Miao sour soup alleviates DSS-induced colitis in mice: modulation of gut microbiota and intestinal barrier function.

Miao sour soup (MSS), a daily fermented food in Guizhou, China, is rich in microorganisms with various beneficial activities, including anti-inflammatory and antioxidant activities. However, the therapeutic effects of MSS on IBD remain unexplored. This study aimed to investigate the protective effect of MSS against colitis in mice. In this study, we examined the microbial community structure of MSS by metagenomic sequencing and also explored the protective effect of MSS on DSS-induced colitis in mice. We investigated the effects of MSS on intestinal inflammatory response and intestinal barrier function in mice. Finally, the changes in intestinal flora were analyzed based on the 16S rRNA gene sequencing results. Significantly, the experiment result shows that MSS ameliorated the severity of DSS-induced disease in mice by mitigating colitis-associated weight loss, reducing the disease activity index of IBD, alleviating colonic hemorrhagic lesions, increasing colon length, and improving colonic tissue damage. Moreover, MSS preserved intestinal barrier integrity and restored intestinal epithelial function in mice. Additionally, MSS modulated the structure and composition of the intestinal flora. Furthermore, MSS downregulated pro-inflammatory factors and attenuated the NF-κB p65 expression, thereby mitigating the inflammatory response. These findings highlight the protective effect of MSS against DSS-induced colitis, providing substantial scientific support for potential applications of MSS as a functional food.

Two-Photon Nanoparticle Probe for Formaldehyde Detection via the AILE Luminescence Mechanism.

A two-photon nanoparticle probe was designed and developed based on the principle of intermolecular interaction of the aggregation-induced locally excited emission luminescence mechanism. The probe has the advantages of simple synthesis, convenient use, strong atomic economy, good biocompatibility, and photobleaching resistance. It can produce a specific and sensitive response to formaldehyde, help detect FA in normal cells and cancer cells, and is expected to become a specific detection probe for FA in vitro and in vivo.

Traditional Chinese Medicine Shi-Bi-Man ameliorates psoriasis via inhibiting IL-23/Th17 axis and CXCL16-mediated endothelial activation.

BACKGROUND: Psoriasis is a chronic inflammatory genetic disease, mainly manifesting in the skin. Conventional therapies, such as glucocorticosteroids and corticosteroids, have adverse effects that limit drug use. Hence, it is imperative to identify a new therapeutic strategy that exhibits a favorable safety profile. Shi-Bi-Man (SBM) is a safe herbal supplement sourced from various natural plants, including ginseng, angelica sinensis, polygonum multiflorum, and aloe vera. PURPOSE: We aimed to find a potential treatment for psoriasis and investigate the underlying mechanism through which SBM alleviates psoriatic-like skin inflammation in mice. METHODS: We investigated the effects of supplementing with SBM through intragastric administration or smear administration in a murine model of imiquimod-induced psoriasis. The changes in body weight and Psoriasis Area and Severity Index (PASI) score were recorded throughout the entire process. Additionally, we used hematoxylin-eosin staining to observe the skin structure and performed single-cell RNA sequencing to explore the underlying mechanism of SBM in influencing the psoriasis-like phenotype. Immunofluorescence was conducted to verify our findings. Furthermore, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was employed to investigate the impact of Tetrahydroxy stilbene glycoside (TSG) on the expression levels of IL23 in HaCaT cells. RESULTS: SBM remarkably alleviated the psoriasis-like phenotype by inhibiting IL-23/Th17 cell axis. Single-cell RNA sequencing analysis revealed a decrease in the expression of Il17 and Il23 in keratinocytes and T cells, concomitant with a reduction in the proportion of Th17 cells. Meanwhile, the activation of endothelial cells was inhibited, accompanied by a decrease in the expression of Cxcl16. In vitro, the addition of TSG to HaCaT cells resulted in significant suppression of IL23 expression stimulated by tumor necrosis factor-alpha (TNF-α).

Purine metabolites promote ectopic new bone formation in ankylosing spondylitis.

Ankylosing spondylitis (AS) is a chronic inflammatory rheumatic disease that mainly affects the axial skeleton, whose typical features are inflammatory back pain, bone structural damage and pathological new bone formation. The pathology of ectopic new bone formation is still little known. In this study, we found increased purine metabolites in plasma of patients with AS. Similarly, metabolome analysis indicated increased purine metabolites in both serum of CD4-Cre; Ptpn11fl/fl and SHP2-deficient chondrocytes. SHP2-deficient chondrocytes promoted the growth of wild type chondrocytes and differentiation of osteoblasts in CD4-Cre; Ptpn11fl/fl mice, which spontaneously developed AS-like bone disease. Purine metabolites, along with PTHrP derived from SHP2-deficient chondrocytes, accelerated the growth of chondrocytes and ectopic new bone formation through PKA/CREB signaling. Moreover, Suramin, a purinergic receptor antagonist, suppressed pathological new bone formation in AS-like bone disease. Overall, these results highlight the potential role of targeting purinergic signaling in retarding ectopic new bone formation in AS.

Blockade of dual immune checkpoint inhibitory signals with a CD47/PD-L1 bispecific antibody for cancer treatment.

Background: Even though PD-1/PD-L1 is an identified key "don't find me" signal to active adaptive immune system for cancer treatment, the overall response rate (ORR) for all cancer patients is still limited. Other effective therapeutic modalities to bridge the innate and adaptive immunity to improve ORR are urgently needed. Recently, CD47/SIRPα interaction is confirmed as a critical "don't eat me" signal to active innate immunity. However, the red blood cell (RBC) toxicity is the big concern for the development of CD47-based anti-cancer therapeutics. Methods: Here, we report the development of a CD47/PD-L1 bispecific antibody 6MW3211 to block both PD-1/PD-L1 and CD47/SIRPα signals, and studied the effects of 6MW3211 on anti-tumor immune functions in vitro and in vivo. The pharmacokinetic and toxicity profiles of 6MW3211 were evaluated in GLP non-human primate (NHP) studies. Results: The dual immune checkpoint inhibitory signaling blocker 6MW3211 shows high binding affinity to PD-L1 and low binding affinity to CD47. This inequivalent binding affinity design makes 6MW3211 preferentially bound to PD-L1 on tumor cells followed by disrupting the interaction of CD47/SIRPα. Complex structure determination and flow cytometry assay demonstrated that 6MW3211 has no binding to either human or rhesus monkey RBCs. 6MW3211 effectively blocked both PD-1/DP-L1 and CD47/SIRPα signaling and promoted macrophage phagocytosis of tumor cells. Potent therapeutic efficacies of 6MW3211 in three different mouse models were further observed. Moreover, 6MW3211 was demonstrated to have a fairly good safety profile in a GLP NHP study. In addition, multiplex fluorescent immunohistochemistry (mIHC) staining shows that PD-L1 and CD47 co-express on several different types of human tumor tissues. Conclusions: These results support the development of 6MW3211 for the treatment of PD-L1 and CD47 double positive cancers.

Adipokine chemerin overexpression in trophoblasts leads to dyslipidemia in pregnant mice: implications for preeclampsia.

BACKGROUND: The adipokine chemerin regulates adipogenesis and the metabolic function of both adipocytes and liver. Chemerin is elevated in preeclamptic women, and overexpression of chemerin in placental trophoblasts induces preeclampsia-like symptoms in mice. Preeclampsia is known to be accompanied by dyslipidemia, albeit via unknown mechanisms. Here, we hypothesized that chemerin might be a contributor to dyslipidemia. METHODS: Serum lipid fractions as well as lipid-related genes and proteins were determined in pregnant mice with chemerin overexpression in placental trophoblasts and chemerin-overexpressing human trophoblasts. In addition, a phospholipidomics analysis was performed in chemerin-overexpressing trophoblasts. RESULTS: Overexpression of chemerin in trophoblasts increased the circulating and placental levels of cholesterol rather than triglycerides. It also increased the serum levels of lysophosphatidic acid, high-density lipoprotein cholesterol (HDL-C), and and low-density lipoprotein cholesterol (LDL-C), and induced placental lipid accumulation. Mechanistically, chemerin upregulated the levels of peroxisome proliferator-activated receptor g, fatty acid-binding protein 4, adiponectin, sterol regulatory element-binding protein 1 and 2, and the ratio of phosphorylated extracellular signal-regulated protein kinase (ERK)1/2 / total ERK1/2 in the placenta of mice and human trophoblasts. Furthermore, chemerin overexpression in human trophoblasts increased the production of lysophospholipids and phospholipids, particularly lysophosphatidylethanolamine. CONCLUSIONS: Overexpression of placental chemerin production disrupts trophoblast lipid metabolism, thereby potentially contributing to dyslipidemia in preeclampsia.

New opportunities and challenges of natural products research: When target identification meets single-cell multiomics.

Natural products, and especially the active ingredients found in traditional Chinese medicine (TCM), have a thousand-year-long history of clinical use and a strong theoretical basis in TCM. As such, traditional remedies provide shortcuts for the development of original new drugs in China, and increasing numbers of natural products are showing great therapeutic potential in various diseases. This paper reviews the molecular mechanisms of action of natural products from different sources used in the treatment of inflammatory diseases and cancer, introduces the methods and newly emerging technologies used to identify and validate the targets of natural active ingredients, enumerates the expansive list of TCM used to treat inflammatory diseases and cancer, and summarizes the patterns of action of emerging technologies such as single-cell multiomics, network pharmacology, and artificial intelligence in the pharmacological studies of natural products to provide insights for the development of innovative natural product-based drugs. Our hope is that we can make use of advances in target identification and single-cell multiomics to obtain a deeper understanding of actions of mechanisms of natural products that will allow innovation and revitalization of TCM and its swift industrialization and internationalization.

Tyrosine phosphatase SHP2 exacerbates psoriasis-like skin inflammation in mice via ERK5-dependent NETosis.

Psoriasis is a chronic inflammatory skin disease, often accompanied by increased infiltration of immune cells, especially neutrophils. However, the detailed mechanism of the neutrophil function in psoriasis progression remains unclear. Here, we found that both Src homology-2 domain-containing protein tyrosine phosphatase-2 (SHP2) and neutrophils were highly correlated to developing psoriasis by single-cell ribonucleic acid (RNA) sequencing and experiment verification. The deficiency of SHP2 in neutrophils significantly alleviated psoriasis-like phenotype in an imiquimod-induced murine model. Interestingly, high levels of neutrophil extracellular traps (NETs) were produced in the inflamed lesions of psoriatic patients. In addition, imiquimod-induced psoriasis-like symptoms were remarkably ameliorated in peptidyl arginine deiminase 4 (PAD4) knockout mice, which cannot form NETs. Mechanistically, RNA-seq analysis revealed that SHP2 promoted the formation of NETs in neutrophils via the ERK5 pathway. Functionally, this mechanism resulted in the infiltration of pro-inflammatory cytokines such as TNF-α, IL-1ß, IL-6, IL-17A, and CXCL-15, which enhances the inflammatory response in skin lesions and reinforces the cross-talk between neutrophils and keratinocytes, ultimately aggravating psoriasis. Our findings uncover a role for SHP2 in NET release and subsequent cell death known as NETosis in the progression of psoriasis and suggest that SHP2 may be a promising therapeutic target for psoriasis.

SHP2 allosteric inhibitor TK-453 alleviates psoriasis-like skin inflammation in mice via inhibition of IL-23/Th17 axis.

SHP2 is the first oncogenic tyrosine phosphatase encoded by PTPN11, which plays a significant regulatory role in cancer and inflammation-related diseases. Although SHP2 allosteric inhibitors have been used in phase I/II clinical trials for solid tumors, whether SHP2 inhibition alleviates psoriasis remains unclear. Here we expressed and purified SHP2 related proteins, and established an enzyme activity screening system for different conformations of SHP2. We launched an iterative medicinal chemistry program and identified the lead compound, TK-453. Importantly, TK-453 possessed stronger affinity with SHP2 than SHP099, evidenced by the cocrystal structure of SHP2/TK-453, revealing that the additional aryl-S-aryl bridge in TK-453 induces a 1.8 Å shift of the dichlorophenyl ring and an approximate 20° deviation of the pyrazine ring plane relative to SHP099. Furthermore, TK-453 significantly ameliorated imiquimod-triggered skin inflammation in mice via inhibition of the IL-23/Th17 axis, proving that SHP2 is a potential therapeutic target for psoriasis.

Rotating magnetic field ameliorates experimental autoimmune encephalomyelitis by promoting T cell peripheral accumulation and regulating the balance of Treg and Th1/Th17.

Multiple sclerosis (MS) is an autoimmune disease characterized by T cell infiltration and demyelination of the central nervous system (CNS). Experimental autoimmune encephalomyelitis (EAE) is a classical preclinical animal model of MS. In this study, we found that rotating magnetic field (RMF) treatment exerts potential preventive effects on the discovery of EAE, including reducing the severity of the disease and delaying the onset of the disease. The results indicated that RMF (0.2 T, 4 Hz) treatment increases the accumulation of CD4+ cells in the spleen and lymph nodes by downregulating the expression of CCL-2, CCL-3 and CCL-5, but has no significant effect on myelin oligodendrocyte glycoprotein (MOG) specific T cell responses. Simultaneously, RMF treatment adjusted the imbalance between regulatory T (Treg) cell and T helper 1 (Th1) cells or T helper 17 (Th17) cells by increasing the proportion of Treg cells and inhibiting the ratio of Th1 and Th17 cell subsets. These findings suggest that exposure to RMF may improve EAE disease by promoting CD4+ cell accumulation into peripheral lymphoid tissue, improving the imbalance between Treg and Th1/Th17 cells. Therefore, as a mild physical therapy approach, RMF, is likely to be a potential way to alter the development of EAE.

Loss of hnRNP A1 in murine skeletal muscle exacerbates high-fat diet-induced onset of insulin resistance and hepatic steatosis.

Impairment of glucose (Glu) uptake and storage by skeletal muscle is a prime risk factor for the development of metabolic diseases. Heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) is a highly abundant RNA-binding protein that has been implicated in diverse cellular functions. The aim of this study was to investigate the function of hnRNP A1 on muscle tissue insulin sensitivity and systemic Glu homeostasis. Our results showed that conditional deletion of hnRNP A1 in the muscle gave rise to a severe insulin resistance phenotype in mice fed a high-fat diet (HFD). Conditional knockout mice fed a HFD showed exacerbated obesity, insulin resistance, and hepatic steatosis. In vitro interference of hnRNP A1 in C2C12 myotubes impaired insulin signal transduction and inhibited Glu uptake, whereas hnRNP A1 overexpression in C2C12 myotubes protected against insulin resistance induced by supraphysiological concentrations of insulin. The expression and stability of glycogen synthase (gys1) mRNA were also decreased in the absence of hnRNP A1. Mechanistically, hnRNP A1 interacted with gys1 and stabilized its mRNA, thereby promoting glycogen synthesis and maintaining the insulin sensitivity in muscle tissue. Taken together, our findings are the first to show that reduced expression of hnRNP A1 in skeletal muscle affects the metabolic properties and systemic insulin sensitivity by inhibiting glycogen synthesis.

Rotating magnetic field delays human umbilical vein endothelial cell aging and prolongs the lifespan of Caenorhabditis elegans.

The biological effects of magnetic fields are a research hotspot in the field of biomedical engineering. In this study, we further investigated the effects of a rotating magnetic field (RMF; 0.2 T, 4 Hz) on the growth of human umbilical vein endothelial cells (HUVECs) and Caenorhabditis elegans. The results showed that RMF exposure prolonged the lifespan of C. elegans and slowed the aging of HUVECs. RMF treatment of HUVECs showed that activation of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) was associated with decreased mitochondrial membrane potential (MMP) due to increased intracellular Ca2+ concentrations induced by endoplasmic reticulum stress in anti-aging mechanisms. RMF also promoted the health status of C. elegans by improving activity, reducing age-related pigment accumulation, delaying Aß-induced paralysis and increasing resistance to heat and oxidative stress. The prolonged lifespan of C. elegans was associated with decreased levels of daf-16 which related to the insulin/insulin-like growth factor signaling pathway (IIS) activity and reactive oxygen species (ROS), whereas the heat shock transcription factor-1 (hsf-1) pathway was not involved. Moreover, the level of autophagy was increased after RMF treatment. These findings expand our understanding of the potential mechanisms by which RMF treatment prolongs lifespan.

Suppression of adenosine monophosphate-activated protein kinase selectively triggers apoptosis in activated T cells and ameliorates immune diseases.

Deficient apoptosis of activated T cells can result in immunological disorders. Molecules associated with energy and metabolisms are suggested to be involved in pathogenesis of immune diseases, but remain uninvestigated. In the present study we reported that glibenclamide exerted a new pharmacological effect on inflammatory responses by selectively triggering apoptosis of activated T cells. Glibenclamide demonstrated an inhibition on activated T lymphocytes, whereas showed no toxicity in the naive cells. This effect was mainly related with its ability to facilitate apoptosis in activated T cells with an up-regulation of cleaved-caspases and cleaved-PARP. Glibenclamide enhanced Fas expression and suppressed the expression of antiapoptotic cellular FLICE-inhibitory protein. The underlying mechanism of glibenclamide was not associated with its classical inhibitory effect on ATP-sensitive potassium channels, but due to a unique suppression on the phosphorylation of 5' adenosine monophosphate-activated protein kinase, which was augmented during T cell activation. An in vivo experiment further demonstrated that glibenclamide ameliorated T-cell-mediated contact hypersensitivity in mice. Altogether, these results suggest that AMPK inhibition by glibenclamide can regulate the survival and death of T lymphocytes and be beneficial for the treatment of autoimmune diseases.

A natural compound jaceosidin ameliorates endoplasmic reticulum stress and insulin resistance via upregulation of SERCA2b.

Increased endoplasmic reticulum (ER) stress has emerged as a vital contributor to dysregulated glucose homeostasis, and impaired function of sarco-endoplasmic reticulum Ca2+-ATPase 2b (SERCA2b) is one of the central mechanisms underlying ER stress. In this study, we reported that SERCA2b upregulation contributed to the amelioration of ER stress and insulin resistance by a small natural compound jaceosidin. In a model of differentiated C2C12 myotubes, jaceosidin-triggered SERCA2b upregulation enhanced insulin sensitivity and decreased ER stress. Moreover, the activity of Ca2+-ATPase in thapsigargin-treated myotubes was also augmented by jaceosidin. Furthermore, jaceosidin significantly suppressed blood glucose levels, improved glucose tolerance and lowered body weight, but did not alter food intake in insulin-resistant obese mice. In addition, this compound markedly reduced lipid accumulation, suppressed the expression of lipogenic genes in liver and ameliorated liver injury. The ameliorative effects of jaceosidin were due to its ability to reduce ER stress via increasing the expression of SERCA2b in the muscles of obese mice. Taken together, jaceosidin could improve ER stress and attenuate insulin resistance via SERCA2b upregulation in mice skeletal muscles.

Obaculactone protects against bleomycin-induced pulmonary fibrosis in mice.

Idiopathic pulmonary fibrosis is a progressive, degenerative and almost irreversible disease. There is hardly an effective cure for lung damage due to pulmonary fibrosis. The purpose of this study was to evaluate the role of obaculactone in an already-assessed model of idiopathic pulmonary fibrosis induced by bleomycin administration. Mice were subjected to intratracheal instillation of bleomycin, and obaculactone was given orally after bleomycin instillation daily for 23days. Treatment with obaculactone ameliorated body weight loss, lung histopathology abnormalities and pulmonary collagen deposition, with a decrease of the inflammatory cell number and the cytokine level in bronchoalveolar lavage fluid. Moreover, obaculactone inhibited the expression of icam1, vcam1, inos and cox2, and attenuated oxidative stress in bleomycin-treated lungs. Importantly, the production of collagen I and α-SMA in lung tissues as well as the levels of TGF-ß1, ALK5, p-Smad2 and p-Smad3 in lung homogenates was also reduced after obaculactone treatment. Finally, the TGF-ß1-induced epithelial-mesenchymal transition via Smad-dependent and Smad-independent pathways was reversed by obaculactone. Collectively, these data suggest that obaculactone may be a promising drug candidate for the treatment of idiopathic pulmonary fibrosis.

Obaculactone exerts a novel ameliorating effect on contact dermatitis through regulating T lymphocyte.

It is still deficient that an immunosuppressant with a negligible toxicity for patients suffering from contact hypersensitivity. In the present study, we identified a natural occurring compound named obaculactone that effectively alleviated the macroscopic and microscopic appearances of the contact hypersensitivity, while it scarcely possessed toxic effect on mice at 5-20mg/kg. The mRNAs of IL-2, IL-17a, TNF-α and IFN-γ expressed in lymph nodes of mice with dermatitis were also decreased by obaculactone in a dose-dependent manner. Moreover, the hypersensitivity couldn't be adoptively transferred from obaculactone-treated donor mice to normal mice. In vitro study, proliferation arrest in activated hapten-specific T cells and anti-CD3/CD28 stimulated T cells were observed in obaculactone-treated groups. In addition, the enhanced expressions of CD25 and CD69 in activated T cells were reduced by obaculactone. Meanwhile, obaculactone caused G0/G1 phase arrest and up-regulated the levels of cleaved-caspases and cleaved-PARP inducing apoptosis in activated T cells. Taken together, suppressing cell growth in activated T lymphocytes may contribute to the novel ameliorating effect for obaculactone against the contact hypersensitivity.

Suppression of NF-κB signaling and NLRP3 inflammasome activation in macrophages is responsible for the amelioration of experimental murine colitis by the natural compound fraxinellone.

Inflammatory bowel disease (IBD) affects millions of people worldwide. Although the etiology of this disease is uncertain, accumulating evidence indicates a key role for the activated mucosal immune system. In the present study, we examined the effects of the natural compound fraxinellone on dextran sulfate sodium (DSS)-induced colitis in mice, an animal model that mimics IBD. Treatment with fraxinellone significantly reduced weight loss and diarrhea in mice and alleviated the macroscopic and microscopic signs of the disease. In addition, the activities of myeloperoxidase and alkaline phosphatase were markedly suppressed, while the levels of glutathione were increased in colitis tissues following fraxinellone treatment. This compound also decreased the colonic levels of interleukin (IL)-1ß, IL-6, IL-18 and tumor necrosis factor (TNF)-α in a concentration-dependent manner. These effects of fraxinellone in mice with experimental colitis were attributed to its inhibition of CD11b(+) macrophage infiltration. The mRNA levels of macrophage-related molecules in the colon, including intercellular adhesion molecule 1 (ICAM1), vascular cell adhesion molecule 1 (VCAM1), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX2), were also markedly inhibited following fraxinellone treatment. The results from in vitro assays showed that fraxinellone significantly reduced lipopolysaccharide (LPS)-induced production of nitric oxide (NO), IL-1ß and IL-18 as well as the activity of iNOS in both THP-1 cells and mouse primary peritoneal macrophages. The mechanisms responsible for these effects were attributed to the inhibitory role of fraxinellone in NF-κB signaling and NLRP3 inflammasome activation. Overall, our results support fraxinellone as a novel drug candidate in the treatment of colonic inflammation.

Tupistra chinensis extract attenuates murine fulminant hepatitis with multiple targets against activated T lymphocytes.

OBJECTIVES: The extract of Tupistra chinensis (TCE) is traditionally used for the treatment of inflammatory diseases in southwestern China for hundreds of years. The present study was designed to investigate the effects of the TCE against experimental hepatitis and to illustrate its potential mechanisms. METHODS: Effects of TCE were investigated on Con A-induced hepatitis. Profiles of multiple cytokines were measured with biometric immuno-sandwich ELISA. Proliferation, activation and apoptosis of T lymphocytes were evaluated using Western blot, MTT analysis and flow cytometry. KEY FINDINGS: TCE significantly inhibited levels of serum transaminases and lactic dehydrogenase in mice with Con A-induced hepatitis, accompanied with marked alleviation of the liver microscopic appearances. Moreover, it decreased levels of inflammatory cytokines in a concentration-dependent manner both in vivo and in vitro. It also suppressed mitogen-activated protein kinases and NF-κB-signalling in liver. These effects of TCE are attributed to its inhibition on activated T cells but not to hepatocytes protection. Flow cytometry and immunoblot assay data showed its effects on STAT1/NF-κB-signalling blockage and apoptosis induction in activated T cells. CONCLUSION: Our findings illustrate the significant potential of TCE as a novel approach for treatment of T cell-mediated inflammatory diseases.

Beauvericin ameliorates experimental colitis by inhibiting activated T cells via downregulation of the PI3K/Akt signaling pathway.

Crohn's disease is a common, chronic inflammatory bowel condition characterized by remission and relapse. Accumulating evidence indicates that activated T cells play an important role in this disease. In the present study, we aimed to examine the effect of beauvericin, a natural cyclic peptide, on 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in mice, which mimics Crohn's disease. Beauvericin significantly reduced weight loss, diarrhea and mortality, accompanied with notable alleviation of macroscopic and microscopic signs. In addition, this compound decreased serum levels of tumor necrosis factor (TNF)-α and interferon (IFN)-γ in a concentration-dependent manner in mice with experimental colitis. These effects of beauvericin are attributed to its inhibition on activated T cells. Flow cytometry and immunoblot assay data showed that beauvericin suppressed T-cell proliferation, activation and IFN-γ-STAT1-T-bet signaling and subsequently led to apoptosis of activated T cells by suppressing Bcl-2 and phosphorylated Bad as well as increasing cleavage of caspase-3, -9, -12 and PARP. Furthermore, inhibition of PI3K/Akt signaling, which was an upstream regulator of cell activation and survival in activated T cells, contributed to the effect of beauvericin. Overall, these results supported beauvericin as a novel drug candidate for the treatment of colonic inflammation mainly by targeting PI3K/Akt in activated T cells.