P-glycoprotein (P-gp)-driven cancer drug resistance: biological profile, non-coding RNAs, drugs and nanomodulators.

Drug resistance has compromised the efficacy of chemotherapy. The dysregulation of drug transporters including P-glycoprotein (P-gp) can mediate drug resistance through drug efflux. In this review, we highlight the role of P-gp in cancer drug resistance and the related molecular pathways, including phosphoinositide 3-kinase (PI3K)-Akt, phosphatase and tensin homolog (PTEN) and nuclear factor-κB (NF-κB), along with non-coding RNAs (ncRNAs). Extracellular vesicles secreted by the cells can transport ncRNAs and other proteins to change P-gp activity in cancer drug resistance. P-gp requires ATP to function, and the induction of mitochondrial dysfunction or inhibition of glutamine metabolism can impair P-gp function, thus increasing chemosensitivity. Phytochemicals, small molecules and nanoparticles have been introduced as P-gp inhibitors to increase drug sensitivity in human cancers.

Tirzepatide: unveiling a new dawn in dual-targeted diabetes and obesity management.

INTRODUCTION: Incretin-based therapies have emerged as effective treatments for type 2 diabetes (T2D) and obesity. However, not all patients achieve optimal outcomes with existing treatments, highlighting the need for more effective solutions. AREAS COVERED: We present a comprehensive evaluation of Tirzepatide (TZP), a novel dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 (GIP/GLP-1) receptor agonist, for managing obesity and T2D. We conducted a systematic search of Cochrane, PubMed, Scopus, and Web of Science databases from inception to April 2024. The focus of the review is on the development and therapeutic potential of TZP, with detailed exploration on pharmacodynamics, pharmacokinetics, clinical efficacy, and safety. Furthermore, it reviews TZP's impacts on glycemic control, weight management, and its potential cardiovascular (CV) benefits. EXPERT OPINION: TZP represents a significant advancement in the dual-targeted approach to treating T2D and obesity. Its unique mechanism of action offers superior efficacy in reducing glycemic levels and body weight compared to existing therapies. New data suggesting improvements in CV outcomes indicate that TZP could set a new standard in the treatment paradigm. While long-term data on efficacy and safety are still forthcoming, current evidence positions TZP as a promising option for patients who have not reached their therapeutic goals with existing treatments.

Deciphering Depression: Epigenetic Mechanisms and Treatment Strategies.

Depression, a significant mental health disorder, is under intense research scrutiny to uncover its molecular foundations. Epigenetics, which focuses on controlling gene expression without altering DNA sequences, offers promising avenues for innovative treatment. This review explores the pivotal role of epigenetics in depression, emphasizing two key aspects: (I) identifying epigenetic targets for new antidepressants and (II) using personalized medicine based on distinct epigenetic profiles, highlighting potential epigenetic focal points such as DNA methylation, histone structure alterations, and non-coding RNA molecules such as miRNAs. Variations in DNA methylation in individuals with depression provide opportunities to target genes that are associated with neuroplasticity and synaptic activity. Aberrant histone acetylation may indicate that antidepressant strategies involve enzyme modifications. Modulating miRNA levels can reshape depression-linked gene expression. The second section discusses personalized medicine based on epigenetic profiles. Analyzing these patterns could identify biomarkers associated with treatment response and susceptibility to depression, facilitating tailored treatments and proactive mental health care. Addressing ethical concerns regarding epigenetic information, such as privacy and stigmatization, is crucial in understanding the biological basis of depression. Therefore, researchers must consider these issues when examining the role of epigenetics in mental health disorders. The importance of epigenetics in depression is a critical aspect of modern medical research. These findings hold great potential for novel antidepressant medications and personalized treatments, which would significantly improve patient outcomes, and transform psychiatry. As research progresses, it is expected to uncover more complex aspects of epigenetic processes associated with depression, enhance our comprehension, and increase the effectiveness of therapies.

Customizable Microfluidic Devices: Progress, Constraints, and Future Advances.

The field of microfluidics encompasses the study of fluid behavior within micro-channels and the development of miniature systems featuring internal compartments or passageways tailored for fluid control and manipulation. Microfluidic devices capitalize on the unique chemical and physical properties exhibited by fluids at the microscopic scale. In contrast to their larger counterparts, microfluidic systems offer a multitude of advantages. Their implementation facilitates the investigation and utilization of reduced sample, solvent, and reagent volumes, thus yielding decreased operational expenses. Owing to their compact dimensions, these devices allow for the concurrent execution of multiple procedures, leading to expedited experimental timelines. Over the past two decades, microfluidics has undergone remarkable advancements, evolving into a multifaceted discipline. Subfields such as organ-on-a-chip and paper-based microfluidics have matured into distinct fields of study. Nonetheless, while scientific progress within the microfluidics realm has been notable, its translation into autonomous end-user applications remains a frontier to be fully explored. This paper sets forth the central objective of scrutinizing the present research paradigm, prevailing limitations, and potential prospects of customizable microfluidic devices. Our inquiry revolves around the latest strides achieved, prevailing constraints, and conceivable trajectories for adaptable microfluidic technologies. We meticulously delineate existing iterations of microfluidic systems, elucidate their operational principles, deliberate upon encountered limitations, and provide a visionary outlook toward the future trajectory of microfluidic advancements. In summation, this work endeavors to shed light on the current state of microfluidic systems, underscore their operative intricacies, address incumbent challenges, and unveil promising pathways that chart the course toward the next frontier of microfluidic innovation.

Autophagy in aging-related diseases and cancer: Principles, regulatory mechanisms and therapeutic potential.

Macroautophagy/autophagy is primarily accountable for the degradation of damaged organelles and toxic macromolecules in the cells. Regarding the essential function of autophagy for preserving cellular homeostasis, changes in, or dysfunction of, autophagy flux can lead to disease development. In the current paper, the complicated function of autophagy in aging-associated pathologies and cancer is evaluated, highlighting the underlying molecular mechanisms that can affect longevity and disease pathogenesis. As a natural biological process, a reduction in autophagy is observed with aging, resulting in an accumulation of cell damage and the development of different diseases, including neurological disorders, cardiovascular diseases, and cancer. The MTOR, AMPK, and ATG proteins demonstrate changes during aging, and they are promising therapeutic targets. Insulin/IGF1, TOR, PKA, AKT/PKB, caloric restriction and mitochondrial respiration are vital for lifespan regulation and can modulate or have an interaction with autophagy. The specific types of autophagy, such as mitophagy that degrades mitochondria, can regulate aging by affecting these organelles and eliminating those mitochondria with genomic mutations. Autophagy and its specific types contribute to the regulation of carcinogenesis and they are able to dually enhance or decrease cancer progression. Cancer hallmarks, including proliferation, metastasis, therapy resistance and immune reactions, are tightly regulated by autophagy, supporting the conclusion that autophagy is a promising target in cancer therapy.

Deciphering the Mechanisms and Biotechnological Implications of Nanoparticle Synthesis Through Microbial Consortia.

Nanomaterial synthesis is a growing study area because of its extensive range of uses. Nanoparticles' high surface-to-volume ratio and rapid interaction with various particles make them appealing for diverse applications. Traditional physical and chemical methods for creating metal nanoparticles are becoming outdated because they involve complex manufacturing processes, high energy consumption, and the formation of harmful by-products that pose major dangers to human health and the environment. Therefore, there is an increasing need to find alternative, cost-effective, dependable, biocompatible, and environmentally acceptable ways of producing nanoparticles. The process of synthesizing nanoparticles using microbes has become highly intriguing because of their ability to create nanoparticles of varying sizes, shapes, and compositions, each with unique physicochemical properties. Microbes are commonly used in nanoparticle production because they are easy to work with, can use low-cost materials, such as agricultural waste, are cheap to scale up, and can adsorb and reduce metal ions into nanoparticles through metabolic activities. Biogenic synthesis of nanoparticles provides a clean, nontoxic, ecologically friendly, and sustainable method using renewable ingredients for reducing metals and stabilizing nanoparticles. Nanomaterials produced by bacteria can serve as an effective pollution control method due to their many functional groups that can effectively target contaminants for efficient bioremediation, aiding in environmental cleanup. At the end of the paper, we will discuss the obstacles that hinder the use of biosynthesized nanoparticles and microbial-based nanoparticles. The paper aims to explore the sustainability of microorganisms in the burgeoning field of green nanotechnology.

Precision arrows: Navigating breast cancer with nanotechnology siRNA.

Nanotechnology-based drug delivery systems, including siRNA, present an innovative approach to treating breast cancer, which disproportionately affects women. These systems enable personalized and targeted therapies, adept at managing drug resistance and minimizing off-target effects. This review delves into the current landscape of nanotechnology-derived siRNA transport systems for breast cancer treatment, discussing their mechanisms of action, preclinical and clinical research, therapeutic applications, challenges, and future prospects. Emphasis is placed on the importance of targeted delivery and precise gene silencing in improving therapeutic efficacy and patient outcomes. The review addresses specific hurdles such as specificity, biodistribution, immunological reactions, and regulatory approval, offering potential solutions and avenues for future research. SiRNA drug delivery systems hold promise in revolutionizing cancer care and improving patient outcomes, but realizing their full potential necessitates ongoing research, innovation, and collaboration. Understanding the intricacies of siRNA delivery mechanisms is pivotal for designing effective cancer treatments, overcoming challenges, and advancing siRNA-based therapies for various diseases, including cancer. The article provides a comprehensive review of the methods involved in siRNA transport for therapeutic applications, particularly in cancer treatment, elucidating the complex journey of siRNA molecules from extracellular space to intracellular targets. Key mechanisms such as endocytosis, receptor-mediated uptake, and membrane fusion are explored, alongside innovative delivery vehicles and technologies that enhance siRNA delivery efficiency. Moreover, the article discusses challenges and opportunities in the field, including issues related to specificity, biodistribution, immune response, and clinical translation. By comprehending the mechanisms of siRNA delivery, researchers can design and develop more effective siRNA-based therapies for various diseases, including cancer.

Exploring Scopoletin's Therapeutic Efficacy in DSS-Induced Ulcerative Colitis: Insights into Inflammatory Pathways, Immune Modulation, and Microbial Dynamics.

This study aimed to investigate the therapeutic potential of scopoletin in ulcerative colitis, with a primary focus on its impact on crucial inflammatory pathways and immune responses. A male mouse model of DSS-induced colitis was employed with six distinct groups: a control group, a group subjected to DSS only, three groups treated with varying scopoletin doses, and the final group treated with dexamethasone. The investigation included an assessment of the effects of scopoletin on colitis symptoms, including alterations in body weight, Disease Activity Index (DAI), and histopathological changes in colonic tissue. Furthermore, this study scrutinized the influence of scopoletin on cytokine production, PPARγ and NF-κB expression, NLRP3 inflammasome, and the composition of intestinal bacteria. Scopoletin treatment yielded noteworthy improvements in DSS-induced colitis in mice, as evidenced by reduced weight loss and colonic shortening (p < 0.05, < 0.01, respectively). It effectively diminished TNF-α, IL-1ß, and IL-12 cytokine levels (p < 0.01, p < 0.05), attenuated NLRP3 inflammasome activation and the associated cytokine release (p < 0.05, p < 0.01), and modulated the immune response by elevating PPARγ expression while suppressing NF-κB pathway activation (p < 0.05, p < 0.01). Additionally, scopoletin induced alterations in the gut microbiota composition, augmenting beneficial Lactobacillus and Bifidobacteria while reducing E. coli (p < 0.05). It also enhanced tight junction proteins, signifying an improvement in the intestinal barrier integrity (p < 0.05, < 0.01). Scopoletin is a promising therapeutic agent for managing ulcerative colitis, showing benefits that extend beyond mere anti-inflammatory actions to encompass regulatory effects on gut microbiota and restoration of intestinal integrity.

Nanomaterial-Driven Precision Immunomodulation: A New Paradigm in Therapeutic Interventions.

Immunotherapy is a rapidly advancing field of research in the treatment of conditions such as cancer and autoimmunity. Nanomaterials can be designed for immune system manipulation, with precise targeted delivery and improved immunomodulatory efficacy. Here, we elaborate on various strategies using nanomaterials, including liposomes, polymers, and inorganic NPs, and discuss their detailed design intricacies, mechanisms, and applications, including the current regulatory issues. This type of nanomaterial design for targeting specific immune cells or tissues and controlling release kinetics could push current technological frontiers and provide new and innovative solutions for immune-related disorders and diseases without off-target effects. These materials enable targeted interactions with immune cells, thereby enhancing the effectiveness of checkpoint inhibitors, cancer vaccines, and adoptive cell therapies. Moreover, they allow for fine-tuning of immune responses while minimizing side effects. At the intersection of nanotechnology and immunology, nanomaterial-based platforms have immense potential to revolutionize patient-centered immunotherapy and reshape disease management. By prioritizing safety, customization, and compliance with regulatory standards, these systems can make significant contributions to precision medicine, thereby significantly impacting the healthcare landscape.

The Complex Connection between Obesity and Cancer: Signaling Pathways and Therapeutic Implications.

Obesity has emerged as an important global health challenge, significantly influencing the incidence and progression of various cancers. This comprehensive review elucidates the complex relationship between obesity and oncogenesis, focusing particularly on the role of dysregulated signaling pathways as central mediators of this association. We delve into the contributions of obesity-induced alterations in key signaling cascades, including PI3K/AKT/mTOR, JAK/STAT, NF-κB, and Wnt/ß-catenin to carcinogenesis. These alterations facilitate unchecked cellular proliferation, chronic inflammation and apoptosis resistance. Epidemiological evidence links obesity with increased cancer susceptibility and adverse prognostic outcomes, with pronounced risks for specific cancers such as breast, colorectal, endometrial and hepatic malignancies. This review synthesizes data from both animal and clinical studies to underscore the pivotal role of disrupted signaling pathways in shaping innovative therapeutic strategies. We highlight the critical importance of lifestyle modifications in obesity management and cancer risk mitigation, stressing the benefits of dietary changes, physical activity, and behavioral interventions. Moreover, we examine targeted pharmacological strategies addressing aberrant pathways in obesity-related tumors and discuss the integration of cutting-edge treatments, including immunotherapy and precision medicine, into clinical practice.

Insomnia and fibromyalgia-like symptoms among women diagnosed with relapsing remitting multiple sclerosis in Jordan: Prevalence and correlates.

OBJECTIVE: This study investigated the prevalence and correlates of fibromyalgia and insomnia in a sample of Women with Multiple Sclerosis (WMS). METHODS: The study was cross-sectional in design and recruited a sample of 163 women with Relapsing-Remitting Multiple Sclerosis (RRMS). Fibromyalgia was assessed using the Patient Self-Report Survey (PSRS), following criteria outlined by the American College of Rheumatology. Insomnia was measured using the Arabic version of the Insomnia Severity Index (ISI-A). RESULTS: The prevalence of fibromyalgia and insomnia was 28.2% (n = 46) and 46.3% (n = 76), respectively. Multivariate analyses were used to determine significant independent correlates. Fibromyalgia was associated with age above 40 years (OR = 2.29, 95% CI = 1.01-5.18, P = .04), high school education (OR = 3.69, 95% CI = 1.62-8.37, P = .002), and non-use of analgesics (OR = .02, 95% CI = .004-.21, P = .001). Insomnia symptoms were significantly associated only with age above 40 years (OR = 2.16, 95% CI = 1.16-4.04, P = .01). CONCLUSION: These findings highlight the need for increased attention by primary care physicians towards diagnosing and treating fibromyalgia and insomnia among women with RRMS in Jordan, particularly among older women.

Circular RNAs in EMT-driven metastasis regulation: modulation of cancer cell plasticity, tumorigenesis and therapy resistance.

The non-coding RNAs comprise a large part of human genome lack of capacity in encoding functional proteins. Among various members of non-coding RNAs, the circular RNAs (circRNAs) have been of importance in the pathogenesis of human diseases, especially cancer. The circRNAs have a unique closed loop structure and due to their stability, they are potential diagnostic and prognostic factors in cancer. The increasing evidences have highlighted the role of circRNAs in the modulation of proliferation and metastasis of cancer cells. On the other hand, metastasis has been responsible for up to 90% of cancer-related deaths in patients, requiring more investigation regarding the underlying mechanisms modulating this mechanism. EMT enhances metastasis and invasion of tumor cells, and can trigger resistance to therapy. The cells demonstrate dynamic changes during EMT including transformation from epithelial phenotype into mesenchymal phenotype and increase in N-cadherin and vimentin levels. The process of EMT is reversible and its reprogramming can disrupt the progression of tumor cells. The aim of current review is to understanding the interaction of circRNAs and EMT in human cancers and such interaction is beyond the regulation of cancer metastasis and can affect the response of tumor cells to chemotherapy and radiotherapy. The onco-suppressor circRNAs inhibit EMT, while the tumor-promoting circRNAs mediate EMT for acceleration of carcinogenesis. Moreover, the EMT-inducing transcription factors can be controlled by circRNAs in different human tumors.

Revolutionizing Glucose Monitoring: Enzyme-Free 2D-MoS2 Nanostructures for Ultra-Sensitive Glucose Sensors with Real-Time Health-Monitoring Capabilities.

The growing requirement for real-time monitoring of health factors such as heart rate, temperature, and blood glucose levels has resulted in an increase in demand for electrochemical sensors. This study focuses on enzyme-free glucose sensors based on 2D-MoS2 nanostructures explored by simple hydrothermal route. The 2D-MoS2 nanostructures were characterized by powder X-ray diffraction, energy-dispersive X-ray spectroscopy, scanning electron microscopy, transmission electron microscopy, Raman spectroscopy, and XPS techniques and were immobilized at GCE to obtain MoS2-GCE interface. The fabricated interface was characterized by electrochemical impedance spectroscopy which shows less charge transfer resistance and demonstrated superior electrocatalytic properties of the modified surface. The sensing interface was applied for the detection of glucose using amperometry. The MoS2-GCE-sensing interface responded effectively as a nonenzymatic glucose sensor (NEGS) over a linearity range of 0.01-0.20 µM with a very low detection limit of 22.08 ng mL-1. This study demonstrates an easy method for developing a MoS2-GCE interface, providing a potential option for the construction of flexible and disposable nonenzymatic glucose sensors (NEGS). Moreover, the fabricated MoS2-GCE electrode precisely detected glucose molecules in real blood serum and urine samples of diabetic and nondiabetic persons. These findings suggest that 2D-MoS2 nanostructured materials show considerable promise as a possible option for hyperglycemia detection and therapy. Furthermore, the development of NEGS might create new prospects in the glucometer industry.

Unraveling the tumor microenvironment: Insights into cancer metastasis and therapeutic strategies.

This comprehensive review delves into the pivotal role of the tumor microenvironment (TME) in cancer metastasis and therapeutic response, offering fresh insights into the intricate interplay between cancer cells and their surrounding milieu. The TME, a dynamic ecosystem comprising diverse cellular and acellular elements, not only fosters tumor progression but also profoundly affects the efficacy of conventional and emerging cancer therapies. Through nuanced exploration, this review illuminates the multifaceted nature of the TME, elucidating its capacity to engender drug resistance via mechanisms such as hypoxia, immune evasion, and the establishment of physical barriers to drug delivery. Moreover, it investigates innovative therapeutic approaches aimed at targeting the TME, including stromal reprogramming, immune microenvironment modulation, extracellular matrix (ECM)-targeting agents, and personalized medicine strategies, highlighting their potential to augment treatment outcomes. Furthermore, this review critically evaluates the challenges posed by the complexity and heterogeneity of the TME, which contribute to variable therapeutic responses and potentially unintended consequences. This underscores the need to identify robust biomarkers and advance predictive models to anticipate treatment outcomes, as well as advocate for combination therapies that address multiple facets of the TME. Finally, the review emphasizes the necessity of an interdisciplinary approach and the integration of cutting-edge technologies to unravel the intricacies of the TME, thereby facilitating the development of more effective, adaptable, and personalized cancer treatments. By providing critical insights into the current state of TME research and its implications for the future of oncology, this review highlights the dynamic and evolving landscape of this field.

Advances in glioblastoma multiforme: Integrating therapy and pathology perspectives.

Glioblastoma, a highly lethal form of brain cancer, is characterized by its aggressive growth and resistance to conventional treatments, often resulting in limited survival. The response to therapy is notably influenced by various patient-specific genetic factors, underscoring the disease's complexity. Despite the utilization of diverse treatment modalities such as surgery, radiation, and chemotherapy, many patients experience local relapse, emphasizing the critical need for improved therapeutic strategies to effectively target these formidable tumors. Recent years have witnessed a surge in interest in natural products derived from plants, particularly alkaloids, for their potential anticancer effects. Alkaloids have shown promise in cancer chemotherapy by selectively targeting crucial signaling pathways implicated in tumor progression and survival. Specifically, they modulate the NF-κB and MAPK pathways, resulting in reduced tumor growth and altered gene expression across various cancer types. Additionally, alkaloids exhibit the capacity to induce cell cycle arrest, further impeding tumor proliferation in several malignancies. This review aims to delineate recent advances in understanding the pathology of glioblastoma multiforme (GBM) and to explore the potential therapeutic implications of alkaloids in managing this deadly disease. By segregating discussions on GBM pathology from those on alkaloid-based therapies, we provide a structured overview of the current challenges in GBM treatment and the promising opportunities presented by alkaloid-based interventions. Furthermore, we briefly discuss potential future directions in GBM research and therapy beyond alkaloids, including emerging treatment modalities or areas of investigation that hold promise for improving patient outcomes. In conclusion, our efforts offer hope for enhanced outcomes and improved quality of life for GBM patients through alkaloid-based therapies. By integrating insights from pathology and therapeutic perspectives, we underscore the significance of a comprehensive approach in addressing this devastating disease.

Correction: Cano-Vicent et al. Biocompatible Alginate Hydrogel Film Containing Acetic Acid Manifests Broad-Spectrum Antiviral and Anticancer Activities. Biomedicines 2023, 11, 2549.

In the original publication [...].

Pathophysiology, diagnosis, and herbal medicine-based therapeutic implication of rheumatoid arthritis: an overview.

Rheumatoid arthritis (RA) stands as an autoimmune disorder characterized by chronic joint inflammation, resulting in profound physiological alterations within the body. Affecting approximately 0.4-1.3% of the global population, this condition poses significant challenges as current therapeutic approaches primarily offer symptomatic relief, with the prospect of complete recovery remaining elusive. This review delves into the contemporary advancements in understanding the pathophysiology, diagnosis, and the therapeutic potential of herbal medicine in managing RA. Notably, early diagnosis during the initial stages emerges as the pivotal determinant for successful recovery post-treatment. Utilizing tools such as Magnetic Resonance Imaging (MRI), anti-citrullinated peptide antibody markers, and radiography proves crucial in pinpointing the diagnosis of RA with precision. Unveiling the intricate pathophysiological mechanisms of RA has paved the way for innovative therapeutic interventions, incorporating plant extracts and isolated phytoconstituents. In the realm of pharmacological therapy for RA, specific disease-modifying antirheumatic drugs have showcased commendable efficacy. However, this conventional approach is not without its drawbacks, as it is often associated with various side effects. The integration of methodological strategies, encompassing both pharmacological and plant-based herbal therapies, presents a promising avenue for achieving substantive recovery. This integrated approach not only addresses the symptoms but also strives to tackle the underlying causes of RA, fostering a more comprehensive and sustainable path towards healing.

Exploring the Roles of Vitamins C and D and Etifoxine in Combination with Citalopram in Depression/Anxiety Model: A Focus on ICAM-1, SIRT1 and Nitric Oxide.

The study of intercellular adhesion molecule-1 (ICAM-1) and SIRT1, a member of the sirtuin family with nitric oxide (NO), is emerging in depression and anxiety. As with all antidepressants, the efficacy is delayed and inconsistent. Ascorbic acid (AA) and vitamin D (D) showed antidepressant properties, while etifoxine (Etx), a GABAA agonist, alleviates anxiety symptoms. The present study aimed to investigate the potential augmentation of citalopram using AA, D and Etx and related the antidepressant effect to brain and serum ICAM-1, SIRT1 and NO in an animal model. BALB/c mice were divided into naive, control, citalopram, citalopram + etx, citalopram + AA, citalopram + D and citalopram + etx + AA + D for 7 days. On the 8th day, the mice were restrained for 8 h, followed by a forced swim test and marble burying test before scarification. Whole-brain and serum expression of ICAM-1, Sirt1 and NO were determined. Citalopram's antidepressant and sedative effects were potentiated by ascorbic acid, vitamin D and etifoxine alone and in combination (p < 0.05), as shown by the decreased floating time and rearing frequency. Brain NO increased significantly (p < 0.05) in depression and anxiety and was associated with an ICAM-1 increase versus naive (p < 0.05) and a Sirt1 decrease (p < 0.05) versus naive. Both ICAM-1 and Sirt1 were modulated by antidepressants through a non-NO-dependent pathway. Serum NO expression was unrelated to serum ICAM-1 and Sirt1. Brain ICAM-1, Sirt1 and NO are implicated in depression and are modulated by antidepressants.

In situ evaluation of the impact of metformin or verapamil coadministration with vildagliptin on its regional absorption from the rabbit's intestine.

This research aims to identify regional differences in vildagliptin absorption across the intestinal membrane. Furthermore, it was to investigate the effect of verapamil or metformin on vildagliptin absorptive clearance. The study utilized an in situ rabbit intestinal perfusion technique to determine vildagliptin oral absorption from duodenum, jejunum, ileum, and ascending colon. This was conducted both with and without perfusion of metformin or verapamil. The findings revealed that the vildagliptin absorptive clearance per unit length varied by site and was in the order as follows: ileum < jejunum < duodenum < ascending colon, implying that P-gp is significant in the reduction of vildagliptin absorption. Also, the arrangement cannot reverse intestinal P-gp, but the observations suggest that P-gp is significant in reducing vildagliptin absorption. Verapamil co-perfusion significantly increased the vildagliptin absorptive clearance by 2.4 and 3.2 fold through the jejunum and ileum, respectively. Metformin co-administration showed a non-significant decrease in vildagliptin absorptive clearance through all tested segments. Vildagliptin absorption was site-dependent and may be related to the intestinal P-glycoprotein content. This may aid in understanding the important elements that influence vildagliptin absorption, besides drug-drug interactions that can occur in type 2 diabetic patients taking vildagliptin in conjunction with other drugs that can modify the P-glycoprotein level.