Immunological mechanisms in steatotic liver diseases: An overview and clinical perspectives.

Steatotic liver diseases (SLD) are the principal worldwide cause of cirrhosis and end-stage liver cancer, affecting nearly a quarter of the global population. SLD includes metabolic dysfunction-associated alcoholic liver disease (MetALD) and metabolic dysfunction-associated steatotic liver disease (MASLD), resulting in asymptomatic liver steatosis, fibrosis, cirrhosis and associated complications. The immune processes include gut dysbiosis, adipose-liver organ crosstalk, hepatocyte death and immune cell-mediated inflammatory processes. Notably, various immune cells such as B cells, plasma cells, dendritic cells, conventional CD4+ and CD8+ T cells, innate-like T cells, platelets, neutrophils and macrophages play vital roles in the development of MetALD and MASLD. Immunological modulations targeting hepatocyte death, inflammatory reactions and gut microbiome include N-acetylcysteine, selonsertib, F-652, prednisone, pentoxifylline, anakinra, JKB-121, HA35, obeticholic acid, probiotics, prebiotics, antibiotics and FMT. Understanding the immunological mechanisms underlying in SLD is crucial for advancing clinical therapeutic strategies.

Formosanin C inhibits pulmonary metastasis by targeting stearyl CoA desaturase-1.

BACKGROUND: Cisplatin (DDP) as the first-line drug has been used in cancer therapy. However, side effects and drug resistance are the challenges of DDP. Disordered lipid metabolism is related to DDP resistance. STUDY DESIGN: In this study, formosanin C (FC) as the main compound of Rhizoma Paridis saponins (RPS) inhibits pulmonary metastasis by targeting stearyl CoA desaturase-1. METHODS AND RESULTS: RPS prolonged the survival period of mice, reduced pulmonary metastases and alleviated colon toxicity caused by DDP. FC as the main compound of RPS enhanced the anti-tumor and anti-metastatic effects of DDP. FC decreased the mRNA level of SCD1 and the content of lipid droplets (LDs) in lung cancer cells. Molecular dynamics and isothermal titration calorimetry verified the binding stability and spontaneously between FC and SCD1. SiSCD1 reduced the content of LDs in cell lines and increased mitochondria (mtROS), which was consistent with the results of FC treatment. The combination group decreased DNA repair associated protein as well as DDP resistance markers such as ERCC1 and 53bp1, and increased DNA damage marker like γH2AX, which indirectly confirmed the occurrence of mtROS. In addition, FC combination with DDP also affected epithelial-mesenchymal transition-related protein like VIM and CDH1 in vivo experiments, and thereby inhibited pulmonary metastasis. CONCLUSION: Our research indicated that the FC as the main compound of RPS targeted the CY2 domain of SCD1, inhibited lipid metabolism in mice, and thereby suppressed cancer metastases. This provided support for use of FC to treat cancer based on lipid metabolism pathway.

Enhanced precision and efficiency in metabolic regulation: Compartmentalized metabolic engineering.

Metabolic engineering has witnessed remarkable advancements, enabling successful large-scale, cost-effective and efficient production of numerous compounds. However, the predominant expression of heterologous genes in the cytoplasm poses limitations, such as low substrate concentration, metabolic competition and product toxicity. To overcome these challenges, compartmentalized metabolic engineering allows the spatial separation of metabolic pathways for the efficient and precise production of target compounds. Compartmentalized metabolic engineering and its common strategies are comprehensively described in this study, where various membranous compartments and membraneless compartments have been used for compartmentalization and constructive progress has been made. Additionally, the challenges and future directions are discussed in depth. This review is dedicated to providing compartmentalized, precise and efficient methods for metabolic production, and provides valuable guidance for further development in the field of metabolic engineering.

Pectin: Health-promoting properties as a natural galectin-3 inhibitor.

Galectin-3 has a variety of important pathophysiological significance in the human body. Much evidence shows that the abnormal expression of galectin-3 is related to the formation and development of many diseases. Pectin is mostly obtained from processed citrus fruits and apples and is a known natural inhibitor of galactin-3. A large number of peels produced each year are discarded, and it is necessary to recycle some of the economically valuable active compounds in these by-products to reduce resource waste and environmental pollution. By binding with galectin-3, pectin can directly reduce the expression level of galectin-3 on the one hand, and regulate the expression level of cytokines by regulating certain signaling pathways on the other hand, to achieve the effect of treating diseases. This paper begins by presenting an overview of the basic structure of pectin, subsequently followed by a description of the structure of galectin-3 and its detrimental impact on human health when expressed abnormally. The health effects of pectin as a galectin-3 inhibitor were then summarized from the perspectives of anticancer, anti-inflammatory, ameliorating fibrotic diseases, and anti-diabetes. Finally, the challenges and prospects of future research on pectin are presented, which provide important references for expanding the application of pectin in the pharmaceutical industry or developing functional dietary supplements.

Evaluation of citrus pectin extraction methods: Synergistic enhancement of pectin's antioxidant capacity and gel properties through combined use of organic acids, ultrasonication, and microwaves.

The biological potency of pectin is intricately intertwined with its intricate molecular architecture. The fine structure of pectin is influenced by the extraction method, while the specific impact of these methods on the fine structure and the affected attributes thereof remains enigmatic. This study delves into the profound analysis of eight distinct extraction methods influence on the structure and biological activity of citrus peel pectin. The findings demonstrate that citric acid ultrasound-assisted microwave extraction yields pectin (PectinCA-US/MV) with higher viscosity and a dense, rigid chain. Pectin extracted with acetic acid ultrasound (PectinAA-US) and citric acid ultrasound (PectinCA-US) exhibits elevated galacturonic acid (GalA) levels and reduced D-galactose (Gal) content, enhancing antioxidant activity. Eight pectin-chitosan (CS) hydrogels, especially PectinCA-US/MV-CS, demonstrate commendable thermal stability, rheological properties, self-healing capability, and swelling behavior. This study characterizes citrus peel pectin properties from different extraction methods, laying a foundation for its application in food, pharmaceuticals, and industry.

Prospects of yam (Dioscorea) polysaccharides: Structural features, bioactivities and applications.

Yam (Dioscorea) is a tuber crop cultivated for food security, revenue, and medicinal purposes. It has been used to treat diabetes, asthma, diarrhea, and other diseases. The main active ingredients in yam, polysaccharides, are regarded to be the important reason for its widespread applications. Now, a comprehensive review of research developments of yam polysaccharides (YPs) was presented to explore their prospects. We outlined the structural characteristics, biological activities, structure-activity relationships, and potential applications. Around 13 neutral components and 17 acidic components were separated. They exhibited various bioactivities, including immunomodulatory, hypoglycemic, hypolipidemic, antioxidant, gastrointestinal protective, anti-fatigue, and senile disease treatment activities, as well as prebiotic effect. Structure-activity relationships illustrated that unique structural properties, chemical modifications, and carried biopolymers could influence the bioactivities of YPs. The potential applications in medicine, food, and other fields have also been summarized.

Expression of Concern: Conjugation of substituted naphthalimides to polyamines as cytotoxic agents targeting the Akt/mTOR signal pathway.

Expression of Concern for 'Conjugation of substituted naphthalimides to polyamines as cytotoxic agents targeting the Akt/mTOR signal pathway' by Zhi-Yong Tian et al., Org. Biomol. Chem., 2009, 7, 4651-4660, https://doi.org/10.1039/B912685F.

A New Potent Inhibitor against α-Glucosidase Based on an In Vitro Enzymatic Synthesis Approach.

Inhibiting the activity of intestinal α-glucosidase is considered an effective approach for treating type II diabetes mellitus (T2DM). In this study, we employed an in vitro enzymatic synthesis approach to synthesize four derivatives of natural products (NPs) for the discovery of therapeutic drugs for T2DM. Network pharmacology analysis revealed that the betulinic acid derivative P3 exerted its effects in the treatment of T2DM through multiple targets. Neuroactive ligand-receptor interaction and the calcium signaling pathway were identified as key signaling pathways involved in the therapeutic action of compound P3 in T2DM. The results of molecular docking, molecular dynamics (MD) simulations, and binding free energy calculations indicate that compound P3 exhibits a more stable binding interaction and lower binding energy (-41.237 kcal/mol) with α-glucosidase compared to acarbose. In addition, compound P3 demonstrates excellent characteristics in various pharmacokinetic prediction models. Therefore, P3 holds promise as a lead compound for the development of drugs for T2DM and warrants further exploration. Finally, we performed site-directed mutagenesis to achieve targeted synthesis of betulinic acid derivative. This work demonstrates a practical strategy of discovering novel anti-hyperglycemic drugs from derivatives of NPs synthesized through in vitro enzymatic synthesis technology, providing potential insights into compound P3 as a lead compound for anti-hyperglycemic drug development.

Diosgenin as a substitute for cholesterol alleviates NAFLD by affecting CYP7A1 and NPC1L1-related pathway.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) rapidly becomes the leading cause of end-stage liver disease or liver transplantation. Nowadays, there has no approved drug for NAFLD treatment. Diosgenin as the structural analogue of cholesterol attenuates hypercholesterolemia by inhibiting cholesterol metabolism, which is an important pathogenesis in NAFLD progression. However, there has been no few report concerning its effects on NAFLD so far. METHODS: Using a high-fat diet & 10% fructose-feeding mice, we evaluated the anti-NAFLD effects of diosgenin. Transcriptome sequencing, LC/MS analysis, molecular docking simulation, molecular dynamics simulations and Luci fluorescent reporter gene analysis were used to evaluate pathways related to cholesterol metabolism. RESULTS: Diosgenin treatment ameliorated hepatic dysfunction and inhibited NAFLD formation including lipid accumulation, inflammation aggregation and fibrosis formation through regulating cholesterol metabolism. For the first time, diosgenin was structurally similar to cholesterol, down-regulated expression of CYP7A1 and regulated cholesterol metabolism in the liver (p < 0.01) and further affecting bile acids like CDCA, CA and TCA in the liver and feces. Besides, diosgenin decreased expression of NPC1L1 and suppressed cholesterol transport (p < 0.05). Molecular docking and molecular dynamics further proved that diosgenin was more strongly bound to CYP7A1. Luci fluorescent reporter gene analysis revealed that diosgenin concentration-dependently inhibited the enzymes activity of CYP7A1. CONCLUSION: Our findings demonstrated that diosgenin was identified as a specific regulator of cholesterol metabolism, which pave way for the design of novel clinical therapeutic strategies.

The lipid droplet in cancer: From being a tumor-supporting hallmark to clinical therapy.

INTRODUCTION: Abnormal lipid metabolism, one of the hallmarks in cancer, has gradually emerged as a novel target for cancer treatment. As organelles that store and release excess lipids, lipid droplets (LDs) resemble "gears" and facilitate cancer development in the body. AIM: This review discusses the life cycle of LDs, the relationship between abnormal LDs and cancer hallmarks, and the application of LDs in theragnostic and clinical contexts to provide a contemporary understanding of the role of LDs in cancer. METHODS: A systematic literature search was conducted in PubMed and SPORTDiscus. Retrieve and summarize clinical trials of drugs that target proteins associated with LD formation using the Clinical Trials website. Create a schematic diagram of lipid droplets in the tumor microenvironment using Adobe Illustrator. CONCLUSION: As one of the top ten hallmarks of cancer, abnormal lipid metabolism caused by excessive generation of LDs interrelates with other hallmarks. The crosstalk between excessive LDs and intracellular free fatty acids (FFAs) promotes an inflammatory environment that supports tumor growth. Moreover, LDs contribute to cancer metastasis and cell death resistance in vivo. Statins, as HMGCR inhibitors, are promising to be the pioneering commercially available anti-cancer drugs that target LD formation.

Freeze-thaw cycles drove chemical weathering and enriched sulfates in the Burns formation at Meridiani, Mars.

Sulfate-rich sedimentary rocks explored by the Opportunity rover during its 14-year surface mission at Meridiani Planum provide an invaluable window into the thousands of sulfate deposits detected on Mars via remote sensing. Existing models explaining the formation of martian sulfates can be generally described as either bottom-up, groundwater-driven playa settings or top-down icy chemical weathering environments. Here, we propose a hybrid model involving both bottom-up and top-down processes driven by freeze-thaw cycles. Freezing leads to cryo-concentration of acidic fluids from precipitations at the surface, facilitating rapid chemical weathering despite low temperatures. Cryosuction causes the upward migration of vadose water and even groundwater with dissolved ions, resulting in the accumulation of ions in near-surface environments. Evaporation precipitates salts, but leaching separates chlorides from sulfates during the thawing period. Freeze-thaw cycles, therefore, can enrich sulfates at the surface. While freeze-thaw is more commonly understood as a mechanism of physical weathering, we suggest that it is a fundamental aspect of chemical weathering on Mars.

Progress of depression mechanism based on Omics method.

Depression is a very common disabling mental disorder, which is typically characterized by high rates of disability and mortality. Although research into the various mechanisms of depression was still underway, its physiopathology remains uncertain. The rapid developments in new technologies and the combined use of a variety of techniques will help to understand the pathogenesis of depression and explore effective treatment methods. In this review, we focus on the combination of proteomic and metabolomic approaches to analyze metabolites and proteins in animal models of depression induced by different modeling approaches, with the aim of broadening the understanding of the physiopathological mechanisms of depression using complementary "omics" strategy.

Microbial production and applications of ß-glucosidase-A review.

ß-Glucosidase exists in all areas of living organisms, and microbial ß-glucosidase has become the main source of its production because of its unique physicochemical properties and the advantages of high-yield production by fermentation. With the rise of the green circular economy, the production of enzymes through the fermentation of waste as the substrate has become a popular trend. Lignocellulosic biomass is an easily accessible and sustainable feedstock that exists in nature, and the production of biofuels from lignocellulosic biomass requires the involvement of ß-glucosidase. This review proposes ways to improve ß-glucosidase yield and catalytic efficiency. Optimization of growth conditions and purification strategies of enzymes can increase enzyme yield, and enzyme immobilization, genetic engineering, protein engineering, and whole-cell catalysis provide solutions to enhance the catalytic efficiency and activity of ß-glucosidase. Besides, the diversified industrial applications, challenges and prospects of ß-glucosidase are also described.

Recent Advances in Reprogramming Strategy of Tumor Microenvironment for Rejuvenating Photosensitizers-Mediated Photodynamic Therapy.

Photodynamic therapy (PDT) has recently been considered a potential tumor therapy due to its time-space specificity and non-invasive advantages. PDT can not only directly kill tumor cells by using cytotoxic reactive oxygen species but also induce an anti-tumor immune response by causing immunogenic cell death of tumor cells. Although it exhibits a promising prospect in treating tumors, there are still many problems to be solved in its practical application. Tumor hypoxia and immunosuppressive microenvironment seriously affect the efficacy of PDT. The hypoxic and immunosuppressive microenvironment is mainly due to the abnormal vascular matrix around the tumor, its abnormal metabolism, and the influence of various immunosuppressive-related cells and their expressed molecules. Thus, reprogramming the tumor microenvironment (TME) is of great significance for rejuvenating PDT. This article reviews the latest strategies for rejuvenating PDT, from regulating tumor vascular matrix, interfering with tumor cell metabolism, and reprogramming immunosuppressive related cells and factors to reverse tumor hypoxia and immunosuppressive microenvironment. These strategies provide valuable information for a better understanding of the significance of TME in PDT and also guide the development of the next-generation multifunctional nanoplatforms for PDT.

Cationic fructan-based pH and intestinal flora dual stimulation nanoparticle with berberine for targeted therapy of IBD.

Inflammatory bowel disease (IBD) can cause intestinal microbial imbalance and aggravate intestinal inflammation. Mixed fructan is more easily fermented by colonic microorganisms and can be used as colonic drug delivery materials. Here, we constructed a mixed fructan based nanoparticle with dual targeted stimulation of pH and intestinal flora to effectively deliver berberine for the treatment of ulcerative colitis (UC). The complex of fructan based nanoparticle and berberine (BBRNPs) significantly ameliorated the inflammatory response of sodium dextran sulfate (DSS)-induced colitis in mice by inhibiting the activation of NF-κB/STAT-3 pathway and increasing tight junction protein expression in vivo. Importantly, BBRNPs improved the responsiveness of colitis microbiome and effectively regulated the relative homeostasis of harmful flora Enterobacteriaceae and Escherichia-shigolla, and beneficial flora Ruminococcaceae and Akkermansiaceae. This study provides a promising strategy for the effective treatment of UC and expands the application of branched fructan in pharmaceutics.

A new insight into material basis of rhizoma Paridis saponins in alleviating pain.

ETHNOPHARMACOLOGICAL RELEVANCE: Paris polyphylla, as a traditional Chinese herbal medicine, was often used to relieve inflammation and pain. Rhizoma Paridis saponins (RPS) as the main active components of Paris polyphylla have excellent analgesic effects. AIM OF THE STUDY: Determine the analgesic material basis of RPS. MATERIALS AND METHODS: LC-MS/MS was used to analyze RPS, plasma after intravenous injection of RPS, and oral administration of RPS. H22 plantar pain model was established to explore the analgesic material basis of RPS. Moreover, correlation analysis, network pharmacology, RT-PCR and molecular docking were applied in this research. RESULTS: RPS had dose-dependently analgesic effects in acetic acid- and formalin-induced pain models. LC-MS/MS detection indicated that diosgenin as the metabolite of RPS mainly distributed in brain tissues. The addition of antibiotics increased the anti-tumor effect of RPS, but reduced its analgesic effect. Network pharmacology, RT-PCR and molecular docking showed that diosgenin exerted its analgesic effect through SRC and Rap1 signaling pathway. CONCLUSION: Diosgenin exhibited analgesic effects, while saponins had good anti-tumor effects in RPS. This discovery provided a better indication for the later application of RPS in anti-tumor and analgesic settings.

Effect of Cerebralcare Granule® combined with memantine on Alzheimer's disease.

ETHNOPHARMACOLOGICAL RELEVANCE: In elderly people, Alzheimer's disease (AD) is the most common form of dementia. It has been shown that traditional Chinese medicine (TCM) based on phytomedicines enhances the therapeutic effects of modern medicine when taken in conjunction with them. Modern medicine N-methyl-D-aspartate receptor (NMDA) antagonist memantine (Mm) are mainly used in the clinical treatment of AD. TCM Cerebralcare Granule® (CG) has long been an effective treatment for headaches, dizziness, and other symptoms. In this study, we employ a blend of CG and Mm to address Alzheimer's disease-like symptoms and explore their impacts and underlying mechanisms. AIM OF THE STUDY: The objective of our study was to observe the effects of CG combined with Memantine (Mm) on learning and memory impairment of AD mice induced by D-galactose and to explore the mechanism at work. MATERIALS AND METHODS: CG and Mm were combined to target multiple pathological processes involved in AD. For a thorough analysis, we performed various experiments such as behavioral detection, pathological detection, proteomic detection, and other experimental methods of detection. RESULTS: It was found that the combination of CG and Mm was significantly effective for improving learning and memory in AD mice as well as brain pathology. The serum and hippocampal tissue of AD mice were significantly enhanced with catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) activities and malondialdehyde (MDA) levels were decreased with this treatment. In AD mice, a combination of Mm and CG (CG + Mm) significantly increased the levels of the anti-inflammatory factors IL-4 and IL-10, decreased the levels of pro-inflammatory factors (IL-6, IL-1ß) and tumor necrosis factor-alpha (TNF-α), improved synaptic plasticity by restoring synaptophysin (SYP) and postsynaptic density protein-95 (PSD-95) expression in the hippocampus, enhanced Aß phagocytosis of microglia in AD mice, and increased mitochondrial respiratory chain enzyme complexes I, II, III, and IV, lead to an increase in the number of functionally active NMDA receptors in the hippocampus. Proteomic analysis GO analysis showed that the positive regulation gene H3BIV5 of G protein coupled receptor signal pathway and synaptic transmission was up-regulated, while the transsynaptic signal of postsynaptic membrane potential and regulation-related gene Q5NCT9 were down-regulated. Most proteins showed significant enriched signal transduction pathway profiles after CG + Mm treatment, based on the KEGG pathway database. CONCLUSION: The data supported the idea that CG and Mm could be more effective in treating AD mice induced by D-galactose than Mm alone. We provided a basis for the clinical use of CG with Mm.

Effect of activated carbon microstructure and adsorption mechanism on the efficient removal of chlorophyll a and chlorophyll b from Andrographis paniculata extract.

In order to reveal the effect of activated carbon (AC) properties on the adsorption of chlorophyll a (Chl a) and chlorophyll b (Chl b) in Andrographis paniculata extract, four commercial activated carbons were first tested and characterized. The results showed that activated carbon 1 (AC1) had the best surface area, pore structure and adsorption capacity. Therefore, adsorption isotherms, adsorption kinetics and adsorption mechanism were further carried out on AC1. The application of Langmuir model (R2 > 0.978) and Freundlich model (R2 > 0.977) indicated that the adsorption process of Chl a and Chl b on AC1 may be a complex adsorption process of single-layer and multilayer adsorption. The adsorption kinetics indicated that the pseudo-second-order kinetic model (R2 > 0.999) was dominant and was mainly chemisorption. The intra-particle diffusion model (R2 > 0.937) shows that the intra-particle diffusion is the rate-limiting step. The decrease of adsorption of AC1 to Chl a and Chl b due to the oxidation of acrylic acid proves the importance of π-π interaction.

Gut liver brain axis in diseases: the implications for therapeutic interventions.

Gut-liver-brain axis is a three-way highway of information interaction system among the gastrointestinal tract, liver, and nervous systems. In the past few decades, breakthrough progress has been made in the gut liver brain axis, mainly through understanding its formation mechanism and increasing treatment strategies. In this review, we discuss various complex networks including barrier permeability, gut hormones, gut microbial metabolites, vagus nerve, neurotransmitters, immunity, brain toxic metabolites, ß-amyloid (Aß) metabolism, and epigenetic regulation in the gut-liver-brain axis. Some therapies containing antibiotics, probiotics, prebiotics, synbiotics, fecal microbiota transplantation (FMT), polyphenols, low FODMAP diet and nanotechnology application regulate the gut liver brain axis. Besides, some special treatments targeting gut-liver axis include farnesoid X receptor (FXR) agonists, takeda G protein-coupled receptor 5 (TGR5) agonists, glucagon-like peptide-1 (GLP-1) receptor antagonists and fibroblast growth factor 19 (FGF19) analogs. Targeting gut-brain axis embraces cognitive behavioral therapy (CBT), antidepressants and tryptophan metabolism-related therapies. Targeting liver-brain axis contains epigenetic regulation and Aß metabolism-related therapies. In the future, a better understanding of gut-liver-brain axis interactions will promote the development of novel preventative strategies and the discovery of precise therapeutic targets in multiple diseases.