Background: Systemic immune-inflammatory biomarkers including systemic immune inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) have been demonstrated to be associated with the risk and severity of various liver diseases. However, studies on their role and clinical significance in metabolic diseases, especially in nonalcoholic fatty liver disease (NAFLD), are limited and results are inconsistent.Methods: 10821 adults aged 20 years or older were enrolled in this cross-sectional study, sourced from six cycles of the National Health and Nutrition Examination Survey (NHANES). Survey-weighted logistic regression was employed to investigate the correlation between systemic immune-inflammatory biomarkers (SII, NLR, PLR, and LMR) and NAFLD risk. Restricted cubic spline regression models and segmented regression models were used to describe nonlinear relationships and threshold effects. Subgroup and sensitivity analyses were also conducted.Results: After adjusting for all confounding variables, there was a significant positive association observed between ln-transformed SII (OR= 1.46, 95% CI: 1.27-1.69, P <0.001), NLR (OR= 1.25, 95% CI: 1.05-1.49, P =0.015), LMR (OR= 1.39, 95% CI: 1.14-1.69, P = 0.002) with NAFLD. A nonlinear dose-response relationship with an inverted “U”-shaped threshold of 4.64 was observed between ln(PLR) and NAFLD risk. When ln(PLR) was below 4.64, each unit increase in ln(PLR) was associated with a 0.55-fold increase in the risk of NAFLD (OR= 1.55, 95% CI: 1.05-2.31, P <0.05). Conversely, when ln(PLR) exceeded 4.64, each unit increase in ln(PLR) was associated with a 0.40-fold decrease in the risk of NAFLD (OR= 0.60, 95% CI. 0.44-0.81, P <0.05).Conclusion: ln-transformed SII, NLR, and LMR were linearly associated with NAFLD risk. ln(PLR) showed an inverted “U”-shaped nonlinear dose-response relationship with the risk of NAFLD.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease impacting patients’ quality of life and imposing heavy societal and economic burdens. Apoptosis of intestinal epithelial cells (IECs) has been considered an early event during the onset of UC and plays a crucial role in disease development. Thus, effectively inhibiting apoptosis of IECs is of critical significance for the clinical management of UC, presenting a potential direction for the research and development of pharmacotherapeutic agents. In recent years, research on the ameliorative effects of natural products on UC through inhibiting IECs apoptosis has attracted increasing attention and made remarkable achievements in ameliorating UC. In this review, we summarized the currently available research about the anti-apoptotic effects of natural products on UC and its mechanisms involving the death-receptor mediated pathway, mitochondrial-dependent pathway, ERS-mediated pathway, MAPK-mediated pathway, NF-κB mediated pathway, P13k/Akt pathway, JAK/STAT3 pathway, and NLRP3/ASC/Caspase-1 pathway. Hopefully, this review may yield useful information about the anti-apoptotic effects of natural products on UC and their potential molecular mechanisms and provide helpful insights for further investigations.

Hederagenin (HG) is a natural pentacyclic triterpenoid that can be isolated from various medicinal herbs. By modifying the structure of HG, multiple derivatives with superior biological activities and safety profiles have been designed and synthesized. Accumulating evidence has demonstrated that HG and its derivatives display multiple pharmacological activities against cancers, inflammatory diseases, infectious diseases, metabolic diseases, fibrotic diseases, cerebrovascular and neurodegenerative diseases, and depression. Previous studies have confirmed that HG and its derivatives combat cancer by exerting cytotoxicity, inhibiting proliferation, inducing apoptosis, modulating autophagy, and reversing chemotherapy resistance in cancer cells, and the action targets involved mainly include STAT3, Aurora B, KIF7, PI3K/AKT, NF-κB, Nrf2/ARE, Drp1, and P-gp. In addition, HG and its derivatives antagonize inflammation through inhibiting the production and release of pro-inflammatory cytokines and inflammatory mediators by regulating inflammation-related pathways and targets, such as NF-κB, MAPK, JAK2/STAT3, Keap1-Nrf2/HO-1, and LncRNA A33/Axin2/β-catenin. Moreover, anti-pathogen, anti-metabolic disorder, anti-fibrosis, neuroprotection, and anti-depression mechanisms of HG and its derivatives have been partially elucidated. The diverse pharmacological properties of HG and its derivatives hold significant implications for future research and development of new drugs derived from HG, which can lead to improved effectiveness and safety profiles.

Euodiae Fructus (EF) is the dried and nearly ripe fruit of Euodia rutaecarpa, first recorded in Shen Nong’s Herbal Classic. EF is a versatile Traditional Chinese Medicine (TCM) known for the effects of dispelling colds and alleviating pain, suppressing adverse qi to relieve vomiting, and boosting yang to mitigate diarrhea. However, it should be noted that EF possesses mild toxicity. In TCM prescriptions, EF is employed to treat various ailments, including abdominal pain, diarrhea, chronic non-atrophic gastritis, irritable bowel syndrome, and primary dysmenorrhea. This review collected the literature published before September 2024 on EF. An exhaustive analysis of EF literature was conducted utilizing multiple sources, namely classic TCM books and various scientific databases like Web of Science, PubMed, Elsevier, ACS, ResearchGate, Google Scholar, and Chinese National Knowledge Infrastructure. So far, more than 300 metabolites have been extracted and identified from EF, exhibiting various pharmacological effects, such as cardiovascular protection, gastrointestinal protection, neuroprotection, anti-inflammation, analgesia, anti-tumor, glucose and lipid metabolism regulation, etc. It also exhibits diverse toxicological properties and poses specific toxic risks to the liver, heart, and kidney. Nonetheless, research is scarce regarding the toxicology of EF, especially on its cardiotoxicity and nephrotoxicity. Further in-depth research is necessary to explore the mechanisms underlying EF’s pharmacological and toxicological mechanisms and to develop strategies for quality control and toxicity mitigation. The toxicity of EF can be reduced by processing, but this aspect is rarely discussed, and the quality control needs to be further standardized. Evodiamine, rutaecarpine, and limonin are the effective metabolites of EF and are also one of the causes of EF toxicity. The pharmacological effects of evodiamine and rutaecarpine have been intensely studied, but there are few studies on limonin and other metabolites of EF. Therefore, this paper focuses on the botanical characteristics, traditional applications, processing methods, phytochemistry, quality control, pharmacology, and toxicology of EF. We hope this paper provides a theoretical basis for the future high-value and high-connotation development of EF.

Background: Cinnamaldehyde (CA), a naturally occurring aromatic aldehyde from cinnamon bark, has been investigated for its biological activity in laboratory settings. However, its α,β-unsaturated aldehyde structure designates it as a pan-assay interference compound (PAINS), which can produce non-specific effects through chemical reactivity—particularly in vitro—raising concerns about the validity and interpretation of its reported anti-tumor activity.Objective: To systematically review and synthesize existing animal studies that examine the biological effects of CA on tumor growth, while critically evaluating the strength, limitations, and plausibility of the evidence, especially in light of CA’s PAINS-related characteristics.Methods: A systematic literature search was conducted across eight electronic databases to identify relevant animal studies assessing the effects of CA on tumor progression. Study quality was evaluated using the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) risk of bias tool. Quantitative synthesis was performed using Review Manager (RevMan) 5.3. In vitro studies were excluded due to concerns regarding non-specific activity and limited translatability.Results: Sixteen studies encompassing 19 independent experiments and 302 animals were included. Pooled results indicated that CA administration was associated with reductions tumor volume and tumor weight in animal models. However, no improvement in survival was observed, and CA-treated animals showed a modest decrease in body weight. Additionally, reduced expression of proliferating cell nuclear antigen (PCNA), hypoxia-inducible factor (HIF), vascular endothelial growth factor (VEGF), and microvessel density was reported. Despite these findings, the absence of controls for. Non-specific reactivity makes it difficult to distinguish true pharmacological effects from general cytotoxic or chemical stress responses.Conclusion: While CA has demonstrated anti-tumor effects in animal models, these observations should be interpreted with caution. Its classification as a PAINS compound, coupled with a lack of mechanistic specificity, appropriate controls, and clinical validation, limits the reliability and translational relevance of the existing data. The observed outcomes are more likely reflective of non-specific chemical activity rather than targeted therapeutic action. Future research should prioritize rigorous mechanistic validation, use of non-reactive analogs, and comprehensive toxicity profiling before considering any clinical applicability.