Camels are commonly administered butylscopolamine (BSA), an antimuscarinic quaternary ammonium derivative, to reduce spasms in the smooth muscles of their urinary and gastrointestinal tracts. However, its presence in body fluids after racing is prohibited by animal racing authorities. The current study aimed to conduct a pilot pharmacokinetic study of BSA in healthy camels. The goal was to obtain initial pharmacokinetic parameters and use these parameters to predict plasma concentrations from the dose and clearance. This will help advise on a withdrawal time for BSA administration before camel racing. The pharmacokinetics of BSA were evaluated in three healthy camels after a single intravenous dose of 0.2 mg/kg body weight. Sensitive liquid chromatography with tandem mass spectrometry was used for the quantification of BSA and the internal standard, ipratropium, in plasma. BSA concentration versus time data were best described by a two-compartment open model. The pharmacokinetic parameters (median and range) were as follows: terminal elimination half-life was 2.29 (1.48–2.46) h, plasma clearance was 1,018.5 (772.4–1,024.0) mL/h/kg, volume of distribution at steady state was 931.9 (700.0–1,068.7) mL/kg, Cmax was 443.9 (351.1–443.9) ng/mL, and Tmax was 0.5 (0.25–0.75) h. BSA’s irrelevant plasma concentration was estimated to be 20 ng/mL. Consequently, it can be concluded that plasma would not contain BSA at the screening level of 20 ng/mL at the usual dose of 0.2 mg/kg body weight 24 h before camel racing.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its more advanced form, metabolic dysfunction-associated steatohepatitis, have emerged as the most prevalent liver diseases worldwide. Currently, lifestyle modification is the foremost guideline-recommended management strategy for MASLD. However, it remains unclear which detrimental signals persist in MASLD even after disease remission. Thus, we aimed to examine the persistent changes in liver transcriptomic profiles following this reversal.

Male C57BL/6J mice were divided into three groups: Western diet (WD) feeding, chow diet (CD) feeding, or diet reversal from WD to CD. After 16 weeks of feeding, RNA sequencing was performed on the mice’s livers to identify persistent alterations characteristic of MASLD. Additionally, RNA sequencing databases containing high-fat diet-fed P53-knockout mice and human MASLD samples were utilized.

WD-induced MASLD triggered persistent activation of the DNA damage response (DDR) and its primary transcription factor, P53, long after the resolution of the hepatic phenotype through dietary reversal. Elevated levels of P53 might promote apoptosis, thereby exacerbating metabolic dysfunction-associated steatohepatitis, as they strongly correlated with hepatocyte ballooning, an indicator of apoptosis activation. Moreover, P53 knockout in mice led to downregulated expression of apoptosis signaling in the liver. Mechanistically, P53 may regulate apoptosis by transcriptionally activating the expression of apoptosis-enhancing nuclease (AEN). Consistently, P53, AEN, and the apoptosis process all exhibited persistently elevated expression and showed a strong inter-correlation in the liver following dietary reversal.

The liver demonstrated upregulation of DDR signaling and the P53-AEN-apoptosis axis both during and after exposure to WD. Our findings provide new insights into the mechanisms of MASLD relapse, highlighting DDR signaling as a promising target to prevent MASLD recurrence.

Aging is an intricate process driven by various factors, including the dynamic interplay between the host microbiome and aging. The gut microbiome undergoes several changes throughout the entire lifespan of a healthy human. Numerous factors, ranging from the mode of childbirth and sex differences to lifestyle, are known to impact the gut microbiome in healthy individuals. As a result, the gut microbiome varies widely among individuals and exhibits robustness after early childhood. However, as one ages, the human body undergoes several important changes, and so does the gut microbiome. This review addresses the relationship between aging and the dynamics of the host microbiome from in utero to over 100 years of age. Additionally, we attempted to untangle this intricate relationship between the gut microbiome and aging by presenting various microbiota-dependent mechanisms involving intrinsic and extrinsic factors such as metabolic, neurological, immunological, dietary, and lifestyle factors that potentially regulate aging. Furthermore, we aimed to highlight microbiome-based aging intervention studies focused on modulating or rejuvenating the microbiota for healthy aging and longevity.

Yersinia pseudotuberculosis (Yptb) causes intestinal infection and can spread to the liver, where the bacterium induces hemosiderosis, abscesses, and hepatitis. To evade the immune response of the host organism, Yptb expresses at least six plasmid-encoded Yersinia outer proteins belonging to the Type III secretion system, which suppress phagocytic activity. Recently, evidence has accumulated that chromosome-encoded protein toxins are also involved in the anti-phagocytic defense of Yptb. Most of these toxins have been found in isolates from patients with Far East scarlet-like fever, often accompanied by liver pathology. Yersinia proteins contribute to bacterial colonization of lymphoid organs through their effects on immune cells. A thorough understanding of the immunomodulatory effects of these toxic proteins on bacterial dissemination and colonization in the liver will contribute to the development of novel approaches to cure hepatic pathology during Yptb infection. The review aimed to summarize the current data on the mechanisms of effects of Yptb plasmid- and chromosome-encoded toxins on bacterial colonization in the liver. The review highlights the fine-tuning of immune system activity by toxins encoded by both a 70-kb plasmid and chromosomes, through various mechanisms of action of individual proteins and their interactions. The focus is on mechanisms that promote bacterial survival in macrophages, including those that facilitate bacterial-induced macrophage polarization towards the M2 phenotype. The role of a type of phagocyte death in bacterial dissemination and colonization in the organs is also discussed.

Hematological malignancies present a complex challenge within oncology, necessitating a thorough understanding of genetic factors for effective detection and management. As we delved into the forefront of cancer research, our focus turned to the emerging field of N6-methyladenosine (m6A) epigenetic approaches. Among RNA modifications, m6A is the most common and thoroughly investigated post-transcriptional alteration in messenger RNA. The m6A modification involves the addition of a methyl group to the adenosine at the N6 position within RNA molecules, a process mediated by proteins collectively referred to as m6A writers, erasers, and readers. The dynamic nature of m6A modifications on RNA molecules presents a promising avenue for enhancing our understanding of gene expression regulation in hematological malignancies. This review explores the potential breakthroughs that m6A epigenetic tools offer in cancer diagnostics and treatment, highlighting their role in enabling more precise interventions. By acknowledging the importance of genetic insights and integrating advancements in m6A epigenetics, this article advocates for a comprehensive approach to managing hematological malignancies.

Over the past decade, significant progress has been made in managing acute myeloid leukemia (AML). However, refractory disease and relapse continue to pose major challenges. These issues highlight the need for innovative therapeutic options to achieve deeper remission and effectively treat refractory and relapsed diseases, thereby improving survival rates. Natural killer (NK) cell-based therapies have emerged as a promising option. NK cells, a specialized population of innate lymphoid cells, exhibit inherent anti-viral and anti-cancer capabilities. Unlike T cells, NK cells do not require prior antigen sensitization to eliminate their target cells, enhancing their potential as immunotherapeutic agents. However, NK cells often exhibit dysfunction in patients with hematological malignancies. Revitalizing these cells represent another immunotherapeutic strategy. Various NK cell-based therapies have been explored in recent decades, particularly in managing AML. These therapies include chimeric antigen receptor-NK cell therapy, bispecific and trispecific NK cell engagers (bi-specific killer cell engager (BiKEs) and tri-specific killer cell engager (TriKEs), and cytokine-induced memory-like NK cells. These therapies are also associated with fewer adverse events, such as neurotoxicity. Despite their potential for clinical cancer management, challenges such as the in vivo expansion of NK cells remain unresolved. This review summarizes the biology of NK cells and the diverse NK cell-based therapies being developed for the potential management of AML, as evidenced in preclinical studies and clinical trials.

Gastric cancer is the third most common cause of cancer-related death globally. The highest incidence is encountered in Asia, followed by Europe which has the second highest incidence worldwide. In Europe, gastric cancer is typically diagnosed at an advanced stage, with an estimated five-year survival rate of 24%, compared to 59% in Japan. This disparity is largely attributed to the significant role of screening in Japan. Given the expected rise in absolute numbers of gastric cancer cases, there has been a demand for gastric cancer screening programmes in high-intermediate risk countries, advocated by the International Agency for Research on Cancer, the Science Advice for Policy by European Academies, the European Commission as part of the Europe Beating Cancer Plan, and the Maastricht VI/Florence consensus guidelines. This review article summarizes the current disparities in screening strategies between countries in the East and West and comments on future developments in population-based screening research in this field. The references for this article were identified through PubMed, the Cochrane Database of Systematic Reviews, and the Cochrane Controlled Register of Trials using the search terms “gastric cancer”, “stomach cancer”, “Helicobacter pylori”, and “screening” over the period from 1995 until March 2024. Overall, this review identifies three potential approaches to screening: primary, secondary, and opportunistic. It highlights the lack of a uniform consensus on the best approach to screening, the disparity in the information available in different populations, and upcoming research to address this disparity.

Given the global prevalence and rising incidence of metabolic dysfunction-associated steatotic liver disease (MASLD), the absence of licensed medications is striking. A deeper understanding of the heterogeneous nature of MASLD has recently contributed to the discovery of novel groups of agents and the potential repurposing of currently available medications. MASLD therapies center on four major pathways. Considering the close relationship between MASLD and type 2 diabetes, the first approach involves antidiabetic medications, including incretins, thiazolidinedione insulin sensitizers, and sodium-glucose cotransporter 2 inhibitors. The second approach targets hepatic lipid accumulation and the resultant metabolic stress. Agents in this group include peroxisome proliferator-activated receptor agonists (e.g., pioglitazone, elafibranor, saroglitazar), bile acid-farnesoid X receptor axis regulators (obeticholic acid), de novo lipogenesis inhibitors (aramchol, NDI-010976), and fibroblast growth factor 21/19 analogs. The third approach focuses on targeting oxidative stress, inflammation, and fibrosis. Agents in this group include antioxidants (vitamin E), tumor necrosis factor α pathway regulators (emricasan, pentoxifylline, ZSP1601), and immune modulators (cenicriviroc, belapectin). The final group targets the gut (IMM-124e, solithromycin). Combination therapies targeting different pathogenetic pathways may provide an alternative to MASLD treatment with higher efficacy and fewer side effects. This review aimed to provide an update on these medications.

Like other drugs, adjuvants are ligands with distinct structures that interact with specific cell receptors, modulating the immune response. This definition excludes formulations and delivery systems. New adjuvants may be discovered using methods based on a ligand and its receptor’s structural and functional traits, a process known as rational drug design. This strategy requires detailed information about both the receptors and their ligands. Such information is obtained using techniques like X-ray crystallography and 2D-nuclear magnetic resonance (NMR) to establish the spatial interactions between a ligand’s functional groups and its receptor. This data is necessary to establish reliable structure-activity relationships, which, when applied to computer-aided drug design, facilitate the creation of better adjuvants as an empirical strategy. Since Quillaja saponin adjuvants likely act separately on innate and adaptive immune cells via specific functional groups and unidentified cell receptors, it is crucial to identify these receptors. This task may be achieved using bioorthogonal chemistry and proteomic methods to identify and isolate the receptors. Initially focusing on those unidentified receptors where chemical modifications of these glycosides, such as the aldehyde group and fucose residue, cause drastic changes in adjuvanticity. The isolated receptor(s) can then be characterized by X-ray crystallography and/or 2D-NMR; this information can be applied to computer-aided drug design to rationally design new derivatives. This methodology will prevent the proposition of dubious structure-activity relationships based on incomplete immunological data, unknown receptors, and unsuspected physical factors, providing essential information for designing new adjuvants and elucidating these compounds’ mechanisms of action.

Medication non-adherence among youth with chronic health conditions is a healthcare crisis in the United States. Nearly 20% of youth experience a chronic illness, yet most do not comply with their treatment regimen. Various challenges to adherence arise, such as not understanding the purpose of treatment, painful or difficult administration, forgetfulness, and mood disorders such as anxiety. Cognitive behavioral therapy (CBT) is an empirically supported approach to increasing treatment adherence. Modular CBT incorporates psychoeducation, cognitive restructuring, and behavioral experiments to promote better disease management. This article focuses on the application of CBT to four medical conditions characterized by elevated levels of non-adherence: pill-swallowing difficulties, asthma, type 1 diabetes, and inflammatory bowel disease in youth. The review integrates findings on contextual issues (e.g., ethnocultural variations, the impact of the COVID-19 pandemic), research on non-adherence, and CBT outcome studies. Additionally, limitations of the existing literature and training recommendations are provided.

Peroxisome proliferator-activated receptors (PPARs) participate in the fatty acid oxidation, the homeostasis of lipid and glucose metabolism, the regulation of insulin sensitivity, and numerous metabolic processes, making them novel and important therapeutic targets for cancer treatment. However, PPARs manifest dual functions, wherein their activation and inhibition engender diverse outcomes in different types of tumors. The specificity of drugs for tumors is also a challenge when targeting PPARs. In recent years, proteolysis targeting chimeras (PROTACs) have gained significant attention in the field of cancer therapy, demonstrating potent therapeutic potential in both basic and clinical research. Furthermore, heterobifunctional molecules derived from PROTACs have ventured into domains that extend beyond protein degradation. Currently, there are no developed PPAR-targeting PROTACs. Therefore, our review delves into various aspects, including the dual roles of PPARs, known inhibitors, agonists, ligands, and co-crystal structures, and explores the feasibility and advantages of PPAR-targeting PROTACs and other heterobifunctional molecules in cancer therapy.

Cirrhosis is often characterized by decreased liver function, ranging from a compensated, typically asymptomatic phase to a decompensated phase characterized by the appearance of ascites or variceal bleeding, and ultimately hepatorenal syndrome (HRS) or hepatopulmonary syndrome (HPS). The latter two complications are associated with a poor prognosis and limited treatment efficacy. In cases of ascites or variceal bleeding resistant to medical therapy, transjugular intrahepatic portosystemic shunt (TIPS) is effective and safe. Shunting blood by TIPS diverts portal blood to the systemic circulation, potentially increasing systemic blood volume and benefiting renal function. However, TIPS could also divert nitric oxide to the systemic circulation, potentially worsening systemic hypotension and perfusion, which could be detrimental to renal function. Available evidence indicates that TIPS often improves renal function in patients with portal hypertension, with or without HRS. No studies have shown persistently decreased renal function after TIPS. However, these data are insufficient to support a recommendation for the use of TIPS specifically for HRS. In patients without pre-existing HPS, TIPS does not appear to significantly affect pulmonary gas exchange. Results of TIPS in HPS have been inconsistent; some studies have shown improvement, but effects were transient. No studies have shown a persistent decline in pulmonary function after TIPS. The evidence supports the need for large randomized controlled trials to investigate the beneficial effects of TIPS for HRS. Similar pulmonary function data are less clear regarding TIPS for HPS. The aim of the current report was to review the literature regarding the effects of TIPS on renal and pulmonary function in hepatic decompensation, with or without the development of HRS or HPS.

Disorders of blood lipids and lipoproteins are a global problem and a high-risk factor for atherosclerosis in patients with rheumatoid arthritis (RA). This article presents data on the influence of inflammation on proatherogenic disorders of lipid and lipoprotein metabolism, with an emphasis on proinflammatory cytokines. It analyzes the blood lipid profile in RA patients and identifies the need to study subfractions of high-density lipoproteins and their function in reverse cholesterol transport in RA patients as a more promising direction for clarifying cardiovascular risk. Depending on their type and metabolites, lipids may either promote disease progression or protect against RA. Supported by the close connection between altered lipid metabolism and chronic autoimmune inflammation, specific lipid profiles are emerging as unique disease biomarkers with diagnostic, predictive, and prognostic potential. Studying the influence of the immunoinflammatory process on lipids and lipoproteins in the blood of patients with RA will not only deepen knowledge about the pathogenesis of chronic inflammation but also expand understanding of the pathogenetic and prognostic significance of lipids, allowing for early diagnosis of dyslipidemia in RA at a qualitatively new level.

Natural products have been used effectively to treat different ailments since the advent of human history. Angiosperms contain numerous bioactive molecules that have been applied as medicines to treat various human diseases, including cancer. Jamun (Syzygium cumini) is an angiosperm belonging to the Myrtaceae family. This comprehensive review on Jamun includes information collected from Google Scholar, SciFinder, PubMed, ScienceDirect, and other websites on the internet, giving an account of its botanical profile, chemical composition, and medicinal properties. Ethnomedicinally, various parts of Jamun are used to treat various conditions and have been administered since ancient times in Ayurveda to treat arthritis, obesity, urinary diseases, asthma, bowel spasms, stomach pain, flatulence, diabetes, and dysentery. Several scientific studies also have demonstrated the pluripotent medicinal properties of Jamun, including anti-oxidant, anti-allergic, antiretinitis, antipyretic, antidiarrheal, antinociceptive, anticancer, antidiabetic, anti-obesity, antihyperlipidemic, anti-inflammatory, antimicrobial, diuretic, cardioprotective, chemopreventive, gastroprotective, immunomodulatory, hepatoprotective, wound healing, anthelmintic, and radioprotective. Jamun contains alkaloids, anthraquinones, catechins, cardiac glycosides, flavonoids, glycosides, steroids, phenols, tannins, and saponins. Numerous active phytochemicals have been isolated from its roots, stems, leaves, flowers, fruits, and seeds. Jamun increases glutathione, glutathione peroxidase, catalase, and superoxide dismutase expression and reduces lipid peroxidation levels to exert its beneficial effects on important organs and tissues. Jamun also protects against DNA damage induced by toxic agents including metals, chemicals and ionizing radiation. Jamun activates peroxisome proliferator-activated receptors alpha and gamma and increases fatty acid and glucose metabolism. Additionally, Jamun suppresses various genes at the molecular level. Thus, the scientific evaluation of Jamun is a step forward in validating its traditional use to treat various disorders and may pave the way for translational research for its medicinal use.

The most prevalent form of dementia, Alzheimer’s disease (AD), is a neurological disorder that causes gradual memory loss. AD is characterized by amyloid-beta plaques, neurofibrillary tangles, and neuron loss. While preclinical and clinical trials are underway to reduce the generation and overall brain disease load, current treatment focuses on alleviating symptoms. Animal studies are essential for advancing our understanding of AD, identifying potential drug targets, and testing experimental therapies. An ideal animal model not only exhibits the same symptoms and pathological changes as a human disease but also follows the same sequence of pathological events. This review highlights the various inducing agents used to model AD in animals, such as streptozotocin, aluminium chloride, trimethyltin, lipopolysaccharide, scopolamine, and others, along with their underlying mechanisms. The outcomes of some studies that used such inducing agents to develop AD are discussed briefly. Among chemically induced models, streptozotocin and amyloid-beta are the most frequently used, while d-galactose, scopolamine, and aluminium-induced models are being used because they are non-invasive, reproducible, and compatible. However, none of the chemical/drug-induced models fully capture the scope of AD pathology and cognitive impairment. Overall, further research is necessary to establish the stability of the models in terms of consistency and reproducibility.

Organic anion-transporting polypeptides (OATPs) play a crucial role in the transport of bile acids and bilirubin. In our previous study, interleukin 6 (IL-6) reduced OATP1B3 levels in cholestatic disease. However, it remains unclear whether IL-6 inhibits OATP1B1 expression in cholestatic diseases. This study aimed to investigate whether IL-6 can inhibit OATP1B1 expression and explore the underlying mechanisms.

The effect of stimulator of interferon genes (STING) signaling on inflammatory factors was investigated in a cholestatic mouse model using RT-qPCR and enzyme-linked immunosorbent assay. To assess the impact of inflammatory factors on OATP1B1 expression in hepatocellular carcinoma, we analyzed OATP1B1 expression by RT-qPCR and Western Blot after treating PLC/PRF/5 cells with TNF-α, IL-1β, and IL-6. To elucidate the mechanism by which IL-6 inhibits OATP1B1 expression, we examined the expression of the OATP1B1 regulator TCF4 in PLC/PRF/5 and HepG2 cells using RT-qPCR and Western Blot. The interaction mechanism between β-catenin/TCF4 and OATP1B1 was investigated by knocking down β-catenin/TCF4 through siRNA transfection.

The STING inhibitor decreased inflammatory factor levels in the cholestatic mouse model, with IL-6 exhibiting the most potent inhibitory effect on OATP1B1. IL-6 downregulated β-catenin/TCF4, leading to decreased OATP1B1 expression. Knocking-down β-catenin/TCF4 counteracted the β-catenin/TCF4-mediated repression of OATP1B1.

STING-mediated IL-6 up-regulation may inhibit OATP1B1, leading to reduced transport of bile acids and bilirubin by OATP1B1. This may contribute to altered pharmacokinetics in patients with diseases associated with increased IL-6 production.