposed pharmaceuticals (metformin, GLP-1 receptor agonists, SGLT-2 inhibitors, statins, melatonin) and bioactive natural compounds (curcumin, berberine, quercetin, fisetin, myricetin, apigenin, and others), detailing their induction models, mechanistic pathways, and therapeutic outcomes. Together, this review aims to serve as a single, authoritative reference bridging basic science, translational pharmacology, and clinical practice in PCOS, while identifying the most promising avenues for future research and personalized therapeutic development.
Melanoma is a highly aggressive cancer with limited therapeutic options. In melanoma cell lines, β2AR activation leads to the suppression of pro-proliferatory MAPK/ERK signaling. This suggests that fenoterol, a potent β2AR agonist, can be useful in the treatment of melanoma. Here, we investigated the structure-activity relationship (SAR) of fenoterol derivatives for β2AR-depedent ERK suppression. We used the UACC-647 human-derived melanoma cell line to screen a panel of chiral compounds based on the fenoterol scaffold. The levels of phosphoactive ERK1/2 were quantified by immunoblotting. Anti-tumorigenic activity of the drugs was assessed using MTS assay and zebrafish xenograft model. (R,R') stereoisomers of fenoterol derivatives exhibited the highest suppression of ERK phosphorylation, followed by (R,S') and (S,R') isomers, with (S,S') isomers being the least active, mirroring trends observed in β2AR binding and cAMP accumulation. SAR analysis revealed that modifications to the α' alkyl chain and the 4'-hydroxy moieties significantly affected ERK-inhibitory activity of fenoterol derivatives. (R,R')-4'-hydroxy-1-naphthylfenoterol [(R,R')-HNF] was the most active inhibitor of ERK activation with an IC50 of 0.03 nM. However, it showed minimal anti-proliferative activity in the zebrafish xenograft model. In contrast, (R,R')-4'-methoxy-1-naphthylfenoterol [(R,R')-MNF], a weaker ERK inhibitor (IC50 = 0.17 nM), significantly reduced cell viability in vitro (IC50 = 14.07 µM) and tumor growth in vivo. SAR for fenoterol-mediated ERK inhibition in melanoma was defined, highlighting the importance of the (R,R') stereochemistry. Crucially, potent ERK inhibition does not directly predict anti-tumorigenic activity, as shown by (R,R')-HNF. The pronounced anti-proliferatory effect of (R,R')-MNF, despite weaker ERK inhibition, implies additional mechanisms beyond ERK modulation.
Intervertebral disc degeneration (IVDD) is a leading cause of chronic disabling musculoskeletal disorders, with its incidence rising annually among the aging global population. This degenerative process is strongly linked to persistent functional impairment and reduced quality of life in patients, while placing a growing socioeconomic burden on global healthcare systems. Previous studies have demonstrated that kaempferol exerts potent anti-inflammatory effects by modulating pro-inflammatory cytokine expression and attenuating extracellular matrix degradation in degenerated intervertebral discs. However, the precise molecular targets responsible for its therapeutic effects remain unclear. This study integrated network pharmacology, molecular docking, bulk and single-cell transcriptomics, and experimental validation to identify the therapeutic targets of kaempferol in IVDD. Potential targets of kaempferol were predicted using the TCMSP, SwissTargetPrediction, and PharmMapper databases. IVDD-related targets were retrieved from the GeneCards, OMIM, and MalaCards databases. A protein-protein interaction (PPI) network was constructed using STRING and Cytoscape, followed by GO and KEGG enrichment analyses. Hub genes were identified via topological analysis. Molecular docking was conducted using AutoDock Vina. The expression patterns of core targets were validated using two GEO bulk RNA-seq datasets (GSE70362 and GSE147383), one single-cell RNA-seq dataset (GSE251686), and qRT-PCR in IL-1β-induced nucleus pulposus cells. Twenty-one common targets between kaempferol and IVDD were identified. Topological analysis identified three core hub genes-STAT1, CASP1, and NOX4-all significantly upregulated in IVDD tissues. Molecular docking revealed strong binding affinities between kaempferol and these targets, with binding energies ranging from - 6.7 to - 7.9 kcal/mol. Single-cell transcriptomics further confirmed their high expression in nucleus pulposus cells. qRT-PCR analysis demonstrated that kaempferol significantly downregulated STAT1, CASP1, and NOX4 mRNA expression; restored extracellular matrix components (COL2 and ACAN); and suppressed matrix-degrading enzymes (MMP3 and MMP13) in IL-1β-stimulated nucleus pulposus cells. These findings suggest that kaempferol exerts protective effects against IVDD by regulating STAT1, CASP1, and NOX4. The multi-target effects of kaempferol in IVDD provide novel insights and highlight its potential as a therapeutic candidate for IVDD treatment.
The increasing use of oral anticancer drugs (OADs) in cancer therapy shifts greater responsibility towards patients, thereby also placing a higher informational burden on them. While intensified pharmacological/pharmaceutical care programs have proven beneficial for patients undergoing OAD treatment, their universal availability is currently limited. Given that patients frequently seek health information online, AI-powered chatbots may present a promising resource to address these increasing, yet often unmet information needs. This study aims to evaluate the readability, completeness of relevant information, and accuracy provided by AI-powered chatbots in response to patient questions about OAD treatment. Microsoft Bing's Copilot and Google's Gemini were queried in June 2024 on four patient questions regarding ten commonly prescribed and ten recently approved OADs in triplicate. Readability of chatbot answers was assessed using the Flesch reading-ease score (scale 0-100). Completeness of relevant information and accuracy were evaluated based on corresponding standardized written patient information materials. Both chatbots' answers demonstrated low readability according to the overall mean Flesch reading-ease scores of 38.8 (Copilot) and 50.9 (Gemini). Overall median completeness of relevant information of Copilot's and Gemini's answers was 61.1% (IQR, 35.3-78.7%) and 73.8% (IQR, 50.0-100.0%), respectively. Conversely, accuracy of chatbot answers was consistently high, with an overall median accuracy of 100.0% (IQR, 83.3-100.0%) for Copilot and 100.0% (IQR, 98.5-100.0%) for Gemini. AI-powered chatbots provide overall accurate information on OADs. However, their moderate completeness of relevant information and low readability may limit their current practical utility in meeting cancer patients' information need.
Hepatocellular carcinoma is one of the most aggressive and fatal malignancies worldwide, and the limited efficacy and severe toxic side effects of conventional chemotherapy emphasize the urgent need for safer and more effective therapeutic strategies. Nanotherapies have recently gained considerable attention due to their enhanced cellular uptake, improved bioavailability, and selective targeting of malignant cells. Although mineral trioxide aggregate nanoparticles (MTA-NPs) possess unique physicochemical and biological properties, their anticancer potential against hepatocellular carcinoma has not been fully explored. Accordingly, this study evaluated the cytotoxic activity and underlying molecular mechanisms of MTA-NPs in human hepatocellular carcinoma Hep-G2 cells, while simultaneously assessing their safety profile in normal human HFB4 melanocytes. The MTT assay results demonstrated that MTA-NPs exerted potent and selective cytotoxicity against Hep-G2 hepatocellular carcinoma cells, as demonstrated by a significant concentration-dependent decline in cancer cell viability and a markedly low IC50 value of 52.53 μg/ml. Conversely, exposure of normal HFB4 melanocytes to the same MTA-NPs concentrations resulted in only slight reductions in cell viability, primarily at the highest tested concentrations, with a substantially higher IC50 value of 239.30 μg/ml. These findings indicate the preferential anticancer activity of MTA-NPs toward Hep-G2 cells. Moreover, the calculated selectivity index of 4.55 further confirmed the selective cytotoxic potential of MTA-NPs against hepatocellular carcinoma Hep-G2 cells. Furthermore, exposure of Hep-G2 cancer cells to the IC50 concentration of MTA-NPs resulted in marked intracellular ROS overproduction, profound mitochondrial membrane depolarization, and severe genomic DNA damage, which collectively culminated in apoptotic cell death. qRT-PCR analysis further demonstrated significant downregulation of both the apoptotic p53 and mitochondrial ND3 gene expression levels, together with pronounced upregulation of the anti-apoptotic Bcl-2 gene. Collectively, these molecular alterations indicate the activation of a p53-independent mitochondria-mediated apoptotic pathway. In conclusion, MTA-NPs demonstrate potent and preferential anticancer activity against human hepatocellular carcinoma Hep-G2 cells by inducing ROS-mediated oxidative stress, genomic DNA instability, mitochondrial dysfunction, and p53-independent mitochondrial apoptosis. These findings highlight the promising therapeutic potential of MTA-NPs as a novel nanotherapeutic approach for hepatocellular carcinoma treatment. Nevertheless, additional in vitro and in vivo studies and comprehensive biosafety evaluations are still necessary prior to clinical application.
Diabetes combined with obesity is a global public health problem, with insulin resistance and chronic low-grade inflammation as key mechanisms. TCM regards spleen deficiency and phlegm-dampness as its core pathogenesis. This study constructs a research paradigm integrating clinical RCT data mining, UPLC-Q-TOF-MS/MS experimental component identification and network pharmacology-based prediction.This study predicted the multi-component, multi-target and multi-pathway mechanisms of core spleen-strengthening and damp-resolving prescriptions for this comorbidity. High-frequency herbs were screened via data mining from RCTs; chemical components were experimentally identified by UPLC-Q-TOF-MS/MS; intersecting targets and pathways were predicted by network pharmacology and preliminarily verified by semi-flexible molecular docking and molecular dynamics simulation. A 7-herb core prescription and 30 active components (nobiletin, puerarin, etc.) were determined. 350 common targets and hub genes (AKT1, MTOR, MMP9, PTGS2) were screened, with PI3K-Akt, lipid-atherosclerosis and diabetic AGE-RAGE as main pathways. Molecular docking showed strong component-target binding, which was further validated by dynamics simulation. The prescription improves diabetes with obesity through synergistic networks, regulating glycolipid metabolism and inflammation via the above pathways, supporting its modern clinical application.
Colorectal cancer (CRC) ranks as the second most lethal cancer worldwide. Probiotics have long been utilized to treat gastrointestinal diseases. Probiotics may play a role in the prevention and treatment of CRC. Additionally, the anti-inflammatory drugs sulfasalazine (SSA) and mesalazine (MESA) have a preventive role in CRC. This study investigates the modulatory antitumor effects of combining the probiotic Lacticaseibacillus rhamnosus GG (LGG) with SSA or MESA and the associated molecular mechanisms in CRC. In vitro studies of LGG-CFS, both alone and in combination with SSA or MESA, were assessed in HCT-116 and HT-29 CRC cells. In vivo, 61 albino rats aged 8 weeks were used and CRC was induced using 1,2-dimethylhydrazine. The 1,2-dimethylhydrazine-induced rats were divided into six groups, each of eight-in addition to the negative control group (received phosphate buffer saline only)-as follows: (I) positive control group (received DMH only), (II) SSA-treated group, (III) MESA-treated group, (IV) LGG-treated group, (V) SSA + LGG-treated group, and (VI) MESA + LGG-treated group. Rats received daily oral doses of SSA (250 mg/kg), MESA (62.5 mg/kg), LGG (1 × 109 CFU lactobacilli/1 ml), SSA + LGG, and MESA + LGG for 4 weeks. In both cell lines, the control group (positive control, human cancerous cells without further treatment) exhibited a reduction in annexin V, whereas the specified treatments elevated annexin V levels in both cells, thereby inducing apoptosis. In vivo, positive control rats exhibited upregulation of TLR2/AKT/NF-κB, IL-6, IFN-γ/STAT-3/PD-L1, COX-2/HIF-1α/VEGF signaling, and Ki-67, resulting in the induction of proliferation, hypoxia, and angiogenesis and inhibition of apoptosis. All treatment regimens downregulated TLR2/AKT/NF-κB, IL-6, IFN-γ/STAT-3/PD-L1, COX-2/HIF-1α/VEGF crosstalk's, and Ki-67, hence inhibiting proliferation, hypoxia, angiogenesis, and inducing apoptosis. Surprisingly, the combination of LGG with either SSA or MESA demonstrated the greatest efficacy through the aforementioned pathways with the superiority to the LGG + SSA combination in both experimental models. The current findings revealed novel insights into the potential antitumor effects of combining LGG with either SSA or MESA compared to each drug individually in CRC management. Further preclinical and clinical trials are warranted to evaluate this promising regimen compared to standard therapy of CRC.
Preeclampsia considered as multi-organ disorder involving systemic inflammation and endothelial dysfunction. Our work was designed to investigate the protective role of Naringenin (NGN) against Nω-nitro-l-arginine methyl ester (L-NAME)-induced placental damage and congenital abnormalities in a rat model of preeclampsia. Forty-five adult female albino rats (weighing 160-180 g) were randomly allocated into nine groups (n = 6 per group) and treated for a duration of 18 days. Group 1 served as the untreated control, while Group 2 received 10% DMSO as a vehicle control. Group 3 was administered L-NAME (50 mg/kg, i.p.) from 13 to 18th day of gestation to induce preeclampsia and served as the positive control. Groups 4-6 received NGN alone at doses of 10, 25, and 50 mg/kg, p.o, respectively from 10 to 18th day of gestation. Groups 7-9 received NGN at the same doses, followed one hour later by L-NAME from day 13 to 18. Fetal developmental parameters and skeletal abnormalities were evaluated on gestational day 20. Placental inflammatory markers (TNF-α, IL-1β, TGF-β), signaling proteins (AKT and mTOR), and nitric oxide metabolites (NOx) were quantified using ELISA. Endothelial nitric oxide synthase (eNOS) expression was assessed by immunohistochemistry. Pre-treatment of L-NAME-administered dams with NGN reduced fetal death and resorption rates, elevated NO levels and eNOS expression, and significantly suppressed placental inflammatory markers (TNF-α, IL-1β, TGF-β). These effects were linked to the activation of the AKT/mTOR signaling cascade. Histopathological analysis of the placenta, liver, and kidney confirmed the biochemical findings. Furthermore, NGN alleviated intrauterine growth restriction by increasing fetal weight and length, and provided protection against L-NAME-induced morphological and skeletal deformities. The protective effects of NGN against L-NAME-induced preeclampsia appear to be dose-dependent and primarily mediated through the modulation of inflammation and endothelial dysfunction, suggesting a promising approach for combating preeclampsia.
The relationship between oxidative stress and viral infections is well established, yet data on the redox consequences of COVID-19 beyond the acute phase remain sparse. We conducted a comprehensive assessment of oxidative stress biomarkers, antioxidant defences, and DNA damage in post-COVID patients, and examined whether COVID-19 infection disrupts the normal architecture of the antioxidant network. In this single-centre, cross-sectional, case-control study, 40 symptomatic post-COVID patients and 40 age- and sex-matched healthy controls were recruited from the Department of Respiratory Medicine, King George's Medical University, Lucknow, India. Blood levels of lipid peroxidation (LPO), total antioxidant activity (TAA), superoxide dismutase (SOD), and glutathione reductase (GR) were measured. DNA damage was quantified using the alkaline comet assay. Data were analysed using Mann-Whitney U tests and Spearman rank correlations. Post-COVID patients showed profound antioxidant depletion: TAA was reduced by 60.8% (median 51.7 vs 224.3 mM; p < 0.001; Cohen's d = 1.57), SOD by 34.0% (p < 0.001; d = 0.58), and GR by 35.0% (p < 0.001; d = 0.65). LPO was elevated but did not reach significance after correction for non-normality (p = 0.254), though it correlated significantly with radiographic severity (ρ = 0.403; p = 0.010) and was markedly elevated in patients with neurological involvement (2486.6 nmole/ml; p = 0.008). DNA damage was significantly increased across all comet parameters (% Tail DNA: + 24.0%; p < 0.001; d = 0.82). A novel finding was that the physiological age-dependent increase in TAA observed in controls (ρ = 0.425; p = 0.006) was abolished in patients (ρ = - 0.061; p = 0.707). Inter-marker correlation analysis revealed a rewiring of the antioxidant network, with breakdown of the normal LPO-TAA feedback relationship and emergence of SOD-TAA co-depletion. Post-COVID patients exhibit severe antioxidant depletion, significant DNA damage, and disruption of the normal redox network architecture. These findings provide a biochemical rationale for antioxidant-targeted therapeutic strategies in post-COVID management.
Epilepsy is a worldwide health issue associated with cardiac-related conditions and Sudden Unexpected Death in Epilepsy (SUDEP). The pathophysiology of SUDEP involves structural fibrosis of the myocardium, a calcium imbalance, and dysfunction of the autonomic nervous system. The objective of this investigation was to examine cardiac damage resulting from epilepsy triggered by the Pentylenetetrazol (PTZ) kindling rat model at a dosage of 35 mg/kg administered intraperitoneally, and to assess the therapeutic benefits of Resveratrol (RSV) at a dosage of 5 mg/kg. Cardiac function was evaluated using isolated papillary muscle recordings. Damage to the structure was assessed by Sirius Red staining and general tissue morphology. Molecular analyses encompassed qPCR (SERCA2a, CACNA1G, HCN2, CAS3/9) and immunofluorescence (SIRT1, Caspase-3, S100α) in conjunction with the total Ca2⁺ content. PTZ kindling enhanced seizure severity and overall spike number on ECoG. Functionally, contractile force (CF), contractile power (AUC), and contraction/relaxation velocities (± dF/dtmax) were decreased in the PTZ group compared to the Sham group at 3, 4, and 5 Hz frequencies. Contraction duration (CT) was significantly prolonged at 5 Hz, whereas no significant change was observed in relaxation time (RT). Histopathology revealed degeneration and substantial myocardial scarring. At a molecular level, PTZ decreased SERCA 2a mRNA expression (p < 0.0001) while increasing total calcium content (p < 0.0001) and pro-apoptotic markers (Caspase-3/9). Furthermore, the protective SIRT1 protein signal intensity was substantially reduced. RSV therapy resulted in a reduction of seizure severity by 2.54 ± 0.13 and also ameliorated cardiac function. Mechanistically, RSV recovered expression of SERCA2a (p < 0.0001), reduced fibrosis/apoptosis, and reactivated the anti-apoptotic SIRT1 pathway. These findings show that RSV ameliorates epilepsy-induced cardiac injury and has the potential to serve as an effective supportive treatment against SUDEP-related heart dysfunction by regulating calcium levels and activating anti-apoptotic pathways.
Ferroptosis is a specialized form of regulated cell death that is dependent on intracellular iron and is characterized by excessive lipid peroxidation, accumulation of lipid peroxides, and increased intracellular iron levels. This process is regulated through complex and tightly coordinated molecular mechanisms involving multiple signaling pathways and regulatory proteins, including key antioxidant defense components such as glutathione peroxide 4 (GPX4) and ferroptosis suppressor protein-1 (FSP-1). Increasing experimental evidences suggested that modulation of ferroptosis pathway might offer a potent target for breast cancer management, as ferroptosis dysregulation has been strongly associated with tumor invasion, progression, and drug resistance. Current cancer treatment strategies including surgery, chemotherapy, radiation therapy have detrimental effects on cancer patients. Therefore, it is highly needed to focus on safe and effective therapeutics like natural compounds for cancer therapy. These compounds have shown the significance of ferroptosis-mediated cell death, thereby providing drug candidate for developing ferroptosis-inducing agents. Current research studies suggested that numerous plant-based compounds have strong anticancer potential via ferroptosis induction in breast carcinoma. However, these results are dependent upon preclinical experimentation and lacking validation of long-term clinical research. Thus, this review is designed to provide a mechanistic overview of plant-derived natural compounds by targeting ferroptosis pathway specifically in breast cancer. This could help the researchers working in medicinal chemistry field and pharmacology to better understand the mechanism of action of these compounds against breast carcinoma and provide an alternative approach to treat breast cancer.
Cardiorenal syndrome (CRS) is a progressive and life‑threatening disorder associated with high morbidity and mortality. This study aimed to compare the cardio‑ and reno‑protective effects of candesartan and lisinopril in a 5/6 nephrectomy model of type 4 CRS, with emphasis on their modulation of oxidative stress and inflammatory signaling pathways. Immediately after 5/6 subtotal nephrectomy, candesartan (10 mg/kg/day) or lisinopril (12.5 mg/kg/day) was administered by gastric gavage for 10 weeks. Serum urea and creatinine were measured 10 days post‑surgery. At the end of the treatment period, rats were euthanized, and blood, renal, and cardiac tissues were collected. Serum urea, creatinine, and cardiac BNP were quantified, along with renal and cardiac levels of SOD, MDA, NF‑κB, JAK‑2, STAT‑3, and TGF‑β. Histopathological examinations were also performed. Both candesartan and lisinopril significantly improved renal function, reduced arterial blood pressure, attenuated cardiac hypertrophy, lowered BNP levels, decreased renal and cardiac concentrations of MDA, NF‑κB, JAK‑2/STAT‑3, and TGF‑β, and increased SOD levels compared with the 5/6 nephrectomy group. Histopathological examination confirmed marked reductions in renal and cardiac tissue injury. Candesartan exerted greater reno‑protective effects than lisinopril in this model of CRS, whereas lisinopril offered slightly superior cardioprotective benefits. Both agents appear to mediate their therapeutic actions through attenuation of oxidative stress and inflammatory signaling.
The aim of this study was to investigate the effects of deuterium substitution on the in vitro pharmacology of the psychedelic drug 2-(4-bromo-2,5-dimethoxyphenyl)ethan-1-amine (2C-B). Two deuterated isotopologues of 2C-B, namely 2-(4-bromo-5-methoxy-2-(methoxy-d3)phenyl)ethan-1-amine (2CB-2OCD3) and 2-(4-bromo-2-methoxy-5-(methoxy-d3)phenyl)ethan-1-amine (2CB-5OCD3), were synthesized and tested in cell lines expressing human 5-HT2A receptors for potential isotope effects on 5-HT2A receptor binding and functional activity, and for metabolism by human liver microsomes (HLM). The 2C-B isotopologues and 2C-B exhibited picomolar-to-nanomolar potency in binding to [125I]DOI-labelled 5-HT2A receptors and were equally efficacious to 2C-B in stimulating 5-HT2A-mediated intracellular Ca++ release and β-arrestin 2 engagement. No appreciable metabolism was observed for 2C-B or the deuterated analogues by HLM over the time course of the experiment. Deuteration of the ring methoxys of 2C-B appeared to increase affinity at [125I]DOI-labelled 5-HT2A receptors, likely due to dampened internal vibrational frequencies and rotational motions arising from primary and secondary kinetic isotope effects. Deuteration did not affect the ability of the drugs to stimulate intracellular calcium release or to recruit β-arrestin 2, with all compounds displaying similar low nanomolar potency and efficacy in these assays.
This study is aimed at investigating the therapeutic effects and the relevant mechanisms of Lactiflorin in ulcerative colitis (UC) via a combination of various methodologies. The PI3K/AKT pathway identified through network pharmacology, and key pathways and therapeutic effects were validated by animal experiments, molecular docking, and molecular dynamics simulations. The experimental verification was performed using an acute colitis model induced by 2.5% dextran sulfate sodium. This study further explored whether the key bioactive components could improve intestinal barrier integrity and alleviate ulcerative colitis by inhibiting the PI3K/AKT signaling pathway. We performed hematoxylin and eosin staining, cytometric bead array, western blotting, and immunofluorescence. Network analysis identified 718 predicted drug targets, among which 264 were related to UC therapeutic targets. Animal experiments further confirmed the significant role of the key pathways and the effects of the pharmacological intervention. Molecular docking and dynamics simulations demonstrated Lactiflorin with a strong binding affinity to STAT3 (- 11.24 kcal/mol), AKT1 (- 15.61 kcal/mol), and PIK3R1 (- 11.95 kcal/mol). In vivo experiments, Lactiflorin improved the Disease Activity Index score and histopathological score in UC-modelled mice and suppressed the expression of pro-inflammatory cytokines including IL‑23, IL‑12p70, IL‑17A, and IL‑1α. Western blot and immunofluorescence results revealed that Lactiflorin inhibited the expression of AKT, STAT3, and PI3K proteins (P < 0.01). These findings suggest that Lactiflorin exerts potential therapeutic effects against UC through PI3K/AKT pathway.
Ferroptosis is a regulated form of cell death that depends on iron and is marked by lipid peroxidation and the inactivation of glutathione peroxidase 4. It has emerged as a pathway of broad relevance to cancer and neurodegenerative disease. Preclinical studies have identified potent ferroptosis inducers (System Xc⁻ and GPX4 inhibitors) and inhibitors (liproxstatin/ferrostatin derivatives, FSP1-CoQ10 activators) with promising therapeutic potential. However, clinical translation remains limited. Since dedicated therapeutics targeting ferroptosis are still in early development, current clinical evidence mainly comes from drug repurposing, approved drugs whose ferroptosis-modulating properties were discovered retrospectively after their initial approval. None of these completed trials used ferroptosis-specific pharmacodynamic data or prospectively tested ferroptosis as the primary therapeutic mechanism. Instead of just reclassifying these trials, this review introduces a four-category failure-mode framework, mechanism mismatch, biomarker absence, model-to-trial prediction, and target non-selective compound, to explain why preclinical signals of ferroptosis have yet to translate successfully. We conclude that progress depends on three developments: targeted modulators (purpose-developed or repurposed with confirmed engagement), proof-of-mechanism trials using ferroptosis-related endpoints, and patient selection aligned with precision medicine.
Depression causes distress, dysfunction, and disability in terms of physical, mental, and social wellbeing. The challenges of late presentation, no-compliance of patients, and time-lag of antidepressants persist, despite advances. The objective was to determine the efficacy of antidepressants in combination with magnesium, compared to antidepressant monotherapy for treating depression. Forty-four patients with depression (6A70, 6A71, and 6A72 according to ICD-11) were divided into two equal groups, in an open label nonrandomized clinical trial. All patients received evidence-based antidepressants (either escitalopram, sertraline, duloxetine, amitriptyline, or fluoxetine). The experimental group additionally received 800 mg of magnesium glycinate (112 mg elemental magnesium). The psychometric testing was done by Patient Health Questionnaire (PHQ-9) at days 0, 14, and 28. Primary outcome was to see improvement at day 28, while secondary outcomes included time lag and remission (PHQ-9 scores < 4) at day 14 and 28, respectively. Paired sample t-test and Student t-test were applied for within-group and between-group differences using SPSSv27.0. The p-value ≤ 0.05 was considered statistically significant. The improvement in the PHQ-9 scores in groups A and B was 26.42% and 72.17%, respectively, by day 28, and effect size (Cohen's d = 1.76) was in the favor of adjunct therapy. Group B showed 41.34% improvemnet and large effect size (d = 1.29) on day 14 as well. All these values were statistically significant (p ≤ 0.05). The remission rate (44 patients) was higher with adjunt therpay (10.23%), versus 2.27% with monotherapy. Adjunct antidepressant therapy with magnesium is a preliminary effective strategy for patients with depression, potentially augmenting treatment response and decreasing time lag of antidepressants. ClinicalTrials.gov ID: NCT05931965 ( https://clinicaltrials.gov/study/NCT05931965?cond=Depression&intr=magnesium,%20methylfolate,%20B12&rank=1 ), 14-06-2023 (retrospectively registered).
Nuclear factor-kappa B (NF-κB) is a key transcription factor implicated in inflammation, immune regulation, and cancer progression, making it an important target for antioxidant and anti-inflammatory therapy for acne. The present study evaluated the synergistic NF-κB inhibitory potential of cinnamic acid and p-coumaric acid (p-CA) through molecular docking analysis, followed by formulation development and antioxidant assessment. Molecular docking was performed using AutoDock Vina v1.2.6 to investigate binding affinity and interaction profiles. Individual formulations containing cinnamic acid (1%) and p-CA (1%), as well as an equimolar combined formulation (0.5% each), were developed using hydrogel and oleogel phases to obtain a bigel system. Antioxidant activity was determined using the DPPH radical scavenging assay. Docking studies demonstrated binding energies of - 4.046 kcal/mol and - 4.400 kcal/mol for cinnamic acid and p-CA, respectively, whereas the combined ligand complex exhibited an enhanced binding affinity of - 7.837 kcal/mol. The improved interaction was stabilized through hydrogen bonding and hydrophobic interactions involving key amino acid residues, including ARG54, LEU251, GLU341, and THR342. In the antioxidant assay at 250 μg/mL, p-CA and cinnamic acid exhibited 16.76% and 14.02% inhibition, respectively, IC50 value of the cinnamic acid, p-coumaric acid and combined was found to be 750 µg/mL, 1160 µg/ mL, 810 µg/mL, while the equimolar bigel formulation demonstrated significantly higher radical scavenging activity (19.95%-28.55%), suggesting a synergistic effect. This research indicates that the combination of cinnamic acid and p-CA enhances molecular interactions with the NF-κB p50 subunit and improves antioxidant activity compared with the individual compounds. These integrated in silico and experimental results support the potential application of this combination in the development of multi-targeted natural formulations.