NETs contribute to psoriasiform skin inflammation: A novel therapeutic approach targeting IL-36 cytokines by a small molecule tetrahydroxystilbene glucoside.

BACKGROUND: Psoriasis, a chronic immune-mediated skin disease with pathological features such as aberrant differentiation of keratinocytes, dermal-epidermal inflammation, and angiogenesis. 2,3,5,4'-Tetrahydroxy stilbene 2-Ο-ß-d-glucoside (2354Glu) is a natural small molecule polyhydrostilbenes isolated from Polygonum multiglorum Thunb. The regulation of IL-36 subfamily has led to new pharmacologic strategies to reverse psoriasiform dermatitis. PURPOSE: Here we investigated the therapeutic potential of 2354Glu and elucidated the underlying mechanism in psoriasis. METHODS: The effects of 2354Glu on IL-36 signaling were assessed by psoriasiform in vivo, in vitro and ex vivo model. The in vivo mice model of psoriasis-like skin inflammation was established by applying imiquimod (IMQ), and the in vitro and ex vitro models were established by stimulating mouse primary keratinocyte, human keratinocytes cells (HaCaT) and ex vivo skin tissue isolated from the mice back with Polyinosine-polycytidylic acid (Poly(I:C)), IMQ, IL-36γ and Lipopolysaccharide (LPS) respectively. Moreover, NETs formation was inhibited by Cl-amidine to evaluate the effect of NETs in psoriatic mouse model. The effects of 2354Glu on skin inflammation were assessed by western blot, H&E, immunohistochemistry, immunofluorescence, enzyme-linked immunosorbent assay and real-time quantitative PCR. RESULTS: In Poly(I:C)-stimulated keratinocytes, the secretion of IL-36 was inhibited after treatment with 2354Glu, similar to the effects of TLR3, P2X7R and caspase-1 inhibitors. In aldara (imiquimod)-induced mice, 2354Glu (100 and 25 mg/kg) improved immune cell infiltration and hyperkeratosis in psoriasis by directly targeting IL-36 in keratinocytes through P2X7R-caspase-1. When treatment with 2354Glu (25 mg/kg) was insufficient to inhibit IL-36γ, NETs reduced pathological features and IL-36 signaling by interacting with keratinocytes to combat psoriasis like inflammation. CONCLUSION: These results indicated that NETs had a beneficial effect on psoriasiform dermatitis. 2354Glu alleviates psoriasis by directly targeting IL-36/P2X7R axis and NET formation, providing a potential candidate for the treatment of psoriasis.

Diallyl disulfide, the bioactive component of Allium species, ameliorates pulmonary fibrosis by mediating the crosstalk of farnesoid X receptor and yes-associated protein 1 signaling pathway.

Environmental pollution, virus infection, allergens, and other factors may cause respiratory disease, which could be improved by dietary therapy. Allium species are common daily food seasoning and have high nutritional and medical value. Diallyl disulfide (DADS) is the major volatile oil compound of Allium species. The present study aims to explore the preventive effect and potential mechanism of DADS on pulmonary fibrosis. C57BL/6J mice were intratracheally injected with bleomycin (BLM) to establish pulmonary fibrosis and then administrated with DADS. Primary lung fibroblasts or A549 were stimulated with BLM, followed by DADS, farnesoid X receptor (FXR) agonist (GW4064), yes-associated protein 1 (YAP1) inhibitor (verteporfin), or silencing of FXR and YAP1. In BLM-stimulated mice, DADS significantly ameliorated histopathological changes and interleukin-1ß levels in bronchoalveolar lavage fluid. DADS decreased fibrosis markers, HIF-1α, inflammatory cytokines, and epithelial-mesenchymal transition in pulmonary mice and activated fibroblasts. DADS significantly enhanced FXR expression and inhibited YAP1 activation, which functions as GW4064 and verteporfin. A deficiency of FXR or YAP1 could result in the increase of these two protein expressions, respectively. DADS ameliorated extracellular matrix deposition, hypoxia, epithelial-mesenchymal transition, and inflammation in FXR or YAP1 knockdown A549. Taken together, targeting the crosstalk of FXR and YAP1 might be the potential mechanism for DADS against pulmonary fibrosis. DADS can serve as a potential candidate or dietary nutraceutical supplement for the treatment of pulmonary fibrosis.

Synthesis of amide derivatives containing the imidazole moiety and evaluation of their anti-cardiac fibrosis activity.

Three series of N-{[4-([1,2,4]triazolo[1,5-α]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl]methyl}acetamides (14a-d, 15a-n, and 16a-f) were synthesized and evaluated for activin receptor-like kinase 5 (ALK5) inhibitory activities in an enzymatic assay. The target compounds showed high ALK5 inhibitory activity and selectivity. The half maximal inhibitory concentration (IC50) for phosphorylation of ALK5 of 16f (9.1 nM), the most potent compound, was 2.7 times that of the clinical candidate EW-7197 (vactosertib) and 14 times that of the clinical candidate LY-2157299. The selectivity index of 16f against p38α mitogen-activated protein kinase was >109, which was much higher than that of positive controls (EW-7197: >41, and LY-2157299: 4). Furthermore, a molecular docking study provided the interaction modes between the target compounds and ALK5. Compounds 14c, 14d, and 16f effectively inhibited the protein expression of α-smooth muscle actin (α-SMA), collagen I, and tissue inhibitor of metalloproteinase 1 (TIMP-1)/matrix metalloproteinase 13 (MMP-13) in transforming growth factor-ß-induced human umbilical vein endothelial cells. Compounds 14c and 16f showed especially high activity at low concentrations, which suggests that these compounds could inhibit myocardial cell fibrosis. Compounds 14c, 14d, and 16f are potential preclinical candidates for the treatment of cardiac fibrosis.

Synthesis and anti-liver fibrosis activity of imidazole and thiazole compounds containing amino acids.

Four series of imidazoles (15a-g, 20c, and 20d) and thiazoles (18a-g, 22a, and 22b) possessing various amino acids were synthesized and evaluated for activin receptor-like kinase 5 (ALK5) inhibitory activities in an enzymatic assay. Among them, compounds 15g and 18c showed the highest inhibitory activity against ALK5, with IC50 values of 0.017 and 0.025 µM, respectively. Compounds 15g and 18c efficiently inhibited extracellular matrix (ECM) deposition in TGF-ß-induced hepatic stellate cells (HSCs), and eventually suppressed HSC activation. Moreover, compound 15g showed a good pharmacokinetic (PK) profile with a favorable half-life (t1/2 = 9.14 h). The results indicated that these compounds exhibited activity targeting ALK5 and may have potential in the treatment of liver fibrosis; thus they are worthy of further study.

A therapeutic strategy of parthenolide in improving imiquimod-induced psoriasis-like skin inflammation targeting IL-36/NETs through skin transdermal therapeutic system.

BACKGROUND: Psoriasis is an inflammatory skin disease that occurs repeatedly over time. The natural product of sesquiterpene lactones, Parthenolide (Par), is isolated from Tanacetum parthenium L. (feverfew) which has significant effects on anti-inflammatory. The therapeutic effect of the medication itself is crucial, but different routes of administration of the same drug can also produce different effects. PURPOSE: The aim of our research sought to investigate the ameliorating effects of Par in psoriasis-like skin inflammation and its related mechanism of action. RESULTS: In the IMQ-induced model, intragastric administration of Par reduced the Psoriasis Area and Severity Index (PASI) score, improved skin erythema, scaling, and other symptoms. And Par decreased the expression of Ki67, keratin14, keratin16 and keratin17, and increased the expression of keratin1. Par could reduce IL-36 protein expressions, meanwhile the expression of Il1b, Cxcl1 and Cxcl2 mRNA were also decreased. Par regulated the expression levels of F4/80, MPO and NE. However, skin transdermal administration of Par was more effective. Similarly, Par attenuated IL-36γ, IL-1ß and caspase-1 activated by Poly(I:C) in in vitro and ex vivo. In addition, Par also reduced NE, PR3, and Cathepsin G levels in explant skin tissues. CONCLUSION: Par ameliorated psoriasis-like skin inflammation in both in vivo and in vitro, especially after treatment with transdermal drug delivery, possibly by inhibiting neutrophil extracellular traps and thus by interfering IL-36 signaling pathway. It indicated that Par provides a new research strategy for the treatment of psoriasis-like skin inflammation and is expected to be a promising drug.

Angelica dahurica extract and its effective component bergapten alleviated hepatic fibrosis by activating FXR signaling pathway.

Angelica dahurica (A. dahurica) has a wide range of pharmacological effects, including analgesic, anti-inflammatory and hepatoprotective effects. In this study, we investigated the effect of A. dahurica extract (AD) and its effective component bergapten (BG) on hepatic fibrosis and potential mechanisms. Hepatic fibrosis was induced by intraperitoneal injection with carbon tetrachloride (CCl4) for 1 week, and mice were administrated with AD or BG by gavage for 1 week before CCl4 injection. Hepatic stellate cells (HSCs) were stimulated by transforming growth factor-ß (TGF-ß) and cultured with AD, BG, GW4064 (FXR agonist) or Guggulsterone (FXR inhibitor). In CCl4-induced mice, AD significantly decreased serum aminotransferase, reduced excess accumulation of extracellular matrix (ECM), inhibited caspase-1 and IL-1ß, and increased FXR expressions. In activated HSCs, AD suppressed the expressions of α-SMA, collagen I, and TIMP-1/MMP-13 ratio and inflammatory factors, functioning as FXR agonist. In CCl4-induced mice, BG significantly improved serum transaminase and histopathological changes, reduced ECM excessive deposition, inflammatory response, and activated FXR expression. BG increased FXR expression and inhibited α-SMA and IL-1ß expressions in activated HSCs, functioning as GW4064. FXR deficiency significantly attenuated the decreasing effect of BG on α-SMA and IL-1ß expressions in LX-2 cells. In conclusion, AD could regulate hepatic fibrosis by regulating ECM excessive deposition and inflammation. Activating FXR signaling by BG might be the potential mechanism of AD against hepatic fibrosis.

Sesamol as a potential candidate for the treatment of hepatic fibrosis, based on its regulation of FXR/LXR axis-mediated inhibition of autophagy through crosstalk between hepatic cells and macrophage.

BACKGROUND: Sesamol (SEM), a natural lignan compound isolated from sesame, has strong anti-oxidant property, regulating lipid metabolism, decreasing cholesterol and hepatoprotection. However, its anti-hepatic fibrosis effect and mechanisms have not been comprehensively elucidated. HYPOTHESIS/PURPOSE: This study aims to investigate the anti-hepatic fibrosis of SEM and its underlying mechanisms. METHOD: C57BL/6 mice with hepatic fibrosis were induced by TAA, then administrated with SEM or curcumin, respectively. HSCs were stimulated by TGF-ß or conditioned medium, and then cultured with SEM, GW4064, GW3965, Rapamycin (RA) or 3-methyladenine (3-MA), respectively. Mice with hepatic fibrosis also were administrated with SEM, RA or 3-MA to estimate the effect of SEM on autophagy. RESULTS: In vitro, SEM significantly inhibited extracellular matrix deposition, P2 × 7r-NLRP3, and inflammatory cytokines. SEM increased FXR and LXRα/ß expressions and decreased MAPLC3α/ß and P62 expressions, functioning as 3-MA (autophagy inhibitor). In vivo, SEM reduced serum transaminase, histopathology changes, fibrogenesis, autophagy markers and inflammatory cytokines caused by TAA. LX-2 were activated with conditioned medium from LPS-primed THP-1, which resulted in significant enhance of autophagy markers and inflammatory cytokines and decrease of FXR and LXRα/ß expressions. SEM could reverse above these changes and function as 3-MA, GW4064, or GW3965. Deficiency of FXR or LXR attenuated the regulation of SEM on α-SMA, MAPLC3α/ß, P62 and IL-1ß in activated LX-2. In activated THP-1, deficiency of FXR could decrease the expression of LXR, and vice versa. Deficiency of FXR or LXR in activated MΦ decreased the expressions of FXR and LXR in activated LX-2. Deficiency FXR or LXR in activated MΦ also attenuated the regulation of SEM on α-SMA, MAPLC3α/ß, P62, caspase-1 and IL-1ß. In vivo, SEM significantly reversed hepatic fibrosis via FXR/LXR and autophagy. CONCLUSION: SEM could regulate hepatic fibrosis by inhibiting fibrogenesis, autophagy and inflammation. FXR/LXR axis-mediated inhibition of autophagy contributed to the regulation of SEM against hepatic fibrosis, especially based on involving in the crosstalk of HSCs-macrophage. SEM might be a prospective therapeutic candidate, and its mechanism would be a new direction or strategy for hepatic fibrosis treatment.

Targeting RXFP1 by Ligustilide: A novel therapeutic approach for alcoholic hepatic steatosis.

BACKGROUND: Ligustilide (Lig) is the main active ingredient of Umbelliferae Angelicae Sinensis Radix (Chinese Angelica) and Chuanxiong Rhizoma (Sichuan lovase rhizome). Lig possesses various pharmacological properties and could treat obesity by regulating energy metabolism. However, the impact and regulatory mechanism of Lig on alcoholic hepatic steatosis remains unclear. PURPOSE: This study aimed to explore the therapeutic effect of Lig on alcoholic hepatic steatosis and its related pharmacological mechanism. RESULTS: With chronic and binge ethanol feeding, liver tissue damage and lipid accumulation in mice suffering alcoholic hepatic steatosis were significantly improved after Lig treatment. Lig effectively regulated the expression levels of lipid metabolism-related proteins in alcoholic hepatic steatosis. In addition, Lig reduced RXFP1 expression, inhibited the activation of NLRP3 inflammasome, and blocked NET formation. Lig reduced the infiltration of immune cells to the liver and the further prevented the occurrence of alcohol-stimulated inflammatory response in liver. Lig significantly regulated lipid accumulation in alcohol exposed AML12 cells via modulating PPARα and SREBP1. In MPMs, Lig decreased the expression of RXFP1, inhibited the activation of NLRP3 in macrophages stimulated by LPS/ATP, and slowed down the occurrence of inflammatory response. CONCLUSION: Lig sustained lipid metabolism homeostasis in alcoholic hepatic steatosis, through inhibiting the activation of NLRP3 inflammasomes and the formation of NETs, especially targeting RXFP1 in macrophages.

Pterostilbene exerts cytotoxicity on activated hepatic stellate cells by inhibiting excessive proliferation through the crosstalk of Sirt1 and STAT3 pathways.

Pterostilbene (PTE), a natural analogue of resveratrol, abundantly exists in blueberries and grapes and has several beneficial potentials against oxidative stress, inflammation, and cancer. In current study, we investigated the effects of PTE on hepatic fibrosis in vitro and in vivo. Activation of hepatic stellate cells (HSCs) is an initiating event in the initiation of hepatic fibrosis. MTT assay revealed that PTE (3.125-12.5 µM) displayed cytotoxicity on activated HSCs, no cytotoxicity on AML-12 and quiescent HSCs. PTE significantly inhibited the expressions of α-SMA, collagen Ⅰ and TIMP-1/MMP13 ratio; suppressed inflammatory cascade activation to reduce inflammatory cytokines release, such as Caspase-1, IL-1ß and IL-6. PTE activated Sirt1 and decreased STAT3 phosphorylation, functioning as SRT1720 and Niclosamide. Sirt1 deficiency significantly elevated p-STAT3 expression, while STAT3 deficiency resulted in Sirt1 increasing and inhibited fibrosis and inflammatory cytokines expressions. In mice with hepatic fibrosis induced by thioacetamide (TAA), PTE significantly decreased ALT and AST activities, reduced fibrosis markers, STAT3 phosphorylation and activated Sirt1 expression. PTE showed cytotoxicity on activated HSCs to ameliorate hepatic fibrosis via regulating fibrogenesis, energy metabolism and inflammation and targeting the crosstalk of Sirt1 and STAT3. In conclusion, PTE could be potentially beneficial as a natural plant metabolite in preventing and treating hepatic fibrosis.

Synthesis of and anti-fibrotic effect of pyrazole derivative J-1048: Inhibition of ALK5 as a novel approach to liver fibrosis targeting inflammation.

Liver fibrosis is a worldwide challenge of health issue. Developing effective new drugs for treating liver fibrosis is of great importance. In recent years, chemically synthesized drugs have significant advantages in treating liver fibrosis. Small molecule pyrazole derivatives as activin receptor-like kinase 5 (ALK5) inhibitors have also shown anti-fibrotic and tumor growth inhibitory effects. To develop the candidate with anti-fibrotic effect, we synthesized a novel pyrazole derivative, J-1048. The inhibitory effect of J-1048 on ALK5 and p38α mitogen-activated protein (MAP) kinase activity was assessed by enzymatic assays. We established an in vivo liver fibrosis model by injecting thioacetamide (TAA) into mice and in vitro model of TGF-ß stimulated hepatic stellated cells to explore the inhibition mechanisms and therapeutic potential of J-1048 as an ALK5 inhibitor in liver fibrosis. Our data showed that J-1048 inhibited TAA-induced liver fibrosis in mice by explicitly blocking the TGF-ß/Smad signaling pathway. Additionally, J-1048 inhibited the production of inflammatory cytokine Interleukin-1ß (IL-1ß) by inhibiting the purinergic ligand-gated ion channel 7 receptor (P2X7r) -Nucleotide-binding domain-(NOD-)like receptor protein 3 (NLRP3) axis, thereby alleviating liver fibrosis. Our findings demonstrated that a novel small molecule ALK5 inhibitor, J-1048, exhibited strong potential as a clinical therapeutic candidate for liver fibrosis.

The gut microbes in inflammatory bowel disease: Future novel target option for pharmacotherapy.

Gut microbes constitute the main microbiota in the human body, which can regulate biological processes such as immunity, cell proliferation, and differentiation, hence playing a specific function in intestinal diseases. In recent years, gut microbes have become a research hotspot in the pharmaceutical field. Because of their enormous number, diversity, and functional complexity, gut microbes have essential functions in the development of many digestive diseases. Inflammatory bowel disease (IBD) is a chronic non-specific inflammatory disease with a complex etiology, the exact cause and pathogenesis are unclear. There are no medicines that can cure IBD, and more research on therapeutic drugs is urgently needed. It has been reported that gut microbes play a critical role in pathogenesis, and there is a tight and complex association between gut microbes and IBD. The dysregulation of gut microbes may be a predisposing factor for IBD, and at the same time, IBD may exacerbate gut microbes' disorders, but the mechanism of interaction between the two is still not well defined. The study of the relationship between gut microbes and IBD is not only important to elucidate the pathogenesis but also has a positive effect on the treatment based on the regimen of regulating gut microbes. This review describes the latest research progress on the functions of gut microbes and their relationship with IBD, which can provide reference and assistance for further research. It may provide a theoretical basis for the application of probiotics, fecal microbiota transplantation, and other therapeutic methods to regulate gut microbes in IBD.

Gasotransmitters in non-alcoholic fatty liver disease: just the tip of the iceberg.

Non-alcoholic fatty liver disease (NAFLD) is a clinicopathological syndrome characterized by fatty lesions and fat accumulation in hepatic parenchymal cells, which is in the absence of excessive alcohol consumption or definite liver damage factors. The exact pathogenesis of NAFLD is not fully understood, but it is now recognized that oxidative stress, insulin resistance, and inflammation are essential mechanisms involved in the development and treatment of NAFLD. NAFLD therapy aims to stop, delay or reverse disease progressions, as well as improve the quality of life and clinical outcomes of patients with NAFLD. Gasotransmitters are produced by enzymatic reactions, regulated through metabolic pathways in vivo, which can freely penetrate cell membranes with specific physiological functions and targets. Three gasotransmitters, nitric oxide, carbon monoxide, and hydrogen sulfide have been discovered. Gasotransmitters exhibit the effects of anti-inflammatory, anti-oxidant, vasodilatory, and cardioprotective agents. Gasotransmitters and their donors can be used as new gas-derived drugs and provide new approaches to the clinical treatment of NAFLD. Gasotransmitters can modulate inflammation, oxidative stress, and numerous signaling pathways to protect against NAFLD. In this paper, we mainly review the status of gasotransmitters research on NAFLD. It provides clinical applications for the future use of exogenous and endogenous gasotransmitters for the treatment of NAFLD.

Potential skin health promoting benefits of costunolide: a therapeutic strategy to improve skin inflammation in imiquimod-induced psoriasis.

Psoriasis is a recurrent inflammatory skin disease. IL-36-related cytokines are overexpressed in psoriasis, but the mechanism is not yet clear. Costunolide (Cos) is a sesquiterpenoid compound derived from the root of the traditional Chinese medicine Aucklandia lappa Decne. This study aimed to explore the mechanism of Cos on improving psoriasis-like skin inflammation. An in vivo model was established by applying imiquimod treatment to the back skin of mice, and an in vitro model was established by using polyinosinic-polycytidylic acid (Poly(I:C)) stimulated-mouse primary dermal fibroblasts to induce inflammation. The results showed that Cos improved the pathological changes of psoriasis-like skin inflammation. In addition, Cos could inhibit epidermal damage and inflammation-related expression and improve the occurrence of skin-related inflammation in both in vivo and in vitro experiments. The improvement of psoriasis-like skin inflammatory response might be through the P2X7R/IL-36 signaling pathway. Collectively, Cos has an inhibitory effect on the expression of psoriasis-like skin inflammation. This showed that Cos has potential skin health promoting benefits by preventing psoriasis-like skin inflammation.

Carnosic acid suppressed the formation of NETs in alcoholic hepatosteatosis based on P2X7R-NLRP3 axis.

BACKGROUND: Alcoholic liver disease (ALD) is accompanied by a disruption of lipid metabolism and an inflammatory response in the liver during the process of disease. Carnosic acid (CA), a natural diterpene extracted from Rosmarinus officinalis (rosemary) and Salvia officinalis (sage), has more pharmacological activities, which is known to be useful in the treatment of obesity and acts by regulating energy metabolism. However, the role and regulation mechanism of CA against ALD remain unclear. HYPOTHESIS: We hypothesized that CA might improve alcoholic-induced hepatosteatosis. STUDY DESIGN AND METHODS: The alcoholic liver disease model was established a mouse chronic ethanol feeding by Lieber-DeCarli control liquid feed (10 d) plus a single binge with or without CA administration. AML12 cells were exposed to ethanol for 24 h. Murine peritoneal macrophages (MPM) were stimulated with LPS and ATP. RESULTS: CA ameliorated lipid accumulation in the liver of mice in the NIAAA model, acting by inhibiting the expression of genes related to lipid synthesis. CA reduced alcohol-induced immune cell infiltration in the liver, and inhibited the activation of P2X7R-NLRP3 inflammasome, meanwhile blocked the formation of NETs in mouse livers tissue. In AML12 cells, CA attenuated the lipid accumulation triggered by ethanol stimulation, which was achieved by inhibiting the expression of SREBP1 and CA reduced the release of inflammatory factor IL-1ß by inhibiting the activation of P2X7R-NLRP3. In MPM, IL-1ß and HMGB1 were reduced after LPS/ATP stimulation in CA-treated cells and supernatant. CONCLUSIONS: CA attenuated alcohol-induced fat accumulation, suppressed the formation of NETs based on P2X7R-NLRP3 axis in mouse livers. Our data indicated that CA exerted hepatoprotective effects, which might be a promising candidate.

Mongolian medicine in treating type 2 diabetes mellitus combined with nonalcoholic fatty liver disease via FXR/LXR-mediated P2X7R/NLRP3/NF-κB pathway activation.

Type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD) are the most problematic metabolic diseases in the world. NAFLD encompasses a spectrum of severity, ranging from simple steatosis to non-alcoholic steatohepatitis (NASH) and fibrosis, increasing the risk of cirrhosis and hepatocellular carcinoma. Importantly, NAFLD is closely linked to obesity and tightly interrelated with insulin resistance and T2DM. T2DM and NAFLD (T2DM-NAFLD) are called as the Xike Rixijing Disease and Tonglaga Indigestion Disease respectively, in Mongolian medicine. Xike Rixijing Disease maybe develop into Tonglaga Indigestion Disease. Forturnately many Mongolian medicines show efficient treatment of T2DM-NAFLD, such as Agriophyllum squarrosum, Haliyasu (dried powder of camel placenta), Digeda-4 (herbs of Lomatogonium carinthiacum, rhizomata of Coptis chinensis, ripe fruits of Gardenia jasminoides, herbs of Dianthus superbus), Guangmingyan Siwei Decoction Powder (Halite, ripe fruits of Terminalia chebula, rhizomata of Zingiber officinale, fruit clusters of Piper longum), Tonglaga-5 (ripe fruits of Punica granatum, barks of Cinnamomum cassia, ripe fruits of Amomum kravanh, fruit clusters of Piper longum, flowers of Carthamus tinctorius), Tegexidegeqi (rhizomata of Inula helenium, ripe fruits of Gardenia jasminoides, rhizomata of Platycodon grandiflorum, rhizomata of Coptis chinensis, heartwood of Caesalpinia sappan), Ligan Shiliu Bawei San (ripe fruits of Punica granatum, barks of Cinnamomum cassia, ripe fruits of Amomum kravanh, fruit clusters of Piper longum, flowers of Carthamus tinctorius, ripe fruits of Amomum tsao-ko, rhizomata of Zingiber officinale), etc. Principles of Mongolian medicine in treating diseases: by balancing "three essences or roots" and "seven elements", strengthening liver and kidney function, transporting nutrients to enhance physical strength and disease resistance, and combined with drugs for comprehensive conditioning treatment. However, their molecular mechanisms remain unclear. In this review, we prospect that Mongolian medicines might be a promising treatment for T2DM-NAFLD by activating P2X7R/NLRP3/NF-κB inflammatory pathway via lipid-sensitive nuclear receptors (i.e., FXR and LXR).

Stem Cell-Based Therapies for Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is a chronic, relapsing disease that severely affects patients' quality of life. The exact cause of IBD is uncertain, but current studies suggest that abnormal activation of the immune system, genetic susceptibility, and altered intestinal flora due to mucosal barrier defects may play an essential role in the pathogenesis of IBD. Unfortunately, IBD is currently difficult to be wholly cured. Thus, more treatment options are needed for different patients. Stem cell therapy, mainly including hematopoietic stem cell therapy and mesenchymal stem cell therapy, has shown the potential to improve the clinical disease activity of patients when conventional treatments are not effective. Stem cell therapy, an emerging therapy for IBD, can alleviate mucosal inflammation through mechanisms such as immunomodulation and colonization repair. Clinical studies have confirmed the effectiveness of stem cell transplantation in refractory IBD and the ability to maintain long-term remission in some patients. However, stem cell therapy is still in the research stage, and its safety and long-term efficacy remain to be further evaluated. This article reviews the upcoming stem cell transplantation methods for clinical application and the results of ongoing clinical trials to provide ideas for the clinical use of stem cell transplantation as a potential treatment for IBD.

Traditional Chinese Medicine and Natural Products: Potential Approaches for Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is a rare, recurrent, and intractable inflammation obstruction of the stomach tract, usually accompanied by inflammation of cell proliferation and inflammation of the colon and carries a particular cause of inflammation. The clinical use of drugs in western countries affects IBD treatment, but various adverse effects and high prices limit their application. For these reasons, Traditional Chinese Medicine (TCM) is more advantageous in treating IBD. This paper reviews the mechanism and research status of TCM and natural products in IBD treatment by analyzing the relevant literature to provide a scientific and theoretical basis for IBD treatment.

Taxifolin blocks monosodium urate crystal-induced gouty inflammation by regulating phagocytosis and autophagy.

Gout is a chronic disease caused by monosodium urate (MSU) crystal deposition in the joints and surrounding tissues. We examined the effects of Taxifolin, a natural flavonoid mainly existing in vegetables and fruits, on MSU-induced gout. Pretreatment with Taxifolin significantly reduced IL-1ß, Caspase-1 and HMGB1 levels, upregulation of autophagy-related protein, LC3, as well as improved phagocytosis of macrophages. This study indicated that Taxifolin-attenuated inflammatory response in MSU-induced acute gout model by decreasing pro-inflammatory cytokine production and promoting the autophagy and phagocytic capacity of macrophages. Dietary supplementation with Taxifolin induces the autophagy and attenuated inflammatory response, which in consequence modulates acute gout. A preventive strategy combining dietary interventions with Taxifolin may offer a potential therapeutic alternative to pharmacological treatment to reduce inflammatory response to gout.

Inflammatory bowel disease: an overview of Chinese herbal medicine formula-based treatment.

Inflammatory bowel disease (IBD) is a chronic recurrent inflammatory disease of the intestine, including Crohn's disease (CD) and ulcerative colitis (UC), whose etiology and pathogenesis have not been fully understood. Due to its prolonged course and chronic recurrence, IBD imposes a heavy economic burden and psychological stress on patients. Traditional Chinese Herbal Medicine has unique advantages in IBD treatment because of its symptomatic treatment. However, the advantages of the Chinese Herbal Medicine Formula (CHMF) have rarely been discussed. In recent years, many scholars have conducted fundamental studies on CHMF to delay IBD from different perspectives and found that CHMF may help maintain intestinal integrity, reduce inflammation, and decrease oxidative stress, thus playing a positive role in the treatment of IBD. Therefore, this review focuses on the mechanisms associated with CHMF in IBD treatment. CHMF has apparent advantages. In addition to the exact composition and controlled quality of modern drugs, it also has multi-component and multi-target synergistic effects. CHMF has good prospects in the treatment of IBD, but its multi-agent composition and wide range of targets exacerbate the difficulty of studying its treatment of IBD. Future research on CHMF-related mechanisms is needed to achieve better efficacy.