Macrophages are innate immune cells distributed throughout the body that play vital roles in organ development, tissue homeostasis, and immune surveillance. Macrophages acquire a binary M1/M2 polarized phenotype through signaling cascades upon sensing different signaling molecules in the environment, thereby playing a core role in a series of immune tasks, rendering precise regulation essential. M1/M2 macrophage phenotypes regulate inflammatory responses, while controlled activation of inflammatory signaling pathways is involved in regulating macrophage polarization. Among the relevant signaling pathways, we focus on the six well-characterized NF-κB, MAPK, JAK-STAT, PI3K/AKT, inflammasome, and cGAS-STING inflammatory pathways, and elucidate their roles and crosstalk in macrophage polarization. Furthermore, the effects of many environmental signals that influence macrophage polarization are investigated by modulating these pathways in vivo and in vitro. We thus detail the physiological and pathophysiological status of these six inflammatory signaling pathways and involvement in regulating macrophage polarization in cancer and beyond, as well as describe potential therapeutic approaches targeting these signaling pathways. In this review, the latest research advances in inflammatory signaling pathways regulating macrophage polarization are reviewed, as targeting these inflammatory signaling pathways provides suitable strategies to intervene in macrophage polarization and various tumor and non-tumor diseases.

Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease, characterized by excessive fat accumulation in the liver. Caffeine, theophylline, and theobromine are the primary naturally occurring methylxanthines found in various foods and beverages such as coffee, tea, and chocolate. They exhibit diverse pharmacological effects. Although caffeine can inhibit hepatic fat accumulation in mice, the effects and regulatory mechanisms of theophylline and theobromine remain unclear. In this study, we observed that theophylline significantly reduced body weight and triglyceride levels and attenuated hepatic fat accumulation in mice fed a high-fat diet. Conversely, theobromine did not exhibit these effects. Transcriptomic results showed that caffeine and theophylline significantly activated the TNF signaling pathway in C2C12 myoblasts, induced p38MAPK expression and increased Il1b and Il6 secretion, but did not elevate Tnfa and Mcp1 expression. Notably, theobromine neither activated the TNF pathway nor significantly induced p38MAPK expression and Il1b and Il6 secretion. In conclusion, the differences in the regulating NAFLD activity of caffeine, theophylline, and theobromine-three structurally similar compounds used as food ingredients, may be attributed to their distinct regulation of the TNF signaling pathway.

Non-alcoholic fatty liver disease (NAFLD), characterized by the excessive accumulation of fat within the cytoplasm of hepatocytes (exceeding 5% of liver weight) in individuals without significant alcohol consumption, has rapidly evolved into a pressing global health issue, affecting approximately 25% of the world population. This condition, closely associated with obesity, type 2 diabetes, and the metabolic syndrome, encompasses a spectrum of liver disorders ranging from simple steatosis without inflammation to non-alcoholic steatohepatitis (NASH) and cirrhotic liver disease. Recent research has illuminated the complex interplay between metabolic and immune responses in the pathogenesis of NASH, underscoring the critical role played by T and B lymphocytes. These immune cells not only contribute to necroinflammatory changes in hepatic lobules but may also drive the onset and progression of liver fibrosis. This narrative review aims to provide a comprehensive exploration of the effector mechanisms employed by T cells, B cells, and their respective subpopulations in the pathogenesis of NASH. Understanding the immunological complexity of NASH holds profound implications for the development of targeted immunotherapeutic strategies to combat this increasingly prevalent and burdensome metabolic liver disease.

Natural products exhibit structural complexity, diversity, and historical therapeutic significance, boasting attractive functions and biological activities that have significantly influenced drug discovery endeavors. The identification of target proteins of active natural compounds is crucial for advancing novel drug innovation. Currently, methods for identifying targets of natural products can be categorized into labeling and label-free approaches based on whether the natural bioactive constituents are modified into active probes. In addition, there is a new avenue for rapidly exploring the targets of natural products based on their innate functions.

This review aimed to summarize recent advancements in both labeling and label-free approaches to the identification of targets for natural products, as well as the novel target identification method based on the natural functions of natural products.

We systematically collected relevant articles published in recent years from PubMed, Web of Science, and ScienceDirect, focusing on methods employed for identifying protein targets of bioactive natural products. Furthermore, we systematically summarized the principles, procedures, and successful cases, as well as the advantages and limitations of each method.

Labeling methods allow for the direct labeling of target proteins and the exclusion of indirectly targeted proteins. However, these methods are not suitable for studying post-modified compounds with abolished activity, chemically challenging synthesis, or trace amounts of natural active compounds. Label-free methods can be employed to identify targets of any natural active compounds, including trace amounts and multicomponent mixtures, but their reliability is not as high as labeling methods. The structural complementarity between natural products and their innate receptors significantly increase the opportunities for finding more promising structural analogues of the natural products, and natural products may interact with several structural analogues of receptors in humans.

Each approach presents benefits and drawbacks. In practice, a combination of methods is employed to identify targets of natural products. And natural products' innate functions-based approach is a rapid and selective strategy for target identification. This review provides valuable references for future research in this field, offering insights into techniques and methodologies.

The incidence of non-alcoholic fatty liver disease (NAFLD) tends to be younger. And the role of theobromine in fatty liver disease remains unclear. The purpose of this study was to investigate the relationship between dietary theobromine intake and degree of hepatic steatosis in individuals aged 45 and below, using data from the 2017-2020 National Health and Nutrition Examination Survey (NHANES) and liver ultrasonography transient elastography. A total of 1796 participants aged below 45 years were included from NHANES 2017-2020 data after applying exclusion criteria. Multivariate regression and subgroup analyses were conducted to examine the associations between theobromine intake and controlled attenuation parameter (CAP), adjusting for potential confounders. Generalized additive models and two-piecewise linear regression were used to analyze nonlinear relationships. In the unadjusted Model 1 and preliminarily adjusted Model 2, there was no significant correlation between theobromine intake and CAP values. However, in Models 3 and 4, which accounted for confounding factors, a higher intake of theobromine was significantly associated with lower CAP values. Subgroup analyses in the fully adjusted Model 4 revealed a significant negative correlation among individuals aged 18-45, women, and white populations. Nonlinear analysis revealed a U-shaped relationship in black Americans, with the lowest CAP values at 44.5 mg/day theobromine. This study provides evidence that higher theobromine intake is correlated with lower degree of hepatic steatosis in young people, especially those aged 18-45 years, women, and whites. For black Americans, maintaining theobromine intake around 44.5 mg/day may help minimize liver steatosis. These findings may help personalize clinical nutritional guidance, prevent the degree of hepatic steatosis, and provide pharmacological approaches to reverse fatty liver disease in young people.

In this study, the protective efficacy of pentoxifylline (PTX) as a xanthine derivative against arsenic trioxide (ATO)-induced kidney and liver damage in mice was investigated. Thirty-six mice were divided into six groups, receiving intraperitoneal injections of saline, ATO, PTX, or a combination for four weeks. Blood samples were analyzed for serum biochemistry, while hepatic tissue underwent examination for histopathological changes and assessment of oxidative stress markers and antioxidant gene expression through Real-Time PCR. ATO exposure significantly increased serum markers (creatinine, ALT, BUN, ALP, AST) and induced histopathological changes in the liver. Moreover, it elevated renal and hepatic nitric oxide (NO) and lipid peroxidation (LPO) levels, and reduced antioxidant enzyme expression (CAT, GSR, GPx, MPO, SOD), total thiol groups (TTGs), and total antioxidant capacity (TAC). Conversely, PTX treatment effectively lowered serum hepatic and renal markers, improved antioxidant markers, and induced histopathological alterations. Notably, PTX did not significantly affect renal and hepatic NO levels. These findings suggest that PTX offers therapeutic potential in mitigating liver and acute kidney injuries induced by various insults, including exposure to ATO.

Moluodan (MLD) is a traditional Chinese medicine that is composed of 18 herbal medicines based on traditional Chinese medicine theory and practice. It has long been used in treating chronic gastritis and its components were traditionally used in dealing with intestinal inflammation. However, its specific pharmacological mechanism is still unclear.

The upper and lower digestive tract diseases are correlated. In clinical practice, some chronic gastritis patients are also accompanied by intestinal inflammation. Due to the unclear pharmacological mechanism of MLD and its effect on intestinal inflammation, there is doubt whether MLD is still suitable for this type of patient. Therefore, this study aims to elucidate the pharmacological mechanism of MLD and identify its effect in the mouse model of intestinal inflammation.

Mice intestinal inflammation model was induced by 2.5% dextran sulfate sodium (DSS). The mice were given different concentrations of MLD via oral gavage (0.25, 0.5 g/kg b.w.). Pharmacodynamic indicators were assessed including body weight, colon length, disease activity index (DAI), bloody stool score, inflammatory factors, histological change, etc. RAW264.7 macrophage cells were used for in vitro experiments that illuminated the role of MLD in reprogramming macrophage function and polarization. RT-qPCR and western blots were performed to measure the mRNA and protein levels of macrophage polarization marker and effector molecules. The functions of polarized macrophages were tested using ROS detection probes, Edu assay and wound healing assay.

The administration of MLD exhibited obvious hemostatic effects, while unexpectedly accentuating various aspects of the DSS-induced intestinal inflammation in mice, including increased body weight loss and colon shortening, elevated disease activity index, and intensified colonic tissue damage. Additionally, MLD treatment induced more severe inflammatory cell infiltration and higher proinflammatory cytokines expression in colon tissue. Further results showed that MLD promoted M1 macrophage polarization and stimulated its proinflammatory cytokines expression, while only slightly affecting the function of M2 macrophage. Western blot analysis revealed that MLD induced the phosphorylation of AKT and NF-κB. The polarization of M1 macrophages induced by MLD was inhibited by either an Akt inhibitor or a NF-κB inhibitor.

Although MLD has an obvious hemostatic effect, it generally promoted the severity of DSS-induced colitis in mice by facilitating macrophage polarization toward the M1 phenotype through the AKT/NF-κB pathway. Our study suggested that MLD may not be suitable for colitis, especially during the acute inflammation stage.

Nonalcoholic steatohepatitis (NASH), a multi-target disease, is becoming a global epidemic. Although several anti-NASH drug candidates are being evaluated in late-stage clinical trials, none have been approved by the FDA to date. Given the global prevalence of the disease, the lack of effective drugs, and the very limited therapeutic efficacy of most of the existing synthetic drugs focusing on a single target, there is an urgent need to continue to develop new therapeutic agents. In contrast, many natural products, including pure compounds and crude extracts, possess hepatoprotective activities. Usually, these natural components are characterized by multi-targeting and low side effects. Therefore, natural products are important resources for the development of new anti- NASH drugs. In this paper, we focus on reviewing the anti-NASH potential, structure, and some of the side effects of natural products based on structural classification. We hope this mini-review will help researchers design and develop new anti-NASH drugs, especially based on the structure of natural products.

With changing lifestyles, non-alcoholic fatty liver disease (NAFLD) has become the most prevalent liver disease worldwide. A substantial increase in the incidence, mortality, and associated burden of NAFLD-related advanced liver disease is expected. Currently, the initial diagnosis of NAFLD is still based on ultrasound and there is no approved treatment method. Lipid-lowering drugs, vitamin supplementation, and lifestyle improvement treatments are commonly used in clinical practice. However, most lipid-lowering drugs can produce poor patient compliance and specific adverse effects. Therefore, the exploration of bio-diagnostic markers and active lead compounds for the development of innovative drugs is urgently needed. More and more studies have reported the anti-NAFLD effects and mechanisms of natural products (NPs), which have become an important source for new drug development to treat NAFLD due to their high activity and low side effects. At present, berberine and silymarin have been approved by the US FDA to enter clinical phase IV studies, demonstrating the potential of NPs against NAFLD. Studies have found that the regulation of lipid metabolism, insulin resistance, oxidative stress, and inflammation-related pathways may play important roles in the process. With the continuous updating of technical means and scientific theories, in-depth research on the targets and mechanisms of NPs against NAFLD can provide new possibilities to find bio-diagnostic markers and innovative drugs. As we know, FXR agonists, PPARα agonists, and dual CCR2/5 inhibitors are gradually coming on stage for the treatment of NAFLD. Whether NPs can exert anti-NAFLD effects by regulating these targets or some unknown targets remains to be further studied. Therefore, the study reviewed the potential anti-NAFLD NPs and their targets. Some works on the discovery of new targets and the docking of active lead compounds were also discussed. It is hoped that this review can provide some reference values for the development of non-invasive diagnostic markers and new drugs against NAFLD in the clinic.

Adaptor proteins represent key signalling molecules involved in regulating immune responses. The host's innate immune system recognizes pathogens via various surface and intracellular receptors. Adaptor molecules are centrally involved in different receptor-mediated signalling pathways, acting as bridges between the receptors and other molecules. The presence of adaptors in major signalling pathways involved in the pathogenesis of various chronic inflammatory diseases has drawn attention toward the role of these proteins in such diseases. In this review, we summarize the importance and roles of different adaptor molecules in macrophage-mediated signalling in various chronic disease states. We highlight the mechanistic roles of adaptors and how they are involved in protein-protein interactions (PPI) via different domains to carry out signalling. Hence, we also provide insights into how targeting these adaptor proteins can be a good therapeutic strategy against various chronic inflammatory diseases.

This study investigated the effects of pentoxifylline (PTX), high intensity interval training (HIIT) and moderate intensity continuous training (MICT) separately and in combination, on inflammatory and apoptotic pathways in the rat model of induced endometriosis. Endometriosis was induced through surgery on female Sprague-Dawley rats. Six weeks after the first surgery, the second look laparotomy was performed. After induction of endometriosis in rats, they were divided into control, MICT, PTX, MICT+ PTX, HIIT, HIIT+PTX groups. Two weeks after the second look laparotomy, PTX and exercise training interventions were performed for eight weeks. Endometriosis lesions were assessed histologically. Proteins content of the NF-κB, PCNA and Bcl-2 were measured by immunoblotting and genes expression of the TNF-α and VEGF were measured by Real-time PCR methods. Findings of the study indicated that, PTX significantly decreased volume and histological grading of lesions, proteins of NF-κB and Bcl-2; and genes expression of the TNF-α, and VEGF in lesions. HIIT significantly decreased volume and histological grading of lesions, NF-κB, TNF-α and VEGF in lesions. MICT did not induce any significant effect on the study variables. Although, MICT+PTX decreased significantly volume and histological grading of lesions, as well as NF-κB, and Bcl-2 in lesions, however, these factors were not significantly different with the PTX group. HIIT+PTX decreased significantly all of the study variables compared to other interventions, except for VEGF when compared to PTX. In summary, combination of PTX and HIIT can induce enhancing effect on suppression of endometriosis through suppressing inflammation, angiogenesis, and proliferation and enhancing apoptosis.

During the last two decades, nonalcoholic fatty liver disease (NAFLD) has emerged as the most common hepatic disease in pediatrics, mainly owing to the rising prevalence of pediatric obesity. Epidemiological studies have shown that the progressive increase in NAFLD prevalence is associated not only with obesity but also with changes in dietary habits experienced by all age groups, characterized by the increased intake of added sugars and certain fatty acids. In this review article, we focus on the effect of oxidized fatty acids deriving from linoleic acid and arachidonic acid on the pathogenesis and progression of NAFLD in youth.