Abstract: Introduction: Prostate cancer (PC) treatment is limited by resistance mechanisms and cumulative toxicities, necessitating novel therapeutic strategies. While curcumin and piperine exhibit potent anticancer properties, their clinical utility is severely compromised by poor bioavailability and rapid metabolism. Areas covered: This review critically analyzes the preclinical and clinical landscape of curcumin and piperine nanoformulations (CPN) for PC treatment. We utilized PubMed and Scopus (2000–2025) to evaluate molecular mechanisms, focusing on CYP17A1 inhibition, PI3K/Akt/mTOR signaling, and ferroptosis. The report examines the physicochemical attributes of nanocarriers, including PLGA and liposomes, and addresses translational barriers such as the heterogeneity of the Enhanced Permeability and Retention (EPR) effect, stromal density, and piperine-mediated drug–drug interaction risks. Expert opinion: While nano-encapsulation enhances the therapeutic index of curcumin, clinical translation remains stalled by a reliance on passive targeting and insufficient manufacturing scalability. Future success depends on shifting from "beaker" synthesis to microfluidic production (Quality by Design) and adopting active targeting (e.g., PSMA-directed delivery) to penetrate the prostate stroma. Without these strategic pivots and biomarker-driven trials, CPNs risk remaining an academic curiosity rather than evolving into a viable clinical intervention.

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Microneedle (MN) technologies have emerged as a groundbreaking platform for transdermal and intradermal drug delivery, offering a minimally invasive alternative to oral and parenteral routes. Unlike passive transdermal systems, MNs allow the permeation of hydrophilic macromolecules, such as peptides, proteins, and vaccines, by penetrating the stratum corneum barrier without causing pain or tissue damage, unlike hypodermic needles. Recent advances in materials science, microfabrication, and biomedical engineering have enabled the development of various MN types, including solid, coated, dissolving, hollow, hydrogel-forming, and hybrid designs. Each type has unique mechanisms, fabrication techniques, and pharmacokinetic profiles, providing customized solutions for a range of therapeutic applications. The integration of 3D printing technologies and stimulus-responsive polymers into microneedle systems has opened the door for patches that pair drug delivery with real-time physiological sensing. Over the years, microneedle applications have grown beyond vaccines to include the delivery of insulin, anticancer agents, contraceptives, and various cosmeceutical ingredients, highlighting the versatility of this platform. Despite this progress, broader clinical and commercial adoption is still limited by issues such as scalable and reliable manufacturing, patient acceptance, and meeting regulatory expectations. Overcoming these barriers will require coordinated efforts across engineering, clinical research, and regulatory science. This review thoroughly summarizes MN technologies, beginning with their classification and drug-delivery mechanisms, and then explores innovations, therapeutic uses, and translational challenges. It concludes with a critical analysis of clinical case studies and a future outlook for global healthcare. By comparing technological progress with regulatory and commercial hurdles, this article highlights the opportunities and limitations of MN systems as a next-generation drug-delivery platform.

Abstract: p53 tumor suppressor evolved as the critical player in navigating the response to environmental stresses such as DNA, or oxidative damage and drives the cell fate by governing the live and death decision. The p53 protein is encoded by the most commonly mutated gene in human cancers. TP53 gene mutations are associate with worse prognosis and refractory and relapse disease. The most prevalent mutations are of the missense type and often lead to disruption of DNA binding capacity. In healthy cells, p53 protein is tightly regulated by its E3 ubiquitin ligase, MDM2 (HDM2), it’s own transcription target. Mutant p53 therefore escapes the regulation by the negative feedback loop and is often found upregulated in cancer cells. The efforts to exploit mutant p53 for precision medicine has been ongoing in the last decade, yet not successful. One way to target TP53-mutant cancers would be by proximity, where abundant mutp53 protein serves as a molecular glue for a toxin inhibiting essential gene. The strategy might still require the adjustments but emerges as promising strategy for precision oncology.

Abstract: Ifalmin^®, an oral extract of Channa micropeltes (Toman fish) that have registered on Indonesian FDA (BPOM RI) for herbal medicine. Toman fish is known for anti-inflammatory, antidiabetic, wound-healing, and antioxidant activities, but its safety profile requires verification; therefore, this study evaluated the in vivo subchronic toxicity of Channa micropeltes extract. Male and female Rattus norvegicus were allocated to control (0 mg/kg BW), three treatment groups receiving 270, 540, or 1000 mg/kg BW, and a satellite group given 1000 mg/kg BW, with all doses administered orally once daily for 14 consecutive days; animals were observed and assessed on day 15 after dosing cessation. Subchronic toxicity endpoints included clinical signs, body-weight changes, macropathology, relative organ weights, histopathology of heart, liver, kidneys, spleen, and lungs, and standard biochemical and hematological parameters. Across all dose levels, no treatment related abnormalities or organ damage were detected, and physiological and laboratory measures remained comparable to controls. The no-observed-adverse-effect level (NOAEL) was 1000 mg/kg BW. These findings indicate that Ifalmin derived Channa micropeltes extract is relatively non-toxic under the tested subchronic oral exposure conditions.

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Introduction: Opioids are the most commonly used analgesic drugs for acute and chronic severe pain metabolized in the liver via cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT). Methods: A narrative review of the literature was conducted by searching MEDLINE and PubMed databases up to October 2025, using the English language as the only restriction. Relevant studies were identified using the keywords “opioids,” “pharmacogenetic,” “cytochrome mutations,” and “interactions.” Results: Polymorphisms in the CYP2D6 and CYP3A4 genes can affect the pharmacokinetics, clinical effect, and safety of opioids. Furthermore, enzyme induction and inhibition using concomitant drugs or compounds (herbal or food) are variability factors in drug response that may be predictable. Conclusion: This review article provides an overview of the role of pharmacogenetics and opioid interactions as a rationale for multimodal approaches aimed at optimizing treatment in clinical practice, in particular opioids should be tailored to each clinical indication and patients should be stratified to receive the appropriate dose.

Abstract: Beyond its conventional role as an industrial and energy resource, crude oil may also hold promise for drug discovery. This article seeks to provide a conceptual frame-work for reconsidering crude oil as a reservoir of pharmacologically relevant scaffolds and to outline methodological approaches for their systematic assessment. Its rigid sp³-rich frameworks, together with sterane/hopane biomarkers, porphyrins, and func-tional aromatics, overlap structurally and pharmacologically with established thera-peutic classes and are naturally present in crude oil in suitable abundance, offering opportunities to reduce synthetic effort and expand the chemical space accessible to drug discovery. Advances in petroleomics and in silico methodologies now enable petrole-um-derived constituents to be characterized in terms of drug-likeness, bioactivity, and toxicity, providing a framework to reconsider crude oil as an unconventional but scien-tifically tractable resource for pharmaceutical innovation.

Abstract: Background: Pressure overload-induced heart failure is marked by pathological ventricular remodeling and myocardial fibrosis, contributing to impaired cardiac function and adverse clinical outcomes. Vericiguat, a soluble guanylate cyclase stimulator, has shown therapeutic promise in heart failure with reduced ejection fraction. However, its anti-fibrotic and metabolic effects in pressure overload models remain underexplored. Aim: This study aimed to investigate the anti-fibrotic and metabolic effects of Vericiguat in a murine model of pressure overload-induced cardiac remodeling. Material Method: Male mice (~25 g) underwent transverse aortic constriction (TAC) to induce pressure overload and received oral Vericiguat (10 mg/kg/day) for 14 days. Myocardial fibrosis was evaluated using Masson’s trichrome and Picrosirius red staining. Collagen deposition and wall stress indices were quantified. Proteomic profiling was performed on fibroblast- and myocyte-enriched cardiac tissue to identify differentially expressed proteins (DEPs) across metabolic, structural, mitochondrial, and signaling pathways. Results: Vericiguat treatment significantly reduced myocardial fibrosis and collagen accumulation compared to untreated TAC controls (p< 0.001). Improvements in wall stress indices were observed. Proteomic analysis revealed consistent modulation of DEPs, including reversal of TAC-induced downregulation of mitochondrial and energy-related proteins, indicating enhanced bioenergetic support. Conclusion: Vericiguat mitigates pressure overload-induced cardiac remodeling through anti-fibrotic and metabolic reprogramming mechanisms. These findings support its potential as a therapeutic strategy for heart failure and warrant further clinical investigation.

Abstract: The book “Alcohol and Alcoholism in Russia: Recent History” deals with one of the great scourges of humanity: alcoholism. The focus is on Russia since 1970, but the subject matter is significant in a global context. As such the book should be interesting to experts in medicine and toxicology, social workers, psychologists, students of anthropology, sociology, and history: a broad base of readers. There has been a tendency to exaggerate the topic in order to veil shortcomings of the health care system in Russia, with responsibility for the relatively low life expectancy especially in males shifted onto people, that is, self-inflicted diseases caused by the alcohol abuse. Besides, the purpose of this book is to draw attention to the unstable quality of legally sold beverages, which have caused poisonings up to lethality, even after consumption of moderate doses, offenses against alcoholics and people with alcohol-related dementia, aimed at appropriation of their immobile and other properties, and overtreatment of alcoholics in medical institutions. Some invasive procedures have been used without sufficient indications. Instead of warmongering, the Russian government should provide public assistance to citizens in need, including those suffering from alcoholism and alcohol-related dementia.

Abstract: Synthetic cathinones such as 3,4-methylenedioxypyrovalerone (MDPV) are potent psychostimulants with high abuse potential, yet their systemic toxicity and neurobehavioral effects remain poorly characterized during early development. Using Danio rerio (zebrafish) embryos and larvae, we performed an integrated assessment of the cardiotoxic, behavioral, and molecular effects of MDPV. Acute exposure of 3 days post-fertilization (dpf) embryos produced a marked, concentration-dependent bradycardia and atrioventricular (AV) conduction block, leading to reduced ventricular activity and complete AV dissociation at the highest concentrations (EC₅₀ = 228 µM). Quantitative analysis of ventricular motion revealed a significant decrease in cardiac output (CO) at all tested concentrations and a reduction in ejection fraction (EF) only at 480 µM, while fractional shortening (FS) and stroke volume (SV) remained unchanged, indicating predominant chronotropic and conduction effects with secondary contractile impairment. In 5 dpf larvae, MDPV caused a sustained, concentration-dependent decrease in basal locomotor activity (EC₅₀ = 2.51 µM) but did not affect prepulse inhibition (PPI) of the acoustic startle response (ASR), unlike dextroamphetamine, which enhanced PPI via dopaminergic D₂ receptor activation. Short-term (2 h) exposure of 3 dpf embryos to 0.4–400 µM MDPV induced transcriptional changes in dopaminergic and stress-responsive genes, whereas expression of major repolarizing potassium channel genes (kcnh6a and kcnq1) remained unaltered. Collectively, these results demonstrate that MDPV exerts potent negative chronotropic effects likely through direct functional interference with cardiac repolarization, while neurobehavioral effects occur at concentrations nearly two orders of magnitude lower than cardiotoxic thresholds, supporting zebrafish as a predictive model for the integrative assessment of psychostimulant toxicity.

Abstract: Femtosecond laser-ablated gold nanoparticles (AuNPs) offer a unique platform for developing novel cost-effective contrast agents due to their ultraclean, surfactant-free synthesis and precisely tunable surface properties. This study developed three computed tomography (CT) contrast agents from a single stock solution of laser-ablated AuNPs, functionalized with polyethylene glycol (PEG-2kDa, PEG-4kDa), or bovine serum albumin (BSA). The primary objective was to evaluate the safety and functional efficacy of these coated AuNPs in healthy and tumor-bearing mice. After a single intravenous injection (690±30 mg Au/kg), all formulations were well tolerated with no acute toxicity observed. PEGylated AuNPs demonstrated long blood half-life (18±2 h for PEG-2kDa; 37±2 h for PEG-4kDa), making them suitable for cardiovascular imaging up to 24 hours post-injection. BSA-AuNPs had a rapid blood clearance (T₁/₂=2.8±0.9 h), permitting cardiovascular assessment during the first 3 h, and provided intense, persistent contrast in abdominal organs, enabling liver imaging from 5 min and spleen imaging from 1 h post-injection. In a Ca755 mammary adenocarcinoma model, PEGylated AuNPs selectively accumulated in the tumor stroma and fibrous septa, allowing for precise tumor margin delineation and analysis of internal architecture. The findings establish that a single AuNP stock can be used to produce specialized contrast agents for specific imaging applications.

Abstract: Nanobodies (single-domain antibodies, VHHs) have emerged as versatile tools for evaluating and treating Alzheimer’s disease (AD). They offer unique advantages over traditional antibodies and small molecules, including small size, stability, and specificity. In AD, nanobodies were used to neutralize toxic amyloid-β oligomers, inhibit tau generation and aggregation, and modulate neuroinflammation, thereby demonstrating significant therapeutic potential. The delivery of nanobodies requires advanced strategies, including intranasal and intrathecal routes, receptor-mediated transport, plasma protein binding with albumin, and focused ultrasound to facilitate brain penetration. Additionally, to improve nanobody delivery precision, half-life, and efficacy, strategies such as integrating nanobodies with nanoparticles, dendrimers, liposomes, and viral vectors are being employed. In fact, nanobodies are applied beyond monotherapy across multiple technological platforms to optimize brain delivery and target multiple targets. Nanobodies have been used on bispecific and trispecific antibody platforms, as well as in CRISPR/Cas9 editing and AI-driven technologies, to expand their applications. Recently, preclinical evidence has been mounting on the efficacy of nanobodies in clearing Aβ and tau, preserving synapses, and normalizing biomarkers. Notably, clinical trials of bispecific antibodies, including trontinemab, are signaling translational progress and regulatory approvals, and further support would validate this class of therapeutic molecules. This review critically delineates the current molecular mechanisms, emerging strategies, and delivery platforms, and emphasizes the potential of nanobodies as promising therapeutic and diagnostic molecules in AD therapeutics.

Abstract: The depletion degree of reduced glutathione is a critical indicator for assessing the toxicity of alkylating agents. In present research, we have developed a novel method to evaluate the glutathione (GSH) depletion induced by a series of alkylating agents and the protective effect of various active thiol compounds based on a high-content cell analysis system. The cytotoxicity of some alkylating agents was firstly assessed using the CCK-8 assay. The results showed that nitrogen mustard (HN2) and 1,2-bis(2-chloroethythio) ethane (Q) exhibited the highest cytotoxicity, with IC50 values of 14.45 μM and 23.27 μM, respectively. The cytotoxicity of 2-choroethylchoromethylsufide (CECM) and bis (2-choroethylthioethyl) ether (T) was comparable to that of bis (2-choroethyl) sulfide (HD), and that of bis (2-choroethylthiomethyl) ether (CEMEE) showed the lowest cytotoxicity. At the same exposure dose, Q exhibited the strongest GSH depletion ability, followed by HD > CECM > CEPR > CEBU > CEPE > CEME > T > CEMEE, and the depletion ability of ni-trogen mustard compounds followed the order HN2 > HN1 > HN3. In addition, the protective effect of four active thiol compounds was investigated. The results revealed that reduced glutathione ethyl ester (GSH-MEE) was most effective in preventing GSH depletion, whereas glutathione monoethyl ester (MEE) showed the highest efficacy in restoring GSH levels. The proposed method holds significant potential for analyzing the damaging effects of various alkylating agents and screening protective drugs.

Abstract: Current FDA and ICH genotoxicity requirements allow pharmaceutical developers to meet safety obligations using legacy assays designed for small, cell permeable chemicals, resulting in the use of bacterial reverse-mutation tests (Ames) and in vitro micronucleus assays in human peripheral blood mononuclear cells (PBMCs) to evaluate the presumed non genotoxicity of lipid nanoparticle (LNP) based platforms, including ionizable lipids used in mRNA vaccines. However, these assays have the potential to be structurally and mechanistically incapable of detecting relevant risks. Ionizable lipids and fully formulated LNPs exceed the size exclusion limits of bacterial porins in Escherichia coli and Salmonella typhimurium, preventing intracellular entry and interaction with genomic DNA; therefore, negative Ames results do not rule out mutagenic potential. Similarly, in vitro micronucleus assays reported as negative for COVID-19 mRNA vaccines used non activated PBMCs, which largely consist of lymphocytes that do not efficiently endocytose LNPs or free ionizable lipids due to size, charge, and absence of uptake pathways; as a result, the negative findings reflect absent intracellular exposure rather than absence of risk. Ionizable lipids can form covalent adducts with chemically modified RNA in vitro and may likewise bind residual linearized plasmid DNA contaminants present in mRNA vaccine preparations and potentially with human nucleic acids, a high-risk concern that has not been tested in vivo. If plasmids reach the nucleus, they could integrate into genomic DNA, while cytosolic plasmids may activate cGAS-STING signaling. Free or LNP associated ionizable lipids can electrostatically interact with nucleic acids once intracellular, further increasing the plausibility of mutagenic or immunomodulatory effects. Because existing genotoxicity assays do not deliver ionizable lipids or LNPs into relevant human cell compartments, their negative results cannot be considered evidence of safety, yet the FDA and other relevant agencies have not addressed this concern. Updated testing frameworks must use formulated LNPs in human cell models that support endocytosis, endosomal escape, nuclear access, and analytical detection of covalent adducts using mass spectrometry, reverse-phase ion-pair HPLC, additional genomics testing, and downstream microRNA and proteomic analyses to accurately evaluate genomic and immunological risk.

Abstract:

Background/Objectives: Ochratoxin A (OTA) is a widespread foodborne mycotoxin linked to chronic kidney disease of unknown etiology. Despite evidence from animal models showing OTA accumulation in the kidney, the molecular mechanisms underlying its renal disposition in humans remain only partially understood. Here. we identify human renal transporters responsible for OTA kidney accumulation, elimination, and establish Michaelis-Menten kinetics under matched conditions to directly compare transport mechanisms. We also aim to identify inhibition potential of these transport mechanisms with common dietary polyphenols. Methods: Mammalian cells and membrane vesicles overexpressing human renal transporters were used to screen and profile the uptake and efflux of OTA. Miquelianin, (-)-Epicatechin-3-O-gallate, myricetin, luteolin, and caffeic acid were tested as potential concentration-dependent transporter inhibitors. Results: We demonstrate that OTA is a substrate for human organic anion transporter (hOAT) 1 (K_m: 2.10 ± 0.50 μM, V_max: 396.9 ± 27.0 pmol/mg/min), hOAT3 (K_m: 2.58 ± 0.83 μM, V_max: 141.4 ± 30.3 pmol/mg/min), hOAT4 (K_m: 6.38 ± 1.45 μM, V_max: 96.9 ± 18.8 pmol/mg/min), and human organic anion transporting polypeptide (hOATP) 1A2 (K_m: 37.3 ± 6.2 μM, V_max: 801.0 ± 133.9 pmol/mg/min). Among efflux transporters, OTA was transported only by human breast cancer resistance protein (hBCRP), which has minimal renal expression. While none of the uptake transporters were potently inhibited (>90%) by polyphenols at 10 μM, luteolin inhibited hBCRP-mediated transport of OTA with an IC₅₀ of 22 μM and caffeic acid stimulated hBCRP-mediated efflux with an EC₅₀ of 713.8 μM, both of which are physiologically relevant intestinal lumen concentrations. Conclusions: Our results confirm that exposures to OTA will lead to renal accumulation and increased health risks in affected populations, necessitating increased scrutiny of our food sources.

Abstract: Background/Objectives: Metabolic enzymes are crucial for the detoxification of exogenously administered drugs, especially enzymes expressed in the intestine and the liver. Recent advancements in analytical methodologies enable sensitive and specific quantitative measurements of proteins facilitating a more accurate evaluation of their expression and relative contribution to drug metabolism. Methods: The aim of the study was to characterize the protein expression levels of 16 Cytochrome P450s (CYP450s) and 2 carboxylesterases (CESs) in human liver and intestinal tissues using absolute quantification by HPLC-MS/MS. Human hepatocytes (HHEP) and human liver microsomes (HLM) were utilized, along with a novel intestinal preparation from cryopreserved human intestinal mucosa (CHIM), to perform proteomic analyses. Results: A comprehensive evaluation of 16 CYP450s and 2 CES enzyme expression in human liver and intestinal tissues is provided to reflect their relative abundance. Among the various in vitro systems evaluated: 14 of 16, 15/16 and 7/16 CYP450 isoforms analyzed were detected in HHEP, HLM, and CHIM, respectively. In hepatic systems, CYP2C9 exhibited the highest expression among CYP450 isoforms, a trend consistently observed in both HHEP and HLM. CYP3A4 was the most abundantly expressed isoform in CHIM preparations. Across all systems tested, CES1 and CES2 showed the highest overall protein expression levels, surpassing those of the CYP450s. Conclusions: Our findings demonstrate that the absolute quantification method employed is reliable, producing consistent results across 2 different in vitro hepatic systems (HHEP and HLM). This study supports the utility of absolute quantification approaches for accurately profiling drug-metabolizing enzymes and provides new valuable insights to improve in vitro / in vivo extrapolation and more informed predictive pharmacokinetic modeling strategies.

Abstract: β-Methylphenethylamine (BMPEA), a positional isomer of amphetamine increasingly detected in dietary supplements and weight‐loss products, poses significant analytical challenges in forensic and doping control due to its structural similarity to amphetamine. This study presents a validated analytical workflow combining mixed‐mode solid‐phase extraction (MMSPE) with ultra‐performance liquid chromatography–quadrupole time‐of‐flight mass spectrometry (UPLC-qTOF-MS) for the selective quantification of BMPEA and identification of its metabolites in rat cardiac blood. Blood was taken at 20 and 90 minutes after injection from twelve adult male Sprague-Dawley rats that were randomly assigned to four groups (n = 3): an untreated control, a low-dose cohort (10 mg/kg, i.p.), and two high-dose cohorts (30 mg/kg, i.p.). The technique demonstrated strong differentiation between BMPEA and amphetamine isomers, excellent linearity over 20–1,000 ng/mL (R2 &gt; 0.99), and quantification limits appropriate for forensic applications. A short biological half-life and quick elimination kinetics are consistent with related phenethylamines, as evidenced by the peak BMPEA concentrations of 899 ng/mL at 20 min and 22 ng/mL at 90 min. Comprehensive low- and high-energy mass spectrometric analyses revealed a novel BMPEA metabolite, characterized as 1-amino-2-phenylpropan-2-ol, based on fragmentation patterns and retention time comparison with reference standards. This work delivers a rigorous, high‐sensitivity analytical tool for BMPEA detection in biological matrices and enhances understanding of its metabolic fate, offering critical biomarkers for forensic toxicology and anti-doping investigations.

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The use of medicinal plants in traditional healthcare systems has a long history, particularly in regions with limited access to modern medical facilities. In South Africa, indigenous knowledge of plant-based remedies has been preserved through oral traditions, making these plants vital resources for local communities. This study investigates sixteen unexplored Euphorbia species for their potential in inhibiting breast cancer cell growth. Due to the small size of the plants, the entire plant was used for each species. A systematic approach was employed, including plant selection, sequential extraction using organic solvents, phytochemical screening, and in vitro cytotoxicity testing using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. High-performance liquid chromatography (HPLC) was used to identify primary metabolites. All sixteen species contained glycosides and triterpenoids. The ethyl acetate (EtOAc) extract of Euphorbia ledienii, dichloromethane (DCM) extract of Euphorbia cooperi, and DCM extract of Euphorbia clavarioides exhibited the highest inhibitory effects on Michigan Cancer Foundation-7 (MCF-7), and M.D. Anderson-Metastatic Breast-231 (MDA-MB-231) cell lines, with cytotoxic concentration (CC₅₀) values of 0.06 μg/mL, 0.07 μg/mL, and 0.23 μg/mL, respectively. Euphorbia tirucalli (DCM extract) and Euphorbia cooperi (hexane extract) displayed selectivity for MDA-MB231 cells, with selectivity index (SI) values of 49.40 and 84.03, respectively. Euphorbia trigona, Euphorbia gorgonis, Euphorbia ledienii, and Euphorbia arabica had similar distribution of secondary metabolites based on HPLC analysis. These findings suggest that certain Euphorbia species exhibit selective cytotoxicity against breast cancer cells while sparing normal cells, highlighting their potential for breast cancer therapy.

Abstract: Predicting whether a compound is subject to active transport is crucial in drug development. We propose a simple threshold for passive membrane permeability Pm, derived from the cell’s energy limitation, to identify compounds unlikely to be actively effluxed. For MDCK cells, this threshold—normalized to the applied compound concentration (Cext)—was determined to be log(Pm*Cext / [cm/s*µM] ) = -1.7. To derive this threshold, we conducted an extensive analysis of literature-reported efflux ratios (ER) in MDCKII-MDR1, MDCK-BCRP, and MDCK-MRP2 cells (294 datapoints across 136 unique compounds). Concentration-dependent measurements for Amprenavir, Eletriptan, Loperamide, and Quinidine enabled the most accurate determination of the threshold. Literature ER values were re-evaluated through the experimental determination of reliable Pm values, as well as newly measured ER values with MDCK efflux assays. The results of these assays and the re-evaluation allowed us to reclassify all but three outliers (compounds with ER > 2.5 and log(Pm*Cext) > −1.7). In contrast, more than 60% of the compounds analyzed without significant ER values (123 compounds) fell above the threshold, in strong agreement with our theory of an energy limitation to active transport. This permeability threshold thus provides a simple and broadly applicable criterion to identify compounds for which active efflux is energetically not feasible, offering a practical tool for early drug discovery and optimization.

Abstract:

Polyalthia longifolia, a member of the Annonaceae family, is traditionally used for its medicinal properties, including as an antidiabetic remedy, primarily in Asia and sub-Saharan Africa. This study investigated the potential of six P. longifolia extracts in counteracting hyperglycemia and diabetes-related complications. Aqueous, ethanol, and methanol extracts from leaves and stems were evaluated for their antihyperglycemic, antiglycation, and antiradical properties using α-glucosidase, BSA, and ORAC assays, respectively. Phytochemical characterization was conducted using TPC and TFC assays, and HPLC analysis identified specific bioactive compounds, including various phenolic compounds and flavonoids (mainly baicalein). The MTT assay on the human cell line HT-29 assessed the activity of extracts on cell viability, showing slight cytotoxicity. Results demonstrated significant antidiabetic activity of the ethanol and methanol extracts from P. longifolia leaves. This study provides new insights into the potential use of P. longifolia in diabetes mellitus and supports the valorization of traditional medicinal plants.

Abstract: Curcumin is widely used for its antioxidant and anti-inflammatory properties, but its poor oral bioavailability has driven the development of advanced formulations such as CAVACURMIN®, a gamma-cyclodextrin-based curcumin complex with enhanced absorption. Given recent regulatory scrutiny of high-bioavailability curcumin products, we evaluated the subacute oral safety of CAVACURMIN® in Wistar rats. Animals received 2000 mg/kg/day (low dose) or 3500 mg/kg/day (high dose) for 28 days, with controls receiving vehicle or γ-cyclodextrin alone. No mortality or systemic toxicity occurred, except for one incidental death unrelated to treatment. Dose-dependent local, transient post-dosing signs (salivation, bedding displacement) were attributed to sensory or irritant effects. Clinical chemistry showed modest, non-adverse shifts—including decreased urea (up to −25 % in males) and increased albumin (up to +9 % in females)—that may indicate favourable pharmacological effects such as enhanced nitrogen retention and mild anti-inflammatory modulation. All other parameters, including body weight, food intake, haematology, organ weights (except a small, non-adverse liver weight increase in high-dose females), and gross pathology, were comparable to controls. These findings demonstrate that CAVACURMIN® was well tolerated at doses up to 3500 mg/kg/day, supporting its safety and suitability for further evaluation in an OECD 408-compliant 90-day toxicity study.