Oxymatrine Attenuates Ulcerative Colitis through Inhibiting Pyroptosis Mediated by the NLRP3 Inflammasome.

Ulcerative colitis (UC) is difficult to cure and easy to relapse, leading to poor quality of life for patients. Oxymatrine (OMT) is one of the main alkaloids of Sophora flavescens Aiton, which has many effects, such as anti-inflammation, anti-oxidative stress, and immunosuppression. This study aimed to investigate whether OMT could attenuate ulcerative colitis by inhibiting the NOD-like receptor family pyrin domain containing three (NLRP3) inflammasome-mediated pyroptosis. In this study, the UC rat models were established by 2,4,6-Trinitrobenzenesulfonic acid (TNBS) in vivo, while RAW264.7 cells and peritoneal macrophages were stimulated with Lipopolysaccharides/Adenosine Triphosphate (LPS/ATP) in vitro to simulate pyroptosis models, and Western blotting (WB) and other detection techniques were applied to analyze proteins involved in the NLRP3 inflammasome pathway. Our results showed that OMT alleviated colitis ulcers and pathological damage in the TNBS-induced UC rats and exhibited an inhibitory effect on pyroptosis at the early stage of UC. In the model group, the pyroptosis reached the peak at 24 h after modeling with the contents of active-cysteine-aspartic proteases-1 (caspase-1), Gasdermin D (GSDMD)-N, and cleaved-interleukin-1 beta (IL-1ß) to the highest expression level. Meanwhile, we found that OMT (80 mg kg-1) remarkably decreased the expression levels of NLRP3, active-caspase-1, and cleaved-IL-1ß at 24 h in the lesion tissue from UC rats. Further experiments on cells demonstrated that OMT at concentrations of 100 and 250 µM significantly inhibited cell death caused by NLRP3 inflammasome activation (p < 0.05), downregulated caspase-1, GSDMD, and decreased the levels of active-caspase-1, GSDMD-N, cleaved-IL-1ß in RAW326.7 cells, and peritoneal macrophages. In summary, these results indicated that OMT could attenuate ulcerative colitis through inhibiting pyroptosis mediated by the NLRP3 inflammasome. The inhibition of the NLRP3 inflammasome may be a potential strategy for UC.

Grass-Endophyte Interactions and Their Associated Alkaloids as a Potential Management Strategy for Plant Parasitic Nematodes.

Claviceptaceous endophytic fungi in the genus Epichloë mostly form a symbiotic relationship with cool-season grasses. Epichloë spp. are capable of producing bioactive alkaloids such as peramines, lolines, ergot alkaloids, and indole-diterpenes, which protect the host plant from herbivory by animals, insects, and nematodes. The host also benefits from enhanced tolerance to abiotic stresses, such as salt, drought, waterlogging, cold, heavy metals, and low nitrogen stress. The bioactive alkaloids produced can have both direct and indirect effects towards plant parasitic nematodes. Direct interaction with nematodes' motile stages can cause paralysis (nematostatic effect) or death (nematicidal effect). Indirectly, the metabolites may induce host immunity which inhibits feeding and subsequent nematode development. This review highlights the different mechanisms through which this interaction and the metabolites produced have been explored in the suppression of plant parasitic nematodes and also how the specific interactions between different grass genotypes and endophyte strains result in variable suppression of different nematode species. An understanding of the different grass-endophyte interactions and their successes and failures in suppressing various nematode species is essential to enable the proper selection of grass-endophyte combinations to identify the alkaloids produced, concentrations required, and determine which nematodes are sensitive to which specific alkaloids.

Matrine Ameliorates DSS-Induced Colitis by Suppressing Inflammation, Modulating Oxidative Stress and Remodeling the Gut Microbiota.

Matrine (MT) possesses anti-inflammatory, anti-allergic and antioxidative properties. However, the impact and underlying mechanisms of matrine on colitis are unclear. The purpose of this research was to examine the protective impact and regulatory mechanism of matrine on dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in mice. MT alleviated DSS-induced UC by inhibiting weight loss, relieving colon shortening and reducing the disease activity index (DAI). Moreover, DSS-induced intestinal injury and the number of goblet cells were reversed by MT, as were alterations in the expression of zonula occludens-1 (ZO-1) and occludin in colon. Simultaneously, matrine not only effectively restored DSS-induced oxidative stress in colonic tissues but also reduced the production of inflammatory cytokines. Furthermore, MT could treat colitis mice by regulating the regulatory T cell (Treg)/T helper 17 (Th17) cell imbalance. We observed further evidence that MT alleviated the decrease in intestinal flora diversity, reduced the proportion of Firmicutes and Bacteroidetes, decreased the proportion of Proteobacteria and increased the relative abundance of Lactobacillus and Akkermansia in colitis mice. In conclusion, these results suggest that MT may mitigate DSS-induced colitis by enhancing the colon barrier integrity, reducing the Treg/Th17 cell imbalance, inhibiting intestinal inflammation, modulating oxidative stress and regulating the gut microbiota. These findings provide strong evidence for the development and application of MT as a dietary treatment for UC.

Reversal of gentamicin sulfate resistance in avian pathogenic Escherichia coli by matrine combined with berberine hydrochloride.

In recent years, the evolution of antibiotic resistance has led to the inefficacy of several antibiotics, and the reverse of resistance was a novel method to solve this problem. We previously demonstrated that matrine (Mat) and berberine hydrochloride (Ber) had a synergistic effect against multidrug-resistant Escherichia coli (MDREC). This study aimed to demonstrate the effect of Mat combined with Ber in reversing the resistance of MDREC. The MDREC was sequenced passaged in the presence of Mat, Ber, and a combination of Mat and Ber, which did not affect its growth. The reverse rate was up to 39.67% after MDREC exposed to Mat + Ber for 15 days. The strain that reversed resistance was named drug resistance reversed E. coli (DRREC) and its resistance to ampicillin, streptomycin, gentamicin, and tetracycline was reversed. The MIC of Gentamicin Sulfate (GS) against DRREC decreased 128-fold to 0.63 µg/mL, and it was stable within 20 generations. Furthermore, the susceptible phenotype of DRREC remained stable within 20 generations, as well. The LD50 of DRREC for chickens was 8.69 × 109 CFU/mL. qRT-PCR assays revealed that the transcript levels of antibiotic-resistant genes and virulence genes in the DRREC strain were significantly lower than that in the MDREC strain (P < 0.05). In addition, GS decreased the death, decreased the bacterial loading in organs, alleviated the injury of the spleen and liver, and decreased the cytokine levels in the chickens infected by the DRREC strain. In contrast, the therapeutic effect of GS in chickens infected with MDREC was not as evident. These findings suggest that the combination of Mat and Ber has potential for reversing resistance to MDREC.

Design and synthesis of matrine derivatives for anti myocardial ischemia-reperfusion injury by promoting angiogenesis.

Myocardial ischemia/reperfusion (MI/R) is a common cardiovascular disease that seriously affects the quality of life and prognosis of patients. In recent years, matrine has attracted widespread attention in the treatment of cardiovascular diseases. This study designed, synthesized, and characterized 20 new matrine derivatives and studied their protective effects on ischemia-reperfusion injury through in vivo and in vitro experiments. Based on cellular assays, most newly synthesized derivatives have a certain protective effect on Hypoxia/Reoxygenation (H/R) induced H9C2 cell damage, with compound 22 having the best activity and effectively reducing cell apoptosis and necrosis. In vitro experimental data shows that compound 22 can significantly reduce the infarct size of rat myocardium and improve cardiac function after MI/R injury. In summary, compound 22 is a new potential cardioprotective agent that can promote angiogenesis and enhance antioxidant activity by activating ADCY5, CREB3l4, and VEGFA, thereby protecting myocardial cell apoptosis and necrosis induced by MI/R.

Conofolidine: A Natural Plant Alkaloid That Causes Apoptosis and Senescence in Cancer Cells.

Natural products contribute substantially to anticancer therapy; the plant kingdom provides an important source of molecules. Conofolidine is a novel Aspidosperma-Aspidosperma bisindole alkaloid isolated from the Malayan plant Tabernaemontana corymbosa. Herein, we report conofolidine's broad-spectrum anticancer activity together with that of three other bisindoles-conophylline, leucophyllidine, and bipleiophylline-against human-derived breast, colorectal, pancreatic, and lung carcinoma cell lines. Remarkably, conofolidine was able to induce apoptosis (e.g., in MDA-MB-468 breast) or senescence (e.g., in HT-29 colorectal) in cancer cells. Annexin V-FITC/PI, caspase activation, and PARP cleavage confirmed the former while positive ß-gal staining corroborated the latter. Cell cycle perturbations were evident, comprising S-phase depletion, accompanied by downregulated CDK2, and cyclins (A2, D1) with p21 upregulation. Confocal imaging of HCT-116 cells revealed an induction of aberrant mitotic phenotypes-membrane blebbing, DNA-fragmentation with occasional multi-nucleation. DNA integrity assessment in HCT-116, MDA-MB-468, MIAPaCa-2, and HT-29 cells showed increased fluorescent γ-H2AX during the G1 cell cycle phase; γ-H2AX foci were validated in HCT-116 and MDA-MB-468 cells by confocal microscopy. Conofolidine increased oxidative stress, preceding apoptosis- and senescence-induction in most carcinoma cell lines as seen by enhanced ROS levels accompanied by increased NQO1 expression. Collectively, we present conofolidine as a putative potent anticancer agent capable of inducing heterogeneous modes of cancerous cell death in vitro, encouraging further preclinical evaluations of this natural product.

Functionalized magnetic particles coupled with LC-MS strategy facilitated discovery of trace thioalkaloids with potent immunosuppressive activity.

Trace natural products (TNPs) are still the vital source of drug development. However, the mining of novel TNPs is becoming increasingly challenging due to their low abundance and complex interference. A comprehensive strategy was proposed in which the functionalized magnetic particles integrated with LC-MS for TNPs discovery. Under the guidance of the approach, fifteen trace Nuphar alkaloids including seven new ones, cyanopumiline A sulfoxide (1), cyanopumiline C sulfoxide (8) and cyanopumilines A-E (4-5, 10, 12-13) featuring an undescribed nitrile-containing 6/6/5/6/6 pentacyclic ring system were isolated from the rhizomes of Nuphar pumila. Their structures and absolute configurations were determined on the basis of detailed spectroscopic data analysis and single-crystal X-ray diffraction analysis. Notably, a concise method based on 13C NMR spectroscopy was established to determine the relative configurations of spiroatoms. Biologically, compounds 1-12 exhibited potent immunosuppressive activities with IC50 values ranging from 0.1-12.1 µM against anti-CD3/CD28 induced human peripheral T cell proliferation. Mechanistic studies revealed that 4 could dose-dependently decrease pro-inflammatory cytokines and the expression levels of CD25 and CD71.

Molecular Aspects of Piperine in Signaling Pathways Associated with Inflammation in Head and Neck Cancer.

Piperine, an active plant alkaloid from black pepper (Piper nigrum), has several pharmacological effects, namely antioxidant, anti-inflammatory and immunomodulatory effects, which involve inhibiting molecular events associated with various stages of cancer development. The aim of this study was to investigate the molecular mechanisms of action of piperine in relation to its potential anticancer effect on head and neck cancer cells. Parameters related to neoplastic potential and cytokine, protein and gene expression were investigated in head and neck cancer cell lines (HEp-2 and SCC-25) treated with piperine. The results of the tests indicated that piperine modified morphology and inhibited viability and the formation of cell colonies. Piperine promoted genotoxicity by triggering apoptosis and cell cycle arrest in the G2/M and S phases. A decrease in cell migration was also observed, and there was decreased expression of MMP2/9 genes. Piperine also reduced the expression of inflammatory molecules (PTGS2 and PTGER4), regulated the secretion of cytokines (IFN-γ and IL-8) and modulated the expression of ERK and p38. These results suggest that piperine exerts anticancer effects on tumor cells by regulating signaling pathways associated with head and neck cancer.

Metabolomic Profiling Reveals the Anti-Herbivore Mechanisms of Rice (Oryza sativa).

The use of secondary metabolites of rice to control pests has become a research hotspot, but little is known about the mechanism of rice self-resistance. In this study, metabolomics analysis was performed on two groups of rice (T1, with insect pests; T2, without pests), indicating that fatty acids, alkaloids, and phenolic acids were significantly up-regulated in T1. The up-regulated metabolites (p-value < 0.1) were enriched in linoleic acid metabolism, terpene, piperidine, and pyridine alkaloid biosynthesis, α-linolenic acid metabolism, and tryptophan metabolism. Six significantly up-regulated differential metabolites in T1 were screened out: N-trans-feruloyl-3-methoxytyramine (1), N-trans-feruloyltyramine (2), N-trans-p-coumaroyltyramine (3), N-cis-feruloyltyramine (4), N-phenylacetyl-L-glutamine (5), and benzamide (6). The insect growth inhibitory activities of these six different metabolites were determined, and the results show that compound 1 had the highest activity, which significantly inhibited the growth of Chilo suppressalis by 59.63%. Compounds 2-4 also showed a good inhibitory effect on the growth of Chilo suppressalis, while the other compounds had no significant effect. RNA-seq analyses showed that larval exposure to compound 1 up-regulated the genes that were significantly enriched in ribosome biogenesis in eukaryotes, the cell cycle, ribosomes, and other pathways. The down-regulated genes were significantly enriched in metabolic pathways, oxidative phosphorylation, the citrate cycle (TCA cycle), and other pathways. Eighteen up-regulated genes and fifteen down-regulated genes from the above significantly enriched pathways were screened out and verified by real-time quantitative PCR. The activities of detoxification enzymes (glutathione S-transferase (GST); UDP-glucuronosyltransferase (UGT); and carboxylesterase (CarE)) under larval exposure to compound 1 were measured, which indicated that the activity of GST was significantly inhibited by compound 1, while the activities of the UGT and CarE enzymes did not significantly change. As determined by UPLC-MS, the contents of compound 1 in the T1 and T2 groups were 8.55 ng/g and 0.53 ng/g, respectively, which indicated that pest insects significantly induced the synthesis of compound 1. Compound 1 may enhance rice insect resistance by inhibiting the detoxification enzyme activity and metabolism of Chilo suppressalis, as well as promoting cell proliferation to affect its normal growth and development process. The chemical-ecological mechanism of the insect resistance of rice is preliminarily clarified in this paper.

Evaluation of In Vitro Synergistic Effects of Tetracycline with Alkaloid-Related Compounds against Diarrhoeic Bacteria.

Diarrhoea remains an important public health concern, particularly in developing countries, and has become difficult to treat because of antibacterial resistance. The development of synergistic antimicrobial agents appears to be a promising alternative treatment against diarrhoeic infections. In this study, the combined effect of tetracycline together with either nitroxoline, sanguinarine, or zinc pyrithione (representing various classes of plant-based compounds) was evaluated in vitro against selected diarrhoeic bacteria (Enterococcus faecalis, Escherichia coli, Listeria monocytogenes, Shigella flexneri, Vibrio parahaemolyticus, and Yersinia enterocolitica). The chequerboard method in 96-well microtiter plates was used to determine the sum of the fractional inhibitory concentration indices (FICIs). Three independent experiments were performed per combination, each in triplicate. It was observed that the combination of tetracycline with either nitroxoline, sanguinarine, or zinc pyrithione produced synergistic effects against most of the pathogenic bacteria tested, with FICI values ranging from 0.086 to 0.5. Tetracycline-nitroxoline combinations produced the greatest synergistic action against S. flexneri at a FICI value of 0.086. The combinations of the agents tested in this study can thus be used for the development of new anti-diarrhoeic medications. However, studies focusing on their in vivo anti-diarrhoeic activity and safety are required before any consideration for utilization in human medicine.

Piperine-coated zinc oxide nanoparticles target biofilms and induce oral cancer apoptosis via BCl-2/BAX/P53 pathway.

BACKGROUND: Dental pathogens play a crucial role in oral health issues, including tooth decay, gum disease, and oral infections, and recent research suggests a link between these pathogens and oral cancer initiation and progression. Innovative therapeutic approaches are needed due to antibiotic resistance concerns and treatment limitations. METHODS: We synthesized and analyzed piperine-coated zinc oxide nanoparticles (ZnO-PIP NPs) using UV spectroscopy, SEM, XRD, FTIR, and EDAX. Antioxidant and antimicrobial effectiveness were evaluated through DPPH, ABTS, and MIC assays, while the anticancer properties were assessed on KB oral squamous carcinoma cells. RESULTS: ZnO-PIP NPs exhibited significant antioxidant activity and a MIC of 50 µg/mL against dental pathogens, indicating strong antimicrobial properties. Interaction analysis revealed high binding affinity with dental pathogens. ZnO-PIP NPs showed dose-dependent anticancer activity on KB cells, upregulating apoptotic genes BCL2, BAX, and P53. CONCLUSIONS: This approach offers a multifaceted solution to combatting both oral infections and cancer, showcasing their potential for significant advancement in oral healthcare. It is essential to acknowledge potential limitations and challenges associated with the use of ZnO NPs in clinical applications. These may include concerns regarding nanoparticle toxicity, biocompatibility, and long-term safety. Further research and rigorous testing are warranted to address these issues and ensure the safe and effective translation of ZnO-PIP NPs into clinical practice.

Trigonelline as an anticonvulsant agent: mechanistic insights into NMDA receptor expression and oxidative stress balance.

Glutamatergic neurotransmission and oxidative stress are involved in the pathophysiology of seizures. Some anticonvulsants exert their effects through modulation of these pathways. Trigonelline (TRG) has been shown to possess various pharmacological effects like neuroprotection. Therefore, this study was performed to determine TRG's anticonvulsant effects, focusing on its potential effects on N-methyl-D-aspartate (NMDA) receptors, a type of glutamate receptor, and oxidative stress state in the prefrontal cortex (PFC) in PTZ-induced seizure in mice. Seventy-two male mice were randomly divided into nine groups. The groups included mice that received normal saline, TRG at doses of 10, 50, and 100 mg/kg, diazepam, NMDA (an agonist), ketamine (an antagonist), the effective dose of TRG with NMDA, as well as sub-effective dose of TRG with ketamine, respectively. All agents were administrated intraperitoneally 60 min before induction of seizures by PTZ. Latency to seizure, total antioxidant capacity (TAC), and malondialdehyde (MDA) levels in serum and PFC were measured. Furthermore, the gene expression of NR2A and NR2B, subunits of NMDA receptors, was measured in the PFC. TRG administration increased the latency to seizure onset and enhanced TAC while reducing MDA levels in both the PFC and serum. TRG also decreased the gene expression of NR2B in the PFC. Unexpectedly, the findings revealed that the concurrent administration of ketamine amplified, whereas NMDA mitigated, the impact of TRG on latency to seizure. Furthermore, NMDA diminished the positive effects of TRG on antioxidant capacity and oxidative stress, while ketamine amplified these beneficial effects, indicating a complex interaction between TRG and NMDA receptor modulation. In the gene expression of NMDA receptors, results showed that ketamine significantly decreased the gene expression of NR2B when co-administrated with a sub-effective dose of TRG. It was found that, at least partially, the anticonvulsant effect of TRG in PTZ-induced seizures in male mice was mediated by the attenuation of glutamatergic neurotransmission as well as the reduction of oxidative stress.

Oxymatrine attenuates sepsis-induced inflammation and organ injury via inhibition of HMGB1/RAGE/NF-κB signaling pathway.

Sepsis is a life-threatening organ dysfunction that endangers patient lives and is caused by an imbalance in the host defense against infection. Sepsis continues to be a significant cause of morbidity and mortality in critically sick patients. Oxymatrine (OMT), a quinolizidine alkaloid derived from the traditional Chinese herb Sophora flavescens Aiton, has been shown to have anti-inflammatory effects on a number of inflammatory illnesses according to research. In this study, we aimed to evaluate the therapeutic effects of OMT on sepsis and explore the underlying mechanisms. We differentiated THP-1 cells into THP-1 macrophages and studied the anti-inflammatory mechanism of OMT in a lipopolysaccharide (LPS)-induced THP-1 macrophage sepsis model. Activation of the receptor for advanced glycation end products (RAGE), as well as NF-κB, was assessed by Western blot analysis and immunofluorescence staining. ELISA was used to measure the levels of inflammatory factors. We found that OMT significantly inhibited HMGB1-mediated RAGE/NF-κB activation and downstream inflammatory cytokine production in response to LPS stimulation. Finally, an in vivo experiment was performed on septic mice to further study the effect of OMT on injured organs. The animal experiments showed that OMT significantly inhibited HMGB1-mediated RAGE/NF-κB activation, protected against the inflammatory response and organ injury induced by CLP, and prolonged the survival rate of septic mice. Herein, we provide evidence that OMT exerts a significant therapeutic effect on sepsis by inhibiting the HMGB1/RAGE/NF-κB signaling pathway.

Mechanism of oxymatrine in the treatment of cryptosporidiosis through TNF/NF-κB signaling pathway based on network pharmacology and experimental validation.

Cryptosporidiosis is a worldwide zoonotic disease. Oxymatrine, an alkaloid extracted and isolated from the plant bitter ginseng, has been reported to have therapeutic effects on cryptosporidiosis. However, the underlying mechanism of its action remains unclear. In this study, we utilized network pharmacology and experimental validation to investigate the mechanism of oxymatrine in the treatment of cryptosporidiosis. First, the potential targets of drugs and diseases were predicted by TCMSP, Gene Cards, and other databases. Following the intersection of drug-disease targets, the DAVID database was used to implement the enrichment analysis of GO functions and KEGG pathways, and then the network diagram of "intersected target-KEGG" relationship was constructed. Autodock 4.2.6 software was used to carry out the molecular docking of core targets to drug components. Based on the establishment of a mouse model of cryptosporidiosis, the validity of the targets in the TNF/NF-κB signaling pathway was confirmed using Western blot analysis and Quantitative Rea-ltime-PCR. A total of 41 intersectional targets of oxymatrine and Cryptosporidium were generated from the results, and five core targets were screened out by network analysis, including RELA, AKT1, ESR1, TNF, and CASP3. The enrichment analysis showed that oxymatrine could regulate multiple gene targets, mediate TNF, Apoptpsis, IL-17, NF-κB and other signaling pathways. Molecular docking experiments revealed that oxymatrine was tightly bound to core targets with stable conformation. Furthermore, we found through animal experiments that oxymatrine could regulate the mRNA and protein expression of IL-6, NF-κB, and TNF-α in the intestinal tissues of post-infected mice through the TNF/NF-κB signaling pathway. Therefore, it can be concluded that oxymatrine can regulate the inflammatory factors TNF-α, NF-κB, and IL-6 through the TNF/NF-κB signaling pathway for the treatment of cryptosporidiosis. This prediction has also been validated by network pharmacology and animal experiments.

Development of piperine nanoparticles stabilized by OSA modified starch through wet-media milling technique with enhanced anti-adipogenic effect in 3T3-L1 adipocytes.

Piperine (PIP) has been known for its pharmacological activities with low water solubility and poor dissolution, which limits its nutritional application. The purpose of this research was to enhance PIP stability, dispersibility and biological activity by preparing PIP nanoparticles using the wet-media milling approach combined with nanosuspension solidification methods of spray/freeze drying. Octenyl succinic anhydride (OSA)-modified waxy maize starch was applied as the stabilizer to suppress aggregation of PIP nanoparticles. The particle size, redispersibility, storage stability and in vitro release behavior of PIP nanoparticles were measured. The regulating effect on adipocyte differentiation was evaluated using 3T3-L1 cell model. Results showed that PIP nanoparticles had a reduced particle size of 60 ± 1 nm, increased release rate in the simulated gastric (SGF) and intestinal fluids (SIF) and enhanced inhibition effect on adipogenesis in 3T3-L1 cells compared with free PIP, indicating that PIP-loaded nanoparticles with improved stability and anti-adipogenic property were developed successfully by combining wet-media milling and drying methods.

Effects of Combination of Curcumin and Piperine Supplementation on Glycemic Profile in Patients with Prediabetes and Type 2 Diabetes Mellitus: A Systematic Review and Meta-analysis.

Objective: This study aimed to evaluate the effects of the combination of curcumin and piperine supplementation on Fasting Plasma Glucose (FPG), Homeostatic Model of Insulin Resistance (HOMA-IR), and Body Mass Index (BMI) in patients with prediabetes and type 2 Diabetes Mellitus (T2DM). This review was done to identify potential herbal remedies that may help improve glycemic parameters, leading to better health outcomes in combination with current antidiabetic treatment. Methodology: This systematic review was based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). It was conducted in 2023 with sources and databases from MEDLINE, EBSCO-Host, ScienceDirect and ProQuest. This paper included randomized-controlled trials exploring the effects of the combination of curcumin and piperine on patients with prediabetes and T2DM. Systematic reviews, observational studies, case reports, case series, conference abstracts, book sections, commentaries/editorials, non-human studies and articles with unavailable full-text and written in non-English language, were excluded. The key terms for the literature search were "curcumin," "piperine," "prediabetes" and "Type 2 Diabetes Mellitus." We use Cochrane Risk of Bias (RoB) 2 for quality assessment of the included studies and Review Manager (RevMan) 5.4 to do the meta-analysis. Results: A total of three studies were included in this systematic review. Two studies from Neta et al., and Cicero et al., showed no significant difference in HOMA-IR, BMI and FPG levels between the curcumin, piperine and placebo groups. One study from Panahi et al. demonstrated a significant difference in BMI levels between the curcumin and piperine and placebo groups (p <0.01). The meta-analysis showed that FPG levels, HOMA-IR and BMI improved among patients with diabetes given in curcumin and piperine with reported mean differences (MD) of = -7.61, 95% CI [-15.26, 0.03], p = 0.05, MD = -0.36, 95% CI [-0.77 to 0.05], p = 0.09, and MD = -0.41, 95% CI [-0.85 to 0.03], p = 0.07, respectively). Conclusions: The supplementation of curcumin and piperine showed a numerical reduction in FPG, HOMA-IR and BMI, but were not statistically significant. Further research is needed as there is a paucity of studies included in the review.

Anti-inflammatory effects of steroidal alkaloids of Solanum lyratum Thunb.

Solanum lyratum Thunb., a traditional Chinese herbal medicine, has a promising background. However, the anti-inflammatory effects of its component steroid alkaloid have not been explored. In this study, animal and cell experiments were performed to investigate the anti-inflammatory effects and mechanism of action of Solanum lyratum Thunb steroid alkaloid (SLTSA), in order to provide evidence for its potential utilization. SLTSA effectively inhibited ear swelling and acute abdominal inflammation of mice. We observed concentration-dependent inhibition of pro-inflammatory cytokines by SLTSA, as confirmed by the ELISA and RT-qPCR results. Flow cytometry, immunofluorescence and RT-qPCR analyses revealed that SLTSA suppressed TLR4 expression. Western blot results indicated that SLTSA inhibited the activation of the TLR4/MyD88/NF-κB signaling pathway. Our study demonstrated that SLTSA possesses anti-inflammatory properties.

Cytotoxicity of alkaloids isolated from Peganum harmala seeds on HCT116 human colon cancer cells.

BACKGROUND: The present study aimed to elucidate the potential anticancer activity and mechanism of P. harmala's alkaloid extract, harmine (HAR), and harmaline (HAL) in HCT-116 colorectal cancer cells. METHODS AND RESULTS: P. harmala's alkaloid was extracted from harmala seeds. HCT-116 cells were treated with P. harmala's alkaloid extract, HAR and HAL. Cytotoxicity was determined by MTT assay, apoptotic activity detected via flow cytometry and acridine orange (AO)/ethidium bromide (EB) dual staining, and cell cycle distribution analyzed with flow cytometry. The mRNA expression of Bcl-2-associated X protein (Bax) and glycogen synthase kinase-3 beta (GSK3ß) was measured by real-time PCR. Furthermore, the expression of Bax, Bcl-2, GSK3ß and p53 proteins, were determined by western blotting. The findings indicated that, P. harmala's alkaloids extract, HAR and HAL were significantly cytotoxic toward HCT116 cells after 24 and 48 h of treatment. We showed that P. harmala's alkaloid extract induce apoptosis and cell cycle arrest at G2 phase in the HCT116 cell line. Downregulation of GSK3ß and Bcl-2 and upregulation of Bax and p53 were observed. CONCLUSION: The findings of this study indicate that the P. harmala's alkaloid extract has anticancer activity and may be further investigated to develop future anticancer chemotherapeutic agents.

Trigonelline hydrochloride attenuates silica-induced pulmonary fibrosis by orchestrating fibroblast to myofibroblast differentiation.

BACKGROUND: Silicosis represents a paramount occupational health hazard globally, with its incidence, morbidity, and mortality on an upward trajectory, posing substantial clinical dilemmas due to limited effective treatment options available. Trigonelline (Trig), a plant alkaloid extracted mainly from coffee and fenugreek, have diverse biological properties such as protecting dermal fibroblasts against ultraviolet radiation and has the potential to inhibit collagen synthesis. However, it's unclear whether Trig inhibits fibroblast activation to attenuate silicosis-induced pulmonary fibrosis is unclear. METHODS: To evaluate the therapeutic efficacy of Trig in the context of silicosis-related pulmonary fibrosis, a mouse model of silicosis was utilized. The investigation seeks to elucidated Trig's impact on the progression of silica-induced pulmonary fibrosis by evaluating protein expression, mRNA levels and employing Hematoxylin and Eosin (H&E), Masson's trichrome, and Sirius Red staining. Subsequently, we explored the mechanism underlying of its functions. RESULTS: In vivo experiment, Trig has been demonstrated the significant efficacy in mitigating SiO2-induced silicosis and BLM-induced pulmonary fibrosis, as evidenced by improved histochemical staining and reduced fibrotic marker expressions. Additionally, we showed that the differentiation of fibroblast to myofibroblast was imped in Trig + SiO2 group. In terms of mechanism, we obtained in vitro evidence that Trig inhibited fibroblast-to-myofibroblast differentiation by repressing TGF-ß/Smad signaling according to the in vitro evidence. Notably, our finding indicated that Trig seemed to be safe in mice and fibroblasts. CONCLUSION: In summary, Trig attenuated the severity of silicosis-related pulmonary fibrosis by alleviating the differentiation of myofibroblasts, indicating the development of novel therapeutic approaches for silicosis fibrosis.

Protective Effect of the Total Alkaloid Extract from Bulbus Fritillariae pallidiflorae in a Mouse Model of Cigarette Smoke-Induced Chronic Obstructive Pulmonary Disease.

Purpose: In recent years, the incidence of chronic obstructive pulmonary disease (COPD) has been increasing year by year, but therapeutic drugs has no breakthrough. The total alkaloid extract from Bulbus Fritillariae pallidiflorae (BFP-TA) is widely used in treating lung diseases. Therefore, this study aimed to investigate the protective effect and mechanism of BFP-TA in COPD mice. Methods: BFP-TA was prepared by macroporous adsorbent resin, and the material basis of BFP-TA was analyzed by HPLC-ELSD and UHPLC-MS/MS. Then, the COPD mouse model was induced by cigarette smoke (CS) for 12 weeks, administered at weeks 9-12. Subsequently, the body weight, lung-body ratio, pulmonary function, histopathology, and the levels of pro-inflammatory cytokines, matrix metalloproteinases (MMPs) and oxidative stress markers in the serum of mice were determined. The expressions of related protein of EMT and MAPK signaling pathways in the lung tissues of mice were detected by Western blot. Results: The alkaloid relative content of BFP-TA is 64.28%, and nine alkaloids in BFP-TA were identified and quantified by UHPLC-MS/MS. Subsequently, the animal experiment showed that BFP-TA could improve pulmonary function, and alleviate inflammatory cell infiltration, pulmonary emphysema, and collagen fiber deposition in the lung of COPD mice. Furthermore, BFP-TA could decrease the levels of pro-inflammatory cytokines (TNF-α, IL-6 and IL-1ß), MMPs (MMP-9 and MMP-12) and MDA, while increase the levels of TIMP-1 and SOD. Moreover, BFP-TA could decrease the protein expressions of collagen I, vimentin, α-SMA, MMP-9, MMP-9/TIMP-1, Bax, p-JNK/JNK, p-P38/P38, and p-ERK/ERK, while increase the level of E-cadherin. Conclusion: This study is the first to demonstrate the protective effect of BFP-TA in CS-induced COPD mouse model. Furthermore, BFP-TA may improve airway remodeling by inhibiting the EMT process and potentially exert anti-inflammatory effect by inhibiting the MAPK signaling pathway.