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Background: Alzheimer's disease (AD) features progressive cognitive decline and amyloid-beta (Aβ) accumulation. Insulin resistance in type 2 diabetes mellitus (T2DM) is increasingly recognised as a mechanistic link between metabolic dysfunction and neurodegeneration. Although sodium-glucose cotransporter-2 inhibitors (SGLT2is) have established glycaemic and cardioprotective benefits, their neuroprotective role remains less well defined. Objectives: This systematic review examines animal studies on the neuroprotective effects of SGLT2i in T2DM and AD models. Methods: A literature search was conducted across the Web of Science, Scopus, and PubMed databases, covering January 2014 to November 2024. Heterogeneity was assessed with I², and data were pooled using fixed-effects models, reported as standardised mean differences with 95% confidence intervals. We focus on spatial memory performance as measured by the Morris Water Maze (MWM) test, including escape latency and time spent in the target quadrant, as the primary endpoints. The secondary endpoints of Aβ accumulation, oxidative stress, and inflammatory markers were also analysed and summarised. Results: Twelve studies met the inclusion criteria for this review. A meta-analysis showed that SGLT2i treatment significantly improved spatial memory by reducing the escape latency in both T2DM and AD models. In addition, SGLT2i yielded a significant improvement in spatial memory, as indicated by an increased target quadrant time for both T2DM and AD. Furthermore, SGLT2i reduced Aβ accumulation in the hippocampus and cortex, which met the secondary endpoint; the treatment also lessened oxidative stress and inflammatory markers in animal brains. Conclusions: Our findings indicate that SGLT2is confer consistent neuroprotective benefits in experimental T2DM and AD models.

Background/Objectives: This umbrella review critically evaluates the available evidence on psychobiotics for depressive and anxiety symptoms, emphasizing methodological quality, consistency of findings, and persistent gaps in the literature. Methods: A comprehensive search was conducted across PubMed/MEDLINE, Scopus, Web of Science, SciELO, Cochrane, and EBSCO (May-June 2025) to identify systematic reviews with meta-analyses of randomized controlled trials examining probiotic, prebiotic, and synbiotic interventions in adults with depressive and/or anxiety symptoms or diagnoses. Two reviewers independently screened studies, extracted data, and evaluated methodological quality using AMSTAR-2. Additional bibliometric, conceptual, and psychometric features were mapped, including geographical origin, publication timeline, scale distribution, and citation-based connectivity. Results: Thirty systematic reviews and meta-analyses were included. Methodological quality was predominantly moderate, low, or critically low in 76.6% of reviews. Probiotic interventions demonstrated consistent benefits for MDD (SMD = -0.50 [95% CI: -0.58 to -0.42], p = 0.0001). However, findings for anxiety were markedly inconsistent, despite the modest improvements in specific subgroups (SMD = -0.19 [95% CI: -0.28 to -0.10]; p < 0.01). Prebiotics for MDD interventions showed limited positive results (SMD = -0.25 [95% CI: -0.47 to -0.03]; p = 0.03). For anxiety, the effects are inconclusive (SMD = -0.07 [95% CI: -0.30 to 0.10]; p = 0.18). Evidence for synbiotics was scarce. Citation-mapping revealed a fragmented and unevenly connected evidence base. Conclusions: The current evidence suggests that probiotics may confer beneficial effects on depressive and anxiety symptoms; however, the same cannot be said for prebiotics and synbiotics. Evidence for the efficacy of prebiotics and synbiotics to treat depression and anxiety is still insufficient or heterogeneous. Registration: CRD420251164884.

Background/Objectives: Cancer persists as a leading concern in the current medical field, and current therapies are limited by toxicity, cost, and resistance. Targeted inhibition of tubulin polymerization is considered as a promising therapeutic strategy for cancer treatment. Methods: Thirty-one new tubulin polymerization inhibitors were designed via molecular hybridization techniques, and BLI technology was employed to quantitatively investigate their interactions with tubulin. Antiproliferative activities against MCF-7, MDA-MB-231, A549, and HeLa cell lines was evaluated using the CCK8 assay. Apoptosis induction and cell cycle arrest were analyzed by flow cytometry. The anti-tumor activity of compound B6 was validated in a mouse melanoma tumor model. Results: Compounds exhibited varying degrees of antiproliferative activity against four tumor cell lines. Among them, compound B6 was the most promising candidate and displayed strong broad-spectrum anticancer activity with an average IC₅₀ value of 2 μM. The mechanism studies revealed that compound B6 inhibited tubulin polymerization in vitro, disrupted cell microtubule networks, and arrested the cell cycle at G2/M phase. Furthermore, B6 displayed significant in vivo antitumor efficacy in a melanoma tumor model with tumor growth inhibition rates of 70.21% (50 mg/kg). Conclusions: This work shows that B6 is a promising lead compound deserving further investigation as a potential anticancer agent.

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Background/Objectives: Antimicrobial resistance (AMR) is considered a major threat by the healthcare community. In this context, the AWaRe (Access, Watch, Reserve) classification of antibiotics is a valuable tool that can assist physicians during the clinical decision process and pharmacists in promoting the rational use of antibiotics. Pharmacovigilance studies based on real-world evidence offer valuable insight into the AMR phenomenon. The aim of this study was the assessment of the resistance, ineffectiveness, and off-label use signals of all five cephalosporins belonging to the Reserve group (ceftazidime/avibactam, ceftaroline, cetolozane/tazobactam, ceftobiprole, and cefiderocol). Methods: The study was conducted using descriptive approaches on EudraVigilance data and disproportionality analyses comparing each of the fourteen cephalosporins in the Watch group. Results: Ceftazidime/avibactam (n = 904, 38.6%) topped the reports, followed by ceftaroline (n = 559, 23.9%) and ceftolazane/tazobactam (n = 560, 23.9%). The lowest number of reports was submitted for cefiderocol (n = 176, 7.5%) and ceftobiprole (n = 146, 6.2%). The resistance to ceftazidime/avibactam, cefiderocol, and ceftolozane/tazobactam was reported with a higher probability than all others, the strongest signal being observed for cefiderocol against cefixime (ROR: 171.25, 95% CI 79.64-368.27). All cephalosporins from the Reserve group (except ceftobiprole) have higher probability for reporting ineffectiveness than cephalosporins from the Watch group; the strongest signal was observed for cefiderocol-cefditoren (ROR: 14.70, 95% CI 6.73-32.11). All cephalosporines from the Reserve group had a higher probability of reporting off-label use by comparison with the ones from the Watch group, except for two cases of no disproportionate signal between cefiderocol-cefoperazone and cefiderocol-ceftizoxime; the strongest signal was observed for ceftolozane/tazobactam-cefotaxim (ROR: 43.61, 95% CI 30.14-63.09). Conclusions: This analysis supplements information from clinical trials and current clinical practice, underscoring the critical need for rigorous antibiotic stewardship programs. Notably, even restricted use of cephalosporins demonstrated therapeutic failure and inappropriate utilization.

Background/Objectives: Chemical and metabolic kinetics have historically been derived from mass balance differential equations expressed in terms of amounts, and this framework was later extended to pharmacokinetics by converting amount-based equations to concentration-based clearance relationships. That conversion is valid for fixed-volume in vitro experiments, but may be unreliable in vivo, where input, distribution, and elimination can occur in different volumes of distribution. The objective of this study is to present an alternate, mechanistically agnostic framework for deriving pharmacokinetic relationships by adapting Kirchhoff's Laws to treat pharmacokinetic systems as networks of parallel and in-series rate-defining processes, and to identify where differential equation approaches fail in vivo. Methods: Clearance and rate constant equations were derived using the adapted Kirchhoff's Laws by summing parallel rate-defining processes and summing inverses for in-series processes, explicitly incorporating organ blood flow, net transporter, and delivery site effects. The resulting expressions were compared with differential equation hepatic disposition elimination models (well-stirred, parallel tube, dispersion) and the Extended Clearance Concept (ECC). Mean residence time concepts were used to extend the framework to oral input, and the full approach was applied to a case study of a hypothetical drug (KL25A). Results: The adapted Kirchhoff-based approach reproduced standard pharmacokinetic analyses without mechanistic organ assumptions and yielded model-independent hepatic and renal clearance equations that include blood flow, net transport, and delivery kinetics. Inconsistencies with the traditional differential-based derivations were highlighted, including the interpretation of pharmacokinetics associated with slow absorption site clearance, as illustrated by KL25A. Conclusions: For linear drug metabolism and pharmacokinetics, clearance and rate constant relationships can be derived by summing parallel and in-series rate-defining processes, without differential equations. Differential equation methods may misestimate in vivo clearance and bioavailability when drug input is slow or when volumes of distribution differ across processes. The adapted Kirchhoff framework offers a simpler, model-independent basis for interpreting clinical data.

Background: Chronic nonbacterial prostatitis (CNP), the major subset of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), imposes a substantial global burden yet lacks satisfactory therapies. Maizibizi Wan (MZBZ) has long been used clinically for prostatitis, but its pharmacodynamic substance basis and mechanisms remain unclear. Methods: Ultra-high-performance liquid chromatography-Q-Orbitrap high-resolution mass spectrometry (UHPLC-Q-Orbitrap-HRMS) coupled with Global Natural Products Social Molecular Networking (GNPS) molecular networking profiled MZBZ constituents and rat plasma-exposed prototype components and metabolites was used. Based on blood-absorbable components, network pharmacology predicted core targets/pathways; representative interactions were validated by molecular docking. A λ-carrageenan-induced CNBP rat model underwent histopathology (H&E), serum cytokine assays (TNF-α, IL-1β, IL-6/IL-17), immunohistochemistry (COX-2, TNF-α, MMP-9), and Western blotting (P-p65/p65, p-AKT/AKT, COX-2, TGF-β1, BCL2). Results: A total of 188 chemical constituents were identified in MZBZ (79 flavonoids, 38 organic acids, 30 alkaloids, 15 phenylpropanoids, 7 steroids, 4 phenylethanoid glycosides, 15 others). A total of 35 blood-absorbable components (18 prototype components, 17 metabolites) were identified, mainly involving Phase I oxidation and Phase II glucuronidation/sulfation. Network analysis yielded 54 core targets enriched in NF-κB and PI3K/AKT signaling and apoptosis. Docking indicated stable binding of key flavonoids to COX-2, NFKB1, TNF, IL-6, and BCL2. In vivo, MZBZ ameliorated prostatic inflammation, reduced serum TNF-α/IL-1β/IL-6/IL-17 (p < 0.05 or p < 0.01); decreased P-p65/p65, p-AKT/AKT, COX-2, and TGF-β1; and increased BCL2 in prostate tissue. Conclusions: MZBZ exerts anti-CNBP effects via multi-component synergy (prototypes + metabolites) that suppresses inflammatory cytokines, modulates apoptosis, and inhibits NF-κB and PI3K/AKT pathways. These findings provide a mechanistic basis and quality control cues for the rational clinical use of MZBZ.

Background/Objectives: Capric acid (CA)-therapeutic deep eutectic systems (THEDES) are emerging as a distinct class of biofunctional matrices capable of reshaping drug solubilization, permeability, and bioactivity. Methods: Relevant studies on CA-THEDES were identified through targeted database searches and screened for evidence on their design, mechanisms, and pharmaceutical performance. Results: This review synthesizes current evidence on their structural design, mechanistic behavior, and pharmaceutical performance, revealing several unifying principles. Across multiple drug classes, CA consistently drives strong, directional hydrogen bonding and drug amorphization, resulting in marked solubility enhancement and stabilization of non-crystalline or supersaturated states relative to crystalline drugs or conventional solvent systems. Its amphiphilic C10 chain further contributes to membrane fluidization, which explains the improved transdermal and transmucosal permeation repeatedly observed in CA-THEDES. Additionally, synergistic antimicrobial and anticancer effects reported in several systems confirm that CA acts not only as a solvent component but as a bioactive co-therapeutic. Collectively, the reviewed data show that CA serves as a structurally determinant element whose dual hydrogen-bonding and membrane-interacting roles underpin the high pharmaceutical performance of these systems. However, gaps remain in long-term stability, toxicological profiling, and regulatory classification. Emerging Artificial Intelligence (AI) and Machine Learning (ML)-guided predictive approaches offer promising solutions by enabling rational selection of eutectic partners, optimal ratios, and property optimization through computational screening. Conclusions: Overall, CA-THEDES represent a rationally designable platform for next-generation drug delivery, where solvent functionality and therapeutic activity converge within a single, green formulation system.

Liver cancer remains a significant global health challenge, with hepatocellular carcinoma (HCC) being the most prevalent form. Despite advancements in treatment, high recurrence rates and the limited efficacy of conventional therapies highlight the need for novel interventions. Cinobufagin (CB), a bufadienolide extracted from the parotid secretion of Bufo gargarizans and B. melanostictus, has emerged as a promising compound with multiple antitumor mechanisms. This comprehensive review assesses the current evidence regarding CB and its containing medicine, cinobufacini, in liver cancer models. Cinobufacini is a traditional Chinese medicine extract, whereas CB refers specifically to one of its active components. The pharmacodynamic actions of CB include induction of apoptosis, DNA damage, inhibition of proliferation and migration, and modulation of key oncogenic pathways such as PI3K/Akt/mTOR, Akt/ERK, and AURKA-mTOR-eIF4E. Additionally, CB disrupts tumor metabolism and induces oxidative stress. Preclinical studies, both in vitro and in vivo, demonstrate significant antitumor efficacy. However, concerns remain regarding CB's toxicity profile at high doses. This review emphasizes the therapeutic potential of CB in HCC treatment and advocates for further translational research to optimize its clinical applicability, dosage, and safety.

Background: Vedolizumab and ustekinumab are increasingly used off-label in pediatric inflammatory bowel disease (IBD) unresponsive or refractory to anti-TNFα therapy. Despite their increasing use in clinical practice, evidence in the pediatric population remains limited, especially regarding therapeutic exposure thresholds and the clinical utility of therapeutic drug monitoring (TDM). Methods: We report a series of five pediatric cases with Crohn's disease or ulcerative colitis treated with ustekinumab or vedolizumab after anti-TNFα failure. Trough drug concentrations, anti-drug antibodies (ADAs), clinical scores (PCDAI/PUCAI), biomarkers (fecal calprotectin, C-reactive protein), and endoscopic findings were assessed longitudinally. Results: In all cases, we observed recurrent discordance between clinical indices (PCDAI/PUCAI), biochemical markers, and endoscopic activity. Clinical improvement frequently correlated with trough concentrations above commonly cited adult-derived reference ranges (>15 µg/mL for vedolizumab; >3 µg/mL for ustekinumab), although this alignment was not uniform across patients. Notably, one patient developed high-titre ADAs with undetectable ustekinumab levels, yet remained clinically stable, suggesting substantial interindividual variability in pharmacokinetics, immunogenicity, and disease control. Conclusions: Ustekinumab and vedolizumab are promising off-label options for pediatric refractory IBD. In this case series, TDM contributed to the interpretation of pharmacokinetic variability and immunogenicity, offering contextual insights that may support dose adjustments and therapeutic decision-making. Integrating TDM with clinical, biochemical, and endoscopic monitoring may improve optimize individualized treatment in this complex and vulnerable patient group.