Current drug metabolism最新文献

TOX high mobility group box family member 4 (TOX4) has emerged as a critical regulator of Hepatic Glucose Production (HGP), particularly under insulin-resistant condi-tions seen in Type 2 Diabetes Mellitus (T2DM). Hyperglycemia-induced formation of Ad-vanced Glycation End products (AGEs) exacerbates metabolic dysfunction. While the Akt-FoxO1 axis has been the conventional focus of insulin signaling, recent findings highlight the upregulation of TOX4 in T2DM, obesity, and preclinical models (e.g., db/db mice). The cAMP signaling pathway has been shown to modulate TOX4 expression. This review syn-thesizes findings from recent in vivo and in vitro studies investigating the role of TOX4 in hepatic metabolism. The study focuses on its regulatory mechanisms, interaction with insu-lin signalling pathways, and its modulation through pharmacological inhibition. TOX4 in-hibition significantly reduces glucose output in hepatocytes and improves glucose tolerance in animal models. While TOX4 ablation fails to reverse metabolic impairments caused by insulin receptor knockout, it nonetheless attenuates hepatic glucose production under insu-lin-resistant states. Additionally, TOX4 suppression shows hepatoprotective effects and may offer potential neuroprotection in the context of diabetic complications. TOX4 represents a promising therapeutic target for managing T2DM and its comorbidities. Further investiga-tion into selective TOX4 inhibitors and their long-term safety profiles could facilitate the development of adjunct therapies for metabolic disorders involving hepatic and neuronal dysfunction.

Introduction: Cancer poses a tough global health challenge, prompting the exploration of innovative prevention and treatment strategies. Polyphenols, bioactive compounds abundant in various plant-based foods, have gained significant attention for their potential anticancer properties. Legumes, characterized by their excellent nutritional profile, offer a promising source of polyphenols such as ferulic acid, caffeic acid, genistein, and kaempferol, which exhibit notable antioxidative and anti-inflammatory effects.

Methods: This review systematically analyzed peer-reviewed literature on the polyphenolic content of various legumes. No original research or experimental work was carried out as part of this study. Databases such as PubMed, Google Scholar, Scopus, SpringerLink, and ScienceDirect were searched for studies focusing on the identification and pharmacokinetic profiles of legume-derived polyphenols. Emphasis was placed on examining the mechanisms of action, including modulation of cell signalling pathways, induction of apoptosis, inhibition of angiogenesis, and influence on detoxification enzymes. The review also assessed the ADME (absorption, distribution, metabolism, and excretion) properties of key polyphenols to evaluate their bioavailability and therapeutic efficacy.

Results: The analysis revealed that legumes are significant sources of polyphenols with demonstrated anti-cancer activity. Compounds like genistein and kaempferol modulate key signalling pathways such as PI3K/Akt, MAPK, and NF-kB, which are involved in cell proliferation, survival, and inflammation. Additionally, these polyphenols can promote apoptosis and inhibit angiogenesis, thereby impeding tumor growth and metastasis.

Discussion: The findings underscore the potential of legume-derived polyphenols in cancer prevention and management. By addressing the ADME of Polyphenols, this study aims to deepen our understanding of their pharmacological potential, providing a foundation for developing dietary strategies and functional foods to effectively prevent and manage cancer. Addressing the limitations in bioavailability through novel delivery systems and dietary formulations could enhance their effectiveness.

Conclusion: Combining polyphenol-rich legume diets with conventional cancer therapies may offer a synergistic therapeutic effect and promote better health outcomes. However, it is essential to first establish through rigorous scientific research that polyphenols do not produce any unwanted adverse effects when used alongside standard medications. Further research focusing on improving bioavailability and validating in vivo efficacy will be crucial for translating these findings into practical cancer prevention treatment approaches.

Introduction: Type 2 diabetes mellitus (T2DM), characterized by insulin resistance (IR) and hepatic ectopic lipid deposition (ELD), poses a complex metabolic challenge. This study aimed to elucidate the mechanisms of Yiqi Huazhuo Decoction (YD) through an inte-grated approach combining network pharmacology and metabolomics. T2DM is marked by impaired insulin signaling and disrupted hepatic lipid metabolism, resulting in a vicious cycle that accelerates disease progression. While Traditional Chinese Medicine (TCM), such as YD, demonstrates potential in modulating these dysfunctions, its underlying molecular mecha-nisms remain to be fully clarified.

Materials and methods: A diabetic fat rat model was used to evaluate the efficacy of YD. UPLC-MS characterized the main metabolites found in YD. After an 8-week intervention, physiological indices and hepatic pathology were assessed. Network pharmacology identified bioactive metabolites and targets, which were validated by molecular docking. Untargeted metabolomics was employed to analyze hepatic metabolic changes.

Results: YD improved glucose/lipid metabolism, insulin sensitivity, and hepatic function. Net-work pharmacology revealed that YD acts via the EGFR and PI3K-Akt/IL-17 pathways. Mo-lecular docking confirmed luteolin-EGFR binding. Metabolomics identified 20 altered metab-olites in the biosynthesis of unsaturated fatty acids. Multi-omics analysis revealed that YD regulated EGFR and hepatic metabolic networks.

Discussion: The multi-metabolite, multi-target mechanism of YD distinguishes it apart from single-target drugs, such as metformin. The binding of luteolin to EGFR may potentially re-activate the PI3K-Akt signaling pathway, thereby enhancing insulin sensitivity. Regulation of metabolic pathways, including the biosynthesis of unsaturated fatty acids, contributes to the reduction of hepatic lipid deposition. These findings underscore the capacity of YD to disrupt the IR-ELD cycle in T2DM.

Conclusion: YD ameliorates T2DM-IR and hepatic ELD by modulating EGFR signaling and metabolic pathways, providing multi-omics evidence for its clinical application.

Background: Numerous chronic illnesses, including diabetes, cancer, cardiovascular dis-ease, and neurological disorders, are mostly caused by oxidative stress, which is defined as an imbal-ance between the body's antioxidant defenses and the generation of reactive oxygen species (ROS). The success of traditional treatments for oxidative stress has been limited because antioxidant medications are not well-absorbed, are quickly broken down, and do not target specific areas of the body.

Methods: Drug delivery methods based on nanotechnology offer a viable solution to these issues by providing therapeutic molecules with improved release characteristics, enhanced bioavailability, and targeted capabilities. Recent developments in nanotechnology have enabled the creation of multipur-pose carriers that can simultaneously transmit genes for endogenous antioxidant enzymes and antioxi-dants.

Results: This integration promotes a long-term healing response and addresses the immediate oxidative stress. Likewise, functionalizing nanocarriers with particular ligands improves localization to oxidative stress locations, including inflammatory tissues or tumor microenvironments, boosting therapeutic ef-ficacy. The potential of nanotherapeutics in reducing oxidative stress-driven diseases is examined in this article.

Discussion: Nanotechnology-based drug delivery approaches offer a novel avenue for the treatment of several oxidative stress-induced diseases. These delivery systems are highly target-specific and have a longer duration of action. Still, more research is needed to address issues, such as safety margins, large-scale production, and approval of medicine use.

Conclusion: We address several nanocarrier platforms, such as liposomes, polymeric nanoparticles, dendrimers, and metallic nanoparticles that have proven more effective in delivering therapeutic drugs and antioxidants to specific sites of oxidative damage. Furthermore, nanotherapeutics may enhance their therapeutic potential by protecting these bioactive substances from premature degradation and clearance.

Alzheimer's disease (AD), the most common form of dementia, is characterized by progressive cognitive decline and neuropathological hallmarks, including amyloid-beta plaques and tau tangles. Emerging evidence implicates metabolic dysfunction as a critical contributor to the pathogenesis and pro-gression of AD. Impaired glucose metabolism, mitochondrial dysfunction, oxidative stress, and lipid dysregulation are frequently observed in AD brains, suggesting that metabolic dysfunction may exacerbate neurodegeneration and cognitive deficits. This review explores the therapeutic potential of targeting met-abolic pathways to mitigate AD pathology. Key metabolic disruptions, including insulin resistance, re-duced cerebral glucose utilization, and mitochondrial inefficiency, are closely linked to neuronal energy deficits and synaptic dysfunction. Therapeutic approaches, such as insulin sensitizers, ketogenic diets, and mitochondrial-targeted antioxidants, have shown promise in preclinical and early clinical studies. Addi-tionally, strategies to modulate lipid metabolism, such as enhancing cholesterol efflux via APOE or re-ducing neurotoxic ceramides, offer potential avenues for intervention. The review also highlights the roles of neuroinflammation and oxidative stress as mediators of metabolic dysfunction in AD, underscoring the need for multifaceted approaches that target both metabolic and inflammatory pathways. The emerging field of precision medicine offers opportunities to tailor interventions based on individual metabolic pro-files, potentially enhancing treatment efficacy. Despite the growing recognition of metabolic dysfunction in AD, translating these insights into effective therapies remains challenging due to the disease's com-plexity and heterogeneity. Future research must focus on elucidating the interplay between metabolic pathways and AD pathology, identifying reliable biomarkers, and designing targeted interventions. By addressing the metabolic underpinnings of AD, this review underscores the potential of metabolic repro-gramming as a novel and integrative therapeutic strategy to slow or prevent disease progression and im-prove patient outcomes.

Introduction: Remimazolam is a short-acting sedative/anesthetic. For safe breastfeeding, infor-mation on the extent and possible risks of remimazolam passing through a mother´s milk to the infant is needed. The objective of this work was to study the transfer of remimazolam from maternal to infant circula-tion by mother´s milk in an animal model.

Methods: Three lactating British milk sheep received intravenous remimazolam (0.4 mg/kg bolus plus 4-hr-infusion at 1 or 2 mg/kg/hour). Drug profiles were recorded in plasma and milk. Six suckling lambs were administered remimazolam by intravenous and oral gavage administration for a comparison of plasma con-centration profiles of remimazolam and its primary metabolite, CNS7054.

Results: Treatment of lactating sheep induced dose-dependent sedation and loss of consciousness. At the end of infusion, the concentration of remimazolam was higher in milk than in plasma. The subsequent elimination of remimazolam from milk was rapid, although somewhat slower than from plasma.

Discussions: In lambs, intravenous, but not oral, remimazolam (2 mg) caused different grades of sedation/an-esthesia (fully reversible within 8 to 15 min). Mean plasma Cmax was 278.3 ng/mL after intravenous and 1.3 ng/mL after oral administration. Oral gavage resulted in a sizable plasma concentration of CNS7054 (Cmax around 100 ng/mL), indicating efficient intestinal absorption of the parent drug, followed by extensive first-pass metabolic elimination, leading to negligible bioavailability of oral remimazolam.

Conclusion: In mother´s milk, remimazolam reaches higher concentrations than in plasma and is cleared by redistribution to the central compartment for final hepatic elimination. In lambs, oral remimazolam results in minimal plasma concentrations, suggesting that safety concerns regarding breast-fed infants would be minor and could be completely alleviated by a short nursing interruption.

Physiologically based pharmacokinetic (PBPK) modeling is a computational technique that uses the physicochemical properties of drugs and physiological information to simulate plasma and tissue concen-trations. PBPK modeling has become a mainstream approach in drug research and development, frequently employed to support regulatory packages for new drug applications. Understanding the pharmacokinetic char-acteristics of anti-HIV drugs is essential for successful treatment. In recent decades, PBPK modeling has been commonly used in the development and clinical therapy of anti-HIV medications. This review discusses the prevalence and application of PBPK modeling in the pharmacokinetics of anti-HIV drugs. Among the articles retrieved for this review, PBPK modeling was predominantly employed for anti-HIV drugs in contexts, such as pregnancy, drug-drug interactions, and pediatrics. The most commonly used software programs for this model are Simcyp, MATLAB, and PK-sim. This review will provide insights for researchers in applying PBPK models to manage patients with HIV infection, aiming to enhance the efficacy of anti-HIV drug therapy and prevent undesirable adverse effects.

In recent years, the development of medical technologies leveraging nanomedicine has witnessed remarkable progress, particularly in areas such as targeted drug delivery, controlled drug release, tissue engineering, and in vitro diagnostics. This review explores the transformative impact of nanotechnology on medical imaging, focusing on developing novel contrast agents. Diagnostic imaging techniques, including Positron Emission Tomography (PET), Computed Tomography, and Magnetic Resonance Imaging, have become indispensable tools in modern healthcare. Contrast agents play an important role in enhancing the sensitivity of these imaging modalities, enabling the detection of previously undetectable anomalies. Nanotechnology offers unprecedented opportunities to revolutionize contrast agent design, leading to improved imaging modalities and diagnostic accuracy. Due to their high X-ray attenuation coefficients, metal-based inorganic nanoparticles, such as gold, bismuth, and lanthanide-based nanomaterials, exhibit significant potential as CT contrast agents. Furthermore, the pharmacokinetic properties and drug metabolism profiles of these nanomaterials are critical in ensuring their safety, efficacy, and optimal performance in clinical applications. Moreover, nanomaterials with integrated diagnostic and therapeutic capabilities are emerging as promising candidates for real-time disease detection and image-guided treatment. This review highlights the properties of nanomaterials that make them suitable for use as contrast agents. It discusses the challenges and opportunities in developing multifunctional nanomaterials for medical and diagnostic purposes. Overall, nanotechnology-enabled contrast agents have the potential to redefine the landscape of medical imaging, paving the way for more precise diagnosis and personalized treatment strategies.

Introduction: Hepatic lipid accumulation (steatosis) is an early indicator of non-alcoholic fatty liver disease (NAFLD), preceding fibrosis and cirrhosis. Understanding its effects on drug-me-tabolizing enzymes (DMEs) and transporters is crucial for assessing potential alterations in drug dis-position among NAFLD patients. This study aimed to replicate steatosis in an in vitro HepaRG cell model and analyze its impact on DMEs and transporters.

Methods: Differentiated HepaRG cells were treated with a mixture of saturated (palmitate) and unsatu-rated (oleate) fatty acids (in a 1:2 ratio at 0.5 mM), complexed with BSA for 72 hours to induce lipid accumulation. Confirmation of steatosis was performed using Oil Red O staining and triglyceride (TG) quantification, while cell viability was assessed via the WST-1 assay. RNA sequencing and SWATH-MS proteomic analysis were employed to identify differentially expressed transcripts and proteins in lipid-loaded cells compared to controls.

Results: Lipid loading resulted in a ~6-fold increase in TG concentration without compromising cell viability. Transcriptomic analysis identified 393 differentially expressed transcripts (89 upregulated, 304 downregulated), while proteomic analysis detected 165 differentially expressed proteins (127 up-regulated, 38 downregulated). Notably, key mRNA transcripts related to transcription factors (NR1I2, HNF4α), phase 1 DMEs (CYP1A2, 2B6, 2C8, 2C9, 2C19, 3A4), phase 2 DMEs (UGT1A6, 2B7, SULT2A1, 1E1), and transporters (ABCC11, ABCG5, SLCO2B1, SLC10A1) exhibited significant downregulation.

Discussion: The observed alterations in DMEs and transporters suggest a potential shift in drug me-tabolism pathways under NAFLD conditions. Downregulation of transcription factors and metabolic enzymes could impact drug efficacy and toxicity, necessitating further research into the pharmacoki-netic implications.

Conclusion: The in vitro hepatic steatosis model demonstrated significant changes in the expression of clinically relevant DMEs and transporters. These findings highlight the importance of considering NAFLD-induced metabolic alterations when assessing drug disposition in affected patients.

Background: Tetrandrine (TET) demonstrates therapeutic potential for hypoxic pulmonary hypertension (HPH); however, its precise pharmacological mechanisms remain unclear. In this study, we aimed to investigate the effects of TET on pulmonary vascular remodeling (PVR) in HPH and elucidate the molecular pathways through which TET ameliorates HPH.

Methods: We established a rat model of HPH and evaluated the therapeutic effects of TET by measuring hemodynamic parameters, assessing right ventricular hypertrophy, and analyzing pathological changes in lung tissue. To explore the molecular mechanisms, we carried out comprehensive analyses using transcriptome and untargeted metabolomics technologies to examine the impact of TET on gene expression and metabolite profiles in the lung tissue of HPH rats. Using data from these multiomics analyses, we performed biochemical assays, immunofluorescence staining, and Western blotting to validate the effects of TET on vasoconstriction and angiogenesis-related factors. These experiments provide further evidence of the anti-HPH and anti-PVR properties of TET.

Results: TET intervention significantly reduced hemodynamic parameters, including mean pulmonary arterial pressure (mPAP) and right ventricular systolic pressure (RVSP), as well as right ventricular hypertrophy indices, such as the right ventricular hypertrophy index (RVHI) and right ventricle-to-body weight ratio (RV/BW), in HPH rats. TET inhibited smooth muscle cell proliferation and alleviated pathological changes in lung tissue. Transcriptome and metabolome analyses revealed that genes affected by TET intervention were enriched in pathways related to PVR, including those involved in endothelial and smooth muscle cell proliferation, angiogenesis, and blood vessel morphogenesis. Metabolites were predominantly associated with the arachidonic acid (AA) metabolism pathway. Differentially expressed genes included Cyp4a1, Cyp4a3, Cyp2u1, and Alox15. Validation experiments demonstrated that TET upregulated ALOX15 protein expression and downregulated CYP4A and CYP2U1 proteins, modulating levels of arachidonate metabolites 20-HETE and 15(S)-HPETE. We further observed that TET reduced the levels of PVR markers, including endothelin-1 (ET-1) secretion, while increasing nitric oxide (NO) release. TEt also decreased the expression of cell proliferation markers PCNA and Ki-67 and elevated the endothelial marker CD31. Moreover, TET intervention suppressed angiogenic and vasoconstrictive factors, such as MMP-9, TGF-β1, IGF2, and PDGF-B, while enhancing levels of FGF9 and NOS3.

Conclusion: Our findings highlight the protective effects of TET on lung tissue in HPH mediated through the regulation of 15(S)-HPETE and 20-HETE within the arachidonic acid metabolism pathway. This regulation inhibits pulmonary angiogenesis and vasoconstriction, ultimately improving PVR in HPH.