Metabolic disorders in prediabetes: From mechanisms to therapeutic management.

Diabetes, one of the world's top ten diseases, is known for its high mortality and complication rates and low cure rate. Prediabetes precedes the onset of diabetes, during which effective treatment can reduce diabetes risk. Prediabetes risk factors include high-calorie and high-fat diets, sedentary lifestyles, and stress. Consequences may include considerable damage to vital organs, including the retina, liver, and kidneys. Interventions for treating prediabetes include a healthy lifestyle diet and pharmacological treatments. However, while these options are effective in the short term, they may fail due to the difficulty of long-term implementation. Medications may also be used to treat prediabetes. This review examines prediabetic treatments, particularly metformin, glucagon-like peptide-1 receptor agonists, sodium glucose cotransporter 2 inhibitors, vitamin D, and herbal medicines. Given the remarkable impact of prediabetes on the progression of diabetes mellitus, it is crucial to intervene promptly and effectively to regulate prediabetes. However, the current body of research on prediabetes is limited, and there is considerable confusion surrounding clinically relevant medications. This paper aims to provide a comprehensive summary of the pathogenesis of pre-diabetes mellitus and its associated therapeutic drugs. The ultimate goal is to facilitate the clinical utilization of medications and achieve efficient and timely control of diabetes mellitus.

Carrimycin ameliorates lipopolysaccharide and cecal ligation and puncture-induced sepsis in mice.

Carrimycin (CA), sanctioned by China's National Medical Products Administration (NMPA) in 2019 for treating acute bronchitis and sinusitis, has recently been observed to exhibit multifaceted biological activities, encompassing anti-inflammatory, antiviral, and anti-tumor properties. Despite these applications, its efficacy in sepsis treatment remains unexplored. This study introduces a novel function of CA, demonstrating its capacity to mitigate sepsis induced by lipopolysaccharide (LPS) and cecal ligation and puncture (CLP) in mice models. Our research employed in vitro assays, real-time quantitative polymerase chain reaction (RT-qPCR), and RNA-seq analysis to establish that CA significantly reduces the levels of pro-inflammatory cytokines, namely tumor necrosis factor-alpha (TNF-α), interleukin 1 beta (IL-1ß), and interleukin 6 (IL-6), in response to LPS stimulation. Additionally, Western blotting and immunofluorescence assays revealed that CA impedes Nuclear Factor Kappa B (NF-κB) activation in LPS-stimulated RAW264.7 cells. Complementing these findings, in vivo experiments demonstrated that CA effectively alleviates LPS- and CLP-triggered organ inflammation in C57BL/6 mice. Further insights were gained through 16S sequencing, highlighting CA's pivotal role in enhancing gut microbiota diversity and modulating metabolic pathways, particularly by augmenting the production of short-chain fatty acids in mice subjected to CLP. Notably, a comparative analysis revealed that CA's anti-inflammatory efficacy surpasses that of equivalent doses of aspirin (ASP) and TIENAM. Collectively, these findings suggest that CA exhibits significant therapeutic potential in sepsis treatment. This discovery provides a foundational theoretical basis for the clinical application of CA in sepsis management.

Research progress on alternative kombucha substrate transformation and the resulting active components.

Kombucha is a customary tea-based beverage that is produced through the process of fermenting a mixture of tea and sugar water with symbiotic culture of bacteria and yeast (SCOBY). Traditional kombucha has various beneficial effects and can improve immunity. The significant market share of Kombucha can be attributed to the growing consumer inclination towards healthy foods within the functional beverage industry. The research focus has recently expanded from the probiotics of traditional black tea kombucha to encompass other teas, Chinese herbs, plant materials, and alternative substrates. There is a lack of comprehensive literature reviews focusing on substance transformation, functional, active substances, and efficacy mechanisms of alternative kombucha substrates. This article aimed to bridge this gap by providing an in-depth review of the biological transformation pathways of kombucha metabolites and alternative substrates. The review offers valuable insights into kombucha research, including substance metabolism and transformation, efficacy, pharmacological mechanism, and the purification of active components, offering direction and focus for further studies in this field.

Advances in Research on Type 2 Diabetes Mellitus Targets and Therapeutic Agents.

Diabetes mellitus is a chronic multifaceted disease with multiple potential complications, the treatment of which can only delay and prolong the terminal stage of the disease, i.e., type 2 diabetes mellitus (T2DM). The World Health Organization predicts that diabetes will be the seventh leading cause of death by 2030. Although many antidiabetic medicines have been successfully developed in recent years, such as GLP-1 receptor agonists and SGLT-2 inhibitors, single-target drugs are gradually failing to meet the therapeutic requirements owing to the individual variability, diversity of pathogenesis, and organismal resistance. Therefore, there remains a need to investigate the pathogenesis of T2DM in more depth, identify multiple therapeutic targets, and provide improved glycemic control solutions. This review presents an overview of the mechanisms of action and the development of the latest therapeutic agents targeting T2DM in recent years. It also discusses emerging target-based therapies and new potential therapeutic targets that have emerged within the last three years. The aim of our review is to provide a theoretical basis for further advancement in targeted therapies for T2DM.

Research progress on drugs for diabetes based on insulin receptor/insulin receptor substrate.

The number of people with diabetes worldwide is increasing annually, resulting in a serious economic burden. Insulin resistance is a major pathology in the early onset of diabetes mellitus, and therefore, related drug studies have attracted research attention. The insulin receptor/insulin receptor substrate (INSR/IRS) serves as the primary conduit in the insulin signal transduction cascade, and dysregulation of this pathway can lead to insulin resistance. Currently, there exist a plethora of hypoglycemic drugs in the market; however, drugs that specifically target INSR/IRS are comparatively limited. The literature was collected by direct access to the PubMed database, and was searched using the terms "diabetes mellitus; insulin resistance; insulin receptor; insulin receptor substrate; diabetes drug" as the main keywords for literature over the last decade. This article provides a comprehensive analysis of the structure and function of INSR and IRS proteins, as well as the drugs used for the treatment of diabetes. Additionally, it serves as a valuable reference for the advancement of novel therapeutic agents for diabetes management.

Fucoxanthin Ameliorates Sepsis via Modulating Microbiota by Targeting IRF3 Activation.

To improve patient survival in sepsis, it is necessary to curtail exaggerated inflammatory responses. Fucoxanthin (FX), a carotenoid derived from brown algae, efficiently suppresses pro-inflammatory cytokine expression via IRF3 activation, thereby reducing mortality in a mouse model of sepsis. However, the effects of FX-targeted IRF3 on the bacterial flora (which is disrupted in sepsis) and the mechanisms by which it impacts sepsis development remain unclear. This study aims to elucidate how FX-targeted IRF3 modulates intestinal microbiota compositions, influencing sepsis development. FX significantly reduced the bacterial load in the abdominal cavity of mice with cecal ligation and puncture (CLP)-induced sepsis via IRF3 activation and increased short-chain fatty acids, like acetic and propionic acids, with respect to their intestines. FX also altered the structure of the intestinal flora, notably elevating beneficial Verrucomicrobiota and Akkermansia spp. while reducing harmful Morganella spp. Investigating the inflammation-flora link, we found positive correlations between the abundances of Morganella spp., Proteus spp., Escherichia spp., and Klebsiella spp. and pro-inflammatory cytokines (IL-6, IL-1ß, and TNF-α) induced by CLP. These bacteria were negatively correlated with acetic and propionic acid production. FX alters microbial diversity and promotes short-chain fatty acid production in mice with CLP-induced sepsis, reshaping gut homeostasis. These findings support the value of FX for the treatment of sepsis.

Application of Kombucha Fermentation Broth for Antibacterial, Antioxidant, and Anti-Inflammatory Processes.

Treatment for sepsis and its complications in the clinic is primarily in the forms of antibiotics, anti-inflammatory agents, and antioxidant drugs. Kombucha, a traditional fermented beverage rich in tea polyphenols and organic acids, offers several benefits including bacteriostasis, anti-inflammation ability, and boosting the immune system. Currently, research on kombucha is primarily focused on its antibacterial and antioxidant properties; however, in-depth exploration of the involved mechanisms is lacking. Herein, turmeric, Paeoniae alba, and black tea were used as fermentation substrates to detect the bacteriostatic and antioxidant activities of the fermentation broth and evaluate its anti-inflammatory effects on RAW264.7 cells stimulated by lipopolysaccharides (LPSs). The results showed that fermentation enhanced the antibacterial activity of turmeric against E. coli and S. aureus and that of Paeoniae alba against S. aureus. Turmeric black tea exhibited the highest antioxidant activity. The fermentation broth of turmeric and turmeric black tea significantly reduced the expression of inflammatory cytokines induced by LPSs. Our results showed that using turmeric and Paeoniae alba culture media as substrates can enhance the anti-inflammatory effects of fermentation broth and provide a new strategy for developing anti-inflammatory substances.

Research Progress on Natural Small-Molecule Compounds for the Prevention and Treatment of Sepsis.

Sepsis is a serious disease with high mortality and has been a hot research topic in medical research in recent years. With the continuous reporting of in-depth research on the pathological mechanisms of sepsis, various compounds have been developed to prevent and treat sepsis. Natural small-molecule compounds play vital roles in the prevention and treatment of sepsis; for example, compounds such as resveratrol, emodin, salidroside, ginsenoside, and others can modulate signaling through the NF-κB, STAT3, STAT1, PI3K, and other pathways to relieve the inflammatory response, immunosuppression, and organ failure caused by sepsis. Here, we discuss the functions and mechanisms of natural small-molecule compounds in preventing and treating sepsis. This review will lay the theoretical foundation for discovering new natural small-molecule compounds that can potentially prevent and treat sepsis.

Research Progress of DcR3 in the Diagnosis and Treatment of Sepsis.

Decoy receptor 3 (DcR3), a soluble glycosylated protein in the tumor necrosis factor receptor superfamily, plays a role in tumor and inflammatory diseases. Sepsis is a life-threatening organ dysfunction caused by the dysregulation of the response to infection. Currently, no specific drug that can alleviate or even cure sepsis in a comprehensive and multi-level manner has been found. DcR3 is closely related to sepsis and considerably upregulated in the serum of those patients, and its upregulation is positively correlated with the severity of sepsis and can be a potential biomarker for diagnosis. DcR3 alone or in combination with other markers has shown promising results in the early diagnosis of sepsis. Furthermore, DcR3 is a multipotent immunomodulator that can bind FasL, LIGHT, and TL1A through decoy action, and block downstream apoptosis and inflammatory signaling. It also regulates T-cell and macrophage differentiation and modulates immune status through non-decoy action; therefore, DcR3 could be a potential drug for the treatment of sepsis. The application of DcR3 in the treatment of a mouse model of sepsis also achieved good efficacy. Here, we introduce and discuss the progress in, and suggest novel ideas for, research regarding DcR3 in the diagnosis and treatment of sepsis.

Research Progress of Macromolecules in the Prevention and Treatment of Sepsis.

Sepsis is associated with high rates of mortality in the intensive care unit and accompanied by systemic inflammatory reactions, secondary infections, and multiple organ failure. Biological macromolecules are drugs produced using modern biotechnology to prevent or treat diseases. Indeed, antithrombin, antimicrobial peptides, interleukins, antibodies, nucleic acids, and lentinan have been used to prevent and treat sepsis. In vitro, biological macromolecules can significantly ameliorate the inflammatory response, apoptosis, and multiple organ failure caused by sepsis. Several biological macromolecules have entered clinical trials. This review summarizes the sources, efficacy, mechanism of action, and research progress of macromolecular drugs used in the prevention and treatment of sepsis.

Research Progress on the Anti-Aging Potential of the Active Components of Ginseng.

Aging is a cellular state characterized by a permanent cessation of cell division and evasion of apoptosis. DNA damage, metabolic dysfunction, telomere damage, and mitochondrial dysfunction are the main factors associated with senescence. Aging increases ß-galactosidase activity, enhances cell spreading, and induces Lamin B1 loss, which further accelerate the aging process. It is associated with a variety of diseases, such as Alzheimer's disease, Parkinson's, type 2 diabetes, and chronic inflammation. Ginseng is a traditional Chinese medicine with anti-aging effects. The active components of ginseng, including saponins, polysaccharides, and active peptides, have antioxidant, anti-apoptotic, neuroprotective, and age-delaying effects. DNA damage is the main factor associated with aging, and the mechanism through which the active ingredients of ginseng reduce DNA damage and delay aging has not been comprehensively described. This review focuses on the anti-aging mechanisms of the active ingredients of ginseng. Furthermore, it broadens the scope of ideas for further research on natural products and aging.

Fucoxanthin Attenuates Inflammation via Interferon Regulatory Factor 3 (IRF3) to Improve Sepsis.

Suppression of excessive inflammatory responses improves the survival of patients with sepsis. We previously illustrated the anti-inflammatory effects of fucoxanthin (FX), a natural carotenoid isolated from brown algae; nevertheless, the underlying mechanism remains unknown. In this study, we examine the mechanism of the action of FX by targeting interferon regulatory factor 3 (IRF3) to inhibit inflammatory response. We observed that FX regulated innate immunity by inhibiting IRF3 phosphorylation in vitro. The in silico approach demonstrated a good binding mode between FX and IRF3. To examine the in vivo effects of FX, a mouse model of sepsis induced by cecal ligation and puncture (CLP) was created using both wild-type (WT) and Irf3-/- mice. FX significantly reduced pro-inflammatory cytokine levels and reactive oxygen species production, changed the circulating immune cell composition, and increased the survival rate of the CLP-induced sepsis model. Overall, FX ameliorated sepsis by targeting IRF3 activation, providing novel insights into the therapeutic potential and molecular mechanism of action of FX in the treatment of sepsis and suggesting that it may be used clinically to improve the survival rate in mice undergoing sepsis.

Aloe-Emodin Ameliorates Cecal Ligation and Puncture-Induced Sepsis.

Sepsis remains a major challenge owing to its severe adverse effects and high mortality, against which specific pharmacological interventions with high efficacy are limited. Mitigation of hyperactive inflammatory responses is a key factor in enhancing the likelihood of survival in patients with sepsis. The Aloe genus has several health benefits, including anti-inflammatory properties. The toxicological implications of aloe-emodin (AE), extracted from various Aloe species, remain uncertain in clinical contexts. However, AE has been shown to inhibit inflammatory responses in lipopolysaccharide-induced mice, indicating its potential as a therapeutic approach for sepsis treatment. Nonetheless, there is a paucity of data regarding the therapeutic benefits of AE in the widely recognized cecal ligation and puncture (CLP)-induced sepsis model, which is commonly used as the gold standard model for sepsis research. This study demonstrates the potential benefits of AE in the treatment of CLP-induced sepsis and investigates its underlying mechanism, along with the efficacy of postoperative AE treatment in mice with CLP-induced sepsis. The results of this study suggest that AE can mitigate sepsis in mice by diminishing systemic inflammation and regulating the gut microbiota. The study provides novel insights into the molecular mechanisms underlying the anti-inflammatory effects of AE.

The dilemma of antibiotic susceptibility and clinical decision-making in a multi-drug-resistant Pseudomonas aeruginosa bloodstream infection.

Objective: How to choose the appropriate antibiotics and dosage has always been a difficult issue during the treatment of multi-drug-resistant bacterial infections. Our study aims to resolve this difficulty by introducing our multi-disciplinary treatment (MDT) clinical decision-making scheme based on rigorous interpretation of antibiotic susceptibility tests and precise therapeutic drug monitoring (TDM)-guided dosage adjustment. Method: The treatment course of an elderly patient who developed a multi-drug-resistant Pseudomonas aeruginosa (MDRPA) bloodstream infection from a brain abscess was presented. Results: In the treatment process, ceftazidime-avibactam (CAZ-AVI) was used empirically for treating the infection and clinical symptoms improved. However, the follow-up bacterial susceptibility test showed that the bacteria were resistant to CAZ-AVI. Considering the low fault tolerance of clinical therapy, the treatment was switched to a 1 mg/kg maintenance dose of susceptible polymyxin B, and TDM showed that the AUC24h, ss of 65.5 mgh/L had been achieved. However, clinical symptoms were not improved after 6 days of treatment. Facing the complicated situation, the cooperation of physicians, clinical pharmacologists, and microbiologists was applied, and the treatment finally succeeded with the pathogen eradicated when polymyxin B dose was increased to 1.4 mg/kg, with the AUC24h, ss of 98.6 mgh/L. Conclusion: MDT collaboration on the premise of scientific and standardized drug management is helpful for the recovery process in patients. The empirical judgment of doctors, the medication recommendations from experts in the field of TDM and pharmacokinetics/pharmacodynamics, and the drug susceptibility results provided by the clinical microbiology laboratory all provide the direction of treatment.

Advances in Fucoxanthin Research for the Prevention and Treatment of Inflammation-Related Diseases.

Owing to its unique structure and properties, fucoxanthin (FX), a carotenoid, has attracted significant attention. There have been numerous studies that demonstrate FX's anti-inflammatory, antioxidant, antitumor, and anti-obesity properties against inflammation-related diseases. There is no consensus, however, regarding the molecular mechanisms underlying this phenomenon. In this review, we summarize the potential health benefits of FX in inflammatory-related diseases, from the perspective of animal and cellular experiments, to provide insights for future research on FX. Previous work in our lab has demonstrated that FX remarkably decreased LPS-induced inflammation and improved survival in septic mice. Further investigation of the activity of FX against a wide range of diseases will require new approaches to uncover its molecular mechanism. This review will provide an outline of the current state of knowledge regarding FX application in the clinical setting and suggest future directions to implement FX as a therapeutic ingredient in pharmaceutical sciences in order to develop it into a treatment strategy against inflammation-associated disorders.

Progress in Research on the Alleviation of Glucose Metabolism Disorders in Type 2 Diabetes Using Cyclocarya paliurus.

Globally, the incidence of diabetes is increasing annually, and China has the largest number of patients with diabetes. Patients with type 2 diabetes need lifelong medication, with severe cases requiring surgery. Diabetes treatment may cause complications, side-effects, and postoperative sequelae that could lead to adverse health problems and significant social and economic burdens; thus, more efficient hypoglycemic drugs have become a research hotspot. Glucose metabolism disorders can promote diabetes, a systemic metabolic disease that impairs the function of other organs, including the heart, liver, and kidneys. Cyclocarya paliurus leaves have gathered increasing interest among researchers because of their effectiveness in ameliorating glucose metabolism disorders. At present, various compounds have been isolated from C. paliurus, and the main active components include polysaccharides, triterpenes, flavonoids, and phenolic acids. C. paliurus mainly ameliorates glucose metabolism disorders by reducing glucose uptake, regulating blood lipid levels, regulating the insulin signaling pathway, reducing ß-cell apoptosis, increasing insulin synthesis and secretion, regulating abundances of intestinal microorganisms, and exhibiting α-glucosidase inhibitor activity. In this paper, the mechanism of glucose metabolism regulation by C. paliurus was reviewed to provide a reference to prevent and treat diabetes, hyperlipidaemia, obesity, and other metabolic diseases.

Metabolome and Whole-Transcriptome Analyses Reveal the Molecular Mechanisms Underlying Hypoglycemic Nutrient Metabolites Biosynthesis in Cyclocarya paliurus Leaves During Different Harvest Stages.

Cyclocarya paliurus, a well-known nutrient and beverage plant, is under development for use in functional health care products best and natural and organic foods. We hypothesis that the composition and metabolic accumulation of hypoglycemic nutrient metabolites exhibit significant differences depending on harvest time. Therefore, it is of great significance to establish the best harvest time for C. paliurus leaves for the further development of healthy teas and other products. However, the detail compositions and molecular mechanisms of nutrients biosynthesis in C. paliurus leaves during different harvest stages remain largely unclear. Metabolome analysis showed that a suitable leaf-harvesting strategy for C. paliurus could be in September or October each year due to the high content of hypoglycemic nutrient metabolites. We found that two of the seven differentially accumulated phenolic acid metabolites have a relatively good inhibitory effect on α-amylase, indicating that they may play a role in the hypoglycemic function. Combined analysis of coexpression, ceRNA network, and weighted gene correlation network analysis (WGCNA) showed that several genes or transcription factors (TFs) in three modules correlated highly with hypoglycemic nutrient metabolites, including CpPMM, CpMan, CpFK, CpSUS, CpbglX, Cp4CL, CpHCT, and CpWRKY1. These findings help in the understanding of the molecular mechanisms and regulatory networks of the hypoglycemic nutrient metabolites in C. paliurus leaves which are dependent on harvest time and provide theoretical guidance in the development of functional health care products and foods from C. paliurus.

The potential health benefits of aloin from genus Aloe.

The Aloe species is known for its medicinal and cosmetic properties. Aloin is an active ingredient found in the leaves of medicinal plants of the genus Aloe. Aloin has attracted considerable interest for its antiinflammatory, anticancer, antibacterial, and antioxidant activities. However, since its clinical application is restricted by its unclear mechanism of action, a deeper understanding of its pharmacological activity is required. This review provides an overview of current pharmacological and toxicological studies published in English from February 2000 to August 2021. Herein, we summarized the sources and potential health benefits of aloin from a clinical application perspective to guide for further studies on the sources of aloin, aimed at efficiently increasing aloin production. Importantly, the function and mechanism of action of aloin remain unclarified. In future research, it is necessary to develop new approaches for studying the pharmacological molecular mechanisms underlying the activity of this compound against various diseases.

Kombucha ameliorates LPS-induced sepsis in a mouse model.

As a popular traditional fermented beverage, kombucha has been extensively studied for its health benefits. However, the science behind the anti-inflammatory effect of kombucha has not been well studied, and there is an urgent need to uncover the secrets of the anti-inflammatory properties of kombucha. Here, we investigate kombucha's protective effects against lipopolysaccharide (LPS)-induced sepsis and on the intestinal microecology in mice. The contents of reducing sugars, polyphenols, catechins, and organic acids in the kombucha group were identified using various methods. The results showed that the concentrations of acetic acid, gluconic acid, polyphenol, and glucuronic acid in the kombucha group were 55.70 ± 2.57 g L-1, 50.20 ± 1.92 g L-1, 2.36 ± 0.31, and 1.39 ± 0.22 g L-1, respectively. The result also demonstrated that kombucha effectively improves the survival rate from 0% to 40%, and increases the thermoregulation in LPS-treated mice, which showed decreased mobility and had lost their appetite for food. Furthermore, kombucha reduced the levels of tumor necrosis factor-α and interleukins (IL)-1ß and IL-6, restored the levels of T cells and macrophages in LPS-challenged mice, alleviated the histopathological damage, and inhibited NF-κB signaling in mice with LPS-induced sepsis. We demonstrated that kombucha effectively prevents cellular immune function disorder in mice at the initial stage of sepsis and exerts an immunomodulatory effect. In addition, the effect of kombucha on the gut microbiota was investigated during sepsis. Kombucha supplementation altered the diversity of the gut microbiota and promoted the growth of butyrate-producing bacteria, which exert anti-inflammatory effects. Our results illustrate the potential of kombucha as a novel anti-inflammatory agent against the development of systemic inflammatory responses associated with sepsis.

Marine-derived drugs: Recent advances in cancer therapy and immune signaling.

The marine environment is an enormous source of marine-derived natural products (MNPs), and future investigation into anticancer drug discovery. Current progress in anticancer drugs offers a rise in isolation and clinical validation of numerous innovative developments and advances in anticancer therapy. However, only a limited number of FDA-approved marine-derived anticancer drugs are available due to several challenges and limitations highlighted here. The use of chitosan in developing marine-derived drugs is promising in the nanotech sector projected for a prolific anticancer drug delivery system (DDS). The cGAS-STING-mediated immune signaling pathway is crucial, which has not been significantly investigated in anticancer therapy and needs further attention. Additionally, a small range of anticancer mediators is currently involved in regulating various JAK/STAT signaling pathways, such as immunity, cell death, and tumor formation. This review addressed critical features associated with MNPs, origin, and development of anticancer drugs. Moreover, recent advances in the nanotech delivery of anticancer drugs and understanding into cancer immunity are detailed for improved human health.