Body Weight Of Mice Research Articles

Rapidly-manufactured CD276 CAR-T cells exhibit enhanced persistence and efficacy in pancreatic cancer

BackgroundPancreatic cancer is one of the most lethal malignancies and the lack of treatment options makes it more deadly. Chimeric Antigen Receptor T-cell (CAR-T) immunotherapy has revolutionized cancer treatment and made great breakthroughs in treating hematological malignancies, however its success in treating solid cancers remains limited mainly due to the lack of tumor-specific antigens. On the other hand, the prolonged traditional manufacturing process poses challenges, taking 2 to 6 weeks and impacting patient outcomes. CD276 has recently emerged as a potential therapeutic target for anti-solid cancer therapy. Here, we investigated the efficacy of CD276 CAR-T and rapidly-manufactured CAR-T against pancreatic cancer.MethodsIn the present study, CD276 CAR-T was prepared by CAR structure carrying 376.96 scFv sequence, CD8 hinge and transmembrane domain, 4-1BB and CD3ζ intracellular domains. Additionally, CD276 rapidly-manufactured CAR-T (named CD276 Dash CAR-T) was innovatively developed by shortening the duration of ex vitro culture to reduce CAR-T manufacturing time. We evaluated the anti-tumor efficacy of CD276 CAR-T and further compared the functional assessment of Dash CAR-T and conventional CAR-T in vitro and in vivo by detecting the immunophenotypes, killing ability, expansion capacity and tumor-eradicating effect of CAR-T.ResultsWe found that CD276 was strongly expressed in multiple solid cancer cell lines and that CD276 CAR-T could efficiently kill these solid cancer cells. Moreover, Dash CAR-T was successfully manufactured within 48–72 h and the functional validation was carried out subsequently. In vitro, CD276 Dash CAR-T possessed a less-differentiated phenotype and robust proliferative ability compared to conventional CAR-T. In vivo xenograft mouse model, CD276 Dash CAR-T showed enhanced anti-pancreatic cancer efficacy and T cell expansion. Besides, except for the high-dose group, the body weight of mice was maintained stable, and the state of mice was normal.ConclusionsIn this study, we proved CD276 CAR-T exhibited powerful activity against pancreatic cancer cells in vitro and in vivo. More importantly, we demonstrated the manufacturing feasibility, acceptable safety and superior anti-tumor efficacy of CD276 Dash CAR-T generated with reduced time. The results of the above studies indicated that CD276 Dash CAR-T immunotherapy might be a novel and promising strategy for pancreatic cancer treatment.

Preclinical safety assessment of modified gamma globin lentiviral vector-mediated autologous hematopoietic stem cell gene therapy for hemoglobinopathies.

Previously, we reported the development of a human Aγ-globin gene lentivirus (LV), GbG, which expresses high levels of HbF to correct the sickle cell anemia (SCA) phenotype in the Berkeley SCA mouse model, and then modified the γ-globin gene by substituting glycine at codon 16 with aspartic acid in the Aγ-globin gene to generate GbGM LV. In the present study, we evaluated the long-term safety of human Aγ-globin gene carrying GbGM LV in wild-type mice after primary and secondary transplants of GbGM-modified hematopoietic stem cells (HSC) over 18 months. The safety of the GbGM bone marrow transplant was assessed by monitoring the effects on body weight, hematology, histopathology, malignancy formation, and survival. Mice transplanted with Mock-transduced and spleen focus forming virus (SFFV) γ-retroviral vector (RV)-transduced HSC served as negative and positive controls, respectively. The mean donor-cell engraftment was comparable across Mock, GbGM LV, and SFFV RV groups. There were no significant differences in body weight, clinical signs, immunophenotype, or histopathology in the GbGM-treated mice compared to controls. Four SFFV RV-treated mice, but none of the GbGM-treated mice, developed donor-derived, vector-positive lymphomas as demonstrated by flow cytometry analysis and in situ hybridization. These results highlight the safety of the administration of GbGM LV-modified HSC with long-term follow-up after primary and secondary transplants in mice. This data supported the initiation of phase 1/2 first-in-human SCA clinical trial in the United States.

Hinesol attenuates DSS-induced ulcerative colitis through the suppression of Src-mediated NF-κB and chemokine signaling pathway.

As a common inflammatory bowel disease, ulcerative colitis (UC) is featured with inflammation, oxidative damage, and the impairment of intestinal mucosal barrier, which bring threat to patients' quality of live. Hinesol, derived from Atractylodes lancea, is a unique sesquiterpenoid. Our study proposed to survey the effects and mechanism of hinesol in UC. UC mouse model was constructed using dextran sulfate sodium (DSS). Lipopolysaccharide (LPS) was applied for RAW264.7 cells stimulation to construct cell inflammatory model. The changes of disease activity index (DAI), body weight, colon length, and intestinal pathology in mice were analyzed to estimate the severity of colitis. Enzyme-linked immunosorbent assay was applied to check the changes of interleukin (IL)-1β, IL-18, IL-6, and tumor necrosis factor (TNF)-α. The levels of myeloperoxidase (MPO), superoxide dismutase (SOD), glutathione peroxidase (GSH-px), catalase (CAT), and malondialdehyde (MDA) were estimated by corresponding reagent kit. The changes of phosphorylated (p)-NF-κB P65, and p-IκBα, ZO-1, Occludin, Claudin-1, Src, XCL1, CCL2, and CXCL16 protein were examined using western blot. Flow cytometry and cell counting kit-8 assay were utilized for assessment of cell apoptosis and viability. We found that DSS reduced mice body weight, increased DAI, shorten colon length, and led to severe enteric mucosal injury, while hinesol improved the above symptoms induced by DSS. In DSS mice, hinesol raised the levels of ZO-1, Occludin, Claudin-1, SOD, GSH-px, and CAT and decreased the levels of TNF-α, IL-18, IL-1β, IL-6, MPO, and MDA. Additionally, in DSS mice and LPS-stimulated RAW264.7 cells, hinesol inhibited the high expression of Src, XCL1, CCL2, CXCL16, p-NF-κB P65, and p-IκBα. The molecular docking showed that there was a good interaction between hinesol and Src. Moreover, in LPS-stimulated RAW 264.7 cells, Src overexpression partially reversed the inhibition of hinesol on cell apoptosis, pro-inflammatory factors, and oxidative stress. In conclusion, hinesol alleviated DSS-induced colitis, which might have a bearing on the inhibition of Src-mediated NF-κB and chemokine signaling pathway.

Lignin-Assisted local release of triiodothyronine in adipose tissue protects mice against obesity and related metabolic disorders

Lignin is considered a promising carrier for drugs with aromatic structures via co-self-assembly, endowing the composite particles with functional properties for biomedical applications. Triiodothyronine (T3) has exhibited beneficial effects in obesity and obesity-related metabolic disorders by increasing the energy expenditure of adipose tissue; however, excess thyroid hormones may adversely affect various tissues. T3, which contains benzene rings and hydrophilic functional groups, is co-self-assembled with lignin to fabricate composite lignin–triiodothyronine (L-T3) particles using solvent-shifting methods. The dual driving forces of hydrogen bonding and π–π interactions enhance the co-self-assembly tendency of lignin and T3, thereby improving their distributions in the composite particles. L-T3 can be taken up by adipocytes with well controlled particle size. Moreover, a single locally delivered L-T3 dose to the subcutaneous white adipose tissue (sWAT) of mice does not affect mouse plasma T3 levels, but decreases the adipocyte size and increases uncoupling protein (UCP-1) expression in the sWAT of normal diet and short-term high-fat diet (HFD)-fed mice. Notably, L-T3 decreases body and adipose tissue weights in long-term HFD-fed mice. Furthermore, HFD-induced liver steatosis is substantially ameliorated by local delivery of L-T3 to sWAT. These results suggest that local delivery of L-T3 in adipose tissue exhibits protective effects against obesity and related metabolic disorders.

BI-7273, a BRD9 inhibitor, reduces lipid accumulation by downregulating the AKT/mTOR/SREBP1 signaling pathway

Increases in de novo lipogenesis that disturbed lipid homeostasis and caused lipid accumulation are a major cause of NAFLD and obesity. SREBP1 is a crucial regulatory factor controlling the expression of rate-limiting enzymes of lipid synthesis. A reduction in SREBP1expression can reduce lipid accumulation. Thus, we utilized an SREBP1-luciferase-KI HEK293 cell line constructed by our lab to screen 200 kinds of epigenetic drugs for their ability to downregulate SREBP1expression. BI-7273, an inhibitor of bromodomain-containing protein 9 (BRD9), was screened and found to decrease SREBP1 expression. What is more, BI-7273 has been confirmed that it could reduce lipid accumulation in HepG2 cells by BODIPY staining, and significantly decrease the protein expression of SREBP1 and FASN. To explore the potential mechanism BI-7273 reducing lipid accumulation, RNA sequencing (RNA-seq) was performed and demonstrated that BI-7273 reduced lipid accumulation by downregulating the AKT/mTOR/SREBP1 pathway in vitro. Finally, these results were verified in NAFLD and obesity mouse model induced by high fat diet (HFD). The results indicated that BI-7273 could decrease mouse body weight and improve insulin sensitivity, but also exhibited a strong negative correlation with serum lipid levels, and also demonstrated that BI-7273 reduced lipid accumulation via AKT/mTOR/SREBP1 pathway in vivo.In conclusion, our results revealed that BI-7273 decreases lipid accumulation by downregulating the AKT/mTOR/SREBP1 pathway in vivo and in vitro. This is the first report demonstrating the protective effect of this BRD9 inhibitor against NAFLD and obesity. BRD9 may be a novel target for the discovery of effective drugs to treat lipid metabolism disorders.

Taste Preferences at Different Ambient Temperatures and Associated Changes in Gut Microbiota and Body Weight in Mice.

Taste, dietary choices, and gut microbiota are often analyzed as major factors of metabolic health. Populations living in cold or hot regions have different dietary habits. This study aims to investigate the potential association among ambient temperature, food taste preferences, and cecal microbiota community profiles in mice. By exposing mice to mixed diets containing sweet, sour, salty, and bitter flavors at low (4 °C) and high (37 °C) ambient temperatures, the taste preferences of mice at both ambient temperatures were in the order of saltiness > sweetness > bitterness > sourness. Exposing mice to sweet, sour, salty, and bitter diets, respectively, revealed that in a low-temperature environment, mice consuming salty (5.00 ± 1.49 g), sweet (4.99 ± 0.35 g), and sour (3.90 ± 0.61 g) diets had significantly higher weight gain compared to those consuming normal feeds (2.34 ± 0.43 g, p < 0.05). Conversely, in a high-temperature environment, no significant changes in body weight were observed among mice consuming different flavored diets (p > 0.05). In a low-temperature environment, mice fed sour and sweet diets showed a significant difference in the gut microbiota composition when compared to those fed a normal diet. A higher abundance of Lachnospiraceae, UBA1819, and Clostridiales was identified as the most significant taxa in the sour group, and a higher abundance of Ruminiclostridium was identified in the sweet group. These differences were associated with microbial pathways involved in carbohydrate metabolism, amino acid metabolism, and energy metabolism. A high-temperature environment exhibited only minor effects on the gut microbiota profile. Overall, our findings provide evidence for temperature-modulated responses to the taste, gut microbiota functions, and body weight changes in mice.

Acarbose ameliorates Western diet-induced metabolic and cognitive impairments in the 3xTg mouse model of Alzheimer's disease.

Age is the greatest risk factor for Alzheimer's disease (AD) as well as for other disorders that increase the risk of AD such as diabetes and obesity. There is growing interest in determining if interventions that promote metabolic health can prevent or delay AD. Acarbose is an anti-diabetic drug that not only improves glucose homeostasis, but also extends the lifespan of wild-type mice. Here, we test the hypothesis that acarbose will not only preserve metabolic health, but also slow or prevent AD pathology and cognitive deficits in 3xTg mice, a model of AD, fed either a Control diet or a high-fat, high-sucrose Western diet (WD). We find that acarbose decreases the body weight and adiposity of WD-fed 3xTg mice, increasing energy expenditure while also stimulating food consumption, and improves glycemic control. Both male and female WD-fed 3xTg mice have worsened cognitive deficits than Control-fed mice, and these deficits are ameliorated by acarbose treatment. Molecular and histological analysis of tau and amyloid pathology identified sex-specific effects of acarbose which are uncoupled from the dramatic improvements in cognition, suggesting that the benefits of acarbose on AD are largely driven by improved metabolic health. In conclusion, our results suggest that acarbose may be a promising intervention to prevent, delay, or even treat AD, especially in individuals consuming a Western diet.

Effect of fermented Rosa roxburghii tratt fruit juice on gut microbiota in a dextran sulfate sodium (DSS)-induced colitis mouse model

This study mainly investigated the regulatory effect of Rosa roxburghii Tratt fruit juice fermented by Lacticaseibacillus paracasei SR10-1 (LAB-RRTJ) on modulating gut microbiota in dextran sulfate sodium (DSS)-induced ulcerative colitis in mice. Compared to control group, DSS induction decreased body weight of mice, indexes of Shannon, Simpson, Chao 1 and Faith_pd, and increased disease activity index (DAI) and levels of interleukin 1β (IL-1β), IL-6, tumor necrosis factor α (TNF-α) and interferon-γ (IFN-γ); And this induction also led to an increase in Proteobacteria, Verrucomicrobia and Actinobacteria at phylum level, harmful bacterial species richness at genus level, and relative richness of S. sciuri, desulfovibrio C21_c20, R. gnavus and Akkermansia muciniphila at species level, and a decrease in Firmicutes at phylum level and relative richness of B. acidifaciens in mice. LAB-RRTJ increased body weight of mice with DSS induced ulcerative colitis (UC) and indexes of Shannon, Simpson, Chao 1 and Faith_pd, reduced DAI and the content of four inflammatory factors and improved gut microbiota imbalance in DSS induced UC mice. Besides, the number of OTUs increased, alpha diversity and beta diversity were restored and similar to those in mice in the Control group after LAB-RRTJ treatment. Compared with the positive drug treatment group, LAB-RRTJ has a better effect on regulating gut microbiota diversity in colitis mice. Correlation analysis showed that inflammatory factors were positively correlated with harmful bacteria and negatively correlated with beneficial bacteria which commonly found in some colitis mice. Taken together, our study demonstrated that LAB-RRTJ could alleviate DSS-induced colitis in mice through the modulation of inflammatory cytokines and gut microbiota composition.

Saikosaponin A Ameliorates Metabolic Inflammation and Intestinal Barrier Damage in DIO Mice through the Nrf2/ARE Pathway.

Obesity is linked to impaired intestinal barrier function and inflammation. Saikosaponin A (SSA), a triterpene saponin from Bupleurum chinense, has shown beneficial effects on intestinal colitis in mice. However, the mechanisms underlying SSA's protective effects against obesity are not fully understood. To investigate the effects of SSA on body weight, metabolic disturbances, and intestinal health in diet-induced obese (DIO) mice, and to elucidate the potential mechanisms involved. In the in vivo study, DIO mice were supplemented with SSA. Body weight, fasting blood glucose, and metabolic parameters were measured. Intestinal barrier function and inflammation were assessed. In the in vitro study, intestinal epithelial cells were treated with palmitic acid and lipopolysaccharide to induce inflammation. SSA was then administered to evaluate its effects on cell barrier integrity and inflammatory responses. The role of the nuclear factor-E2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathway was investigated by silencing Nrf2. SSA supplementation significantly (p < 0.05) decreased body weight and fasting blood glucose levels in DIO mice, and markedly improved metabolic disturbances. This treatment also enhanced intestinal barrier function and reduced metabolic inflammation, likely through increased antioxidant capacity of intestinal epithelial cells via activation of the Nrf2/ARE signaling pathway. In vitro, SSA maintained cell barrier integrity and reduced inflammatory responses by activating the Nrf2/ARE signaling pathway, decreasing intracellular reactive oxygen species content, and increasing transepithelial electrical resistance. However, silencing Nrf2 abolished SSA's protective effects. SSA enhances the antioxidant capacity of intestinal epithelial cells, maintains intestinal barrier integrity, and reduces intestinal inflammation in DIO mice through the activation of the Nrf2/ARE signaling pathway. These findings offer new insights into the protective role of SSA in obesity and metabolic diseases.

Junshanyinzhen tea extract prevents obesity by regulating gut microbiota and metabolic endotoxemia in high-fat diet fed rats

Obesity is associated with gut dysbiosis and metabolic endotoxin. Junshanyinzhen tea extract (JSTE) reduced fat accumulation and body weight in obese mice. However, the effects and mechanism of JSTE in preventing obesity were unclear. Therefore, we used different doses of JSTE (75, 150 and 300 mg/(kg∙d)) to evaluate the effect on high-fat diet (HFD)-induced rats under 8 weeks of intervention. Here, our results showed that JSTE could significantly reduce body weight gain, blood lipid levels and fat accumulation, improve fatty damage in liver tissue (P < 0.05). In addition, JSTE increased the expression of intestinal tight junction proteins (P < 0.05), relieved metabolic endotoxemia (P < 0.05) and chronic low-grade inflammation in HFD rats. Sequencing of fecal samples showed that JSTE could effectively reverse the microbial diversity and the ratio of Firmicutes to Bacteroidetes to normal levels in HFD-fed rats. Desulfovibrioceae and Erysipelotrichaceae, which are positively related to obesity, were decreased by JSTE intervention (P < 0.05). while Bifidobacteriaceae, Bacteroidaceae, Akkermansia, and Clostridium, which are negatively related to obesity, were increased. Together, these results suggested that JSTE might effectively prevent obesity by modulating gut microbiota dysbiosis, intestinal barrier dysfunction, metabolic endotoxemia and chronic low-grade inflammation in HFD-induced rats.

Intermittent Fasting Attenuates Obesity-Induced Triple-Negative Breast Cancer Progression by Disrupting Cell Cycle, Epithelial-Mesenchymal Transition, Immune Contexture, and Proinflammatory Signature.

Obesity is associated with one-fifth of cancer deaths, and breast cancer is one of the obesity-related cancers. Triple-negative breast cancer (TNBC) lacks estrogen and progesterone receptors and human epidermal growth factor receptor 2, leading to the absence of these therapeutic targets, followed by poor overall survival. We investigated if obesity could hasten TNBC progression and intermittent fasting (IF) could attenuate the progression of obesity-related TNBC. Our meta-analysis of the TNBC outcomes literature showed that obesity led to poorer overall survival in TNBC patients. Fasting-mimicking media reduced cell proliferation disrupted the cell cycle, and decreased cell migration and invasion. IF decreased body weight in obese mice but no change in normal mice. Obese mice exhibited elevated plasma glucose and cholesterol levels, increased tumor volume and weight, and enhanced macrophage accumulation in tumors. The obesity-exacerbated TNBC progression was attenuated after IF, which decreased cyclin B1 and vimentin levels and reduced the proinflammatory signature in the obesity-associated tumor microenvironment. IF attenuated obesity-induced TNBC progression through reduced obesity and tumor burdens in cell and animal experiments, supporting the potential of a cost-effective adjuvant IF therapy for TNBC through lifestyle change. Further evidence is needed of these IF benefits in TNBC, including from human clinical trials.

Systematically investigate the mechanism underlying the therapeutic effect of Astragalus membranaceus in ulcerative colitis

BackgroundWhether Astragalus membranaceus is an effective drug in treatment of ulcerative colitis (UC) and how it exhibit activity effect on UC is unclear. MethodsTCMSP, GeneCards, String, and DAVID database were used to screening target genes construct PPI network and performed for GO and KEGG pathway enrichment analysis respectively. Molecular docking and animal experiment were performed. The body weight and disease activity index (DAI) of mice were recorded. ELISA kits were used to detect the levels of CAT, SOD, MDA and IL-6, IL-10, TNF-α in the blood of mice. Western blot kits were utilized to measured the expressions of MAPK14, RB1, MAPK1, JUN, ATK1, and IL2 proteins. ResultsThe active components of Astragalus membranaceus mainly including 7-O-methylisomucronulatol, quercetin, kaempferol, formononetin and isrhamnetin. Astragalus membranaceus may inhibited the expression of TNF-α, IL-6, MDA, and promoted the expression of CAT, SOD, IL-10. The expression levels of MAPK14, RB1, MAPK1, JUN and ATK1 proteins were significantly decreased while IL2 protein increased administrated with Astragalus membranaceus. ConclusionsAstragalus membranaceus is an effective drug in treatment of UC according to related to above targets that may exhibits the anti-UC effect via its antioxidant pathway and regulating the balance of pro-inflammatory and anti-inflammatory factors.

Shengqing Jiangzhuo decoction regulates the immunosuppressive microenvironment via the STAT3 signaling pathway for the treatment of malignant ascites in HCC

IntroductionMalignant ascites is a common complication of advanced hepatocellular carcinoma (HCC) that seriously affects the quality of life and survival of patients and has poor clinical efficacy. In the early stages, the authors found that the combination of the Shengqing Jiangzhuo decoction (SQJZD)and Endostar can effectively alleviate the clinical symptoms of malignant ascites in patients with HCC and reduce the amount of malignant ascites. The purpose of this study was to investigate the mechanism of action of SQJZD in HCC-related malignant ascites. MethodsA malignant ascites BALB/c mouse model was established by the intraperitoneal inoculation of H22 cells. The mice were randomly divided into model, Endostar, and high-, medium-, and low-dose traditional Chinese medicine (TCM) combined with Endostar groups. Normal mice from the same batch were used as the normal group. The Endostar and TCM + Endostar groups were intraperitoneally injected with Endostar, whereas the model and normal groups were intraperitoneally injected with equal amounts of normal saline. Different doses of SQJZD were administered to each TCM group, and equal amounts of distilled water were administered to the normal, model, and Endostar groups. ResultsThe malignant ascites volume and body weight were higher in the model group than in the normal group. After treatment, the volume and body weight of mice with malignant ascites decreased, especially in the SQJZD combined with Endostar group. Compared with that in the normal group, the number of regulatory T cells (Tregs) in the peripheral blood and spleen of mice in the model group was significantly decreased; the number of regulatory dendritic cells (DCregs), myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs) in the peripheral blood were not significantly changed; and the number of DCregs, MDSCs, and TAMs in the spleen was increased. Compared with those in the model group, the numbers of Tregs, DCregs, MDSCs, and TAMs in the peripheral blood increased in the Endostar or SQJZD combined with Endostar groups, whereas the numbers of Tregs, DCregs, MDSCs, and TAMs in the spleen decreased. Western blotting revealed that the percentage of p-STAT3-positive cells in the liver and spleen of mice increased in the model group, whereas the percentage of p-STAT3-positive cells in the liver and spleen decreased in mice treated with Endostar or SQJZD combined with Endostar. ConclusionsSQJZD combined with Endostar may attenuate immunosuppression and enhance the antitumor immune response by regulating the STAT3 pathway to alleviate malignant ascites in HCC.

Ebselen improves lipid metabolism by activating PI3K/Akt and inhibiting TLR4/JNK signaling pathway to alleviate nonalcoholic fatty liver

Nonalcoholic fatty liver disease (NAFLD), a metabolic disease associated with obesity and type 2 diabetes. Due to its complex pathogenesis, there are still limitations in the knowledge of the disease. To date, no drug has been approved to treat NAFLD. This study aims to explore the role and mechanism of Ebselen (EbSe) in NAFLD. A high-fat diet-induced mouse model of NAFLD was employed to investigate EbSe function in NAFLD mice by EbSe gavage and to regularly monitor the mouse body weight. HE and oil red O staining were performed, respectively, to detect the pathological damage and lipid accumulation in mouse liver tissues. The biochemical and ELISA kits were employed to measure the levels of ALT, AST, TG, TC, LDL-C, HDL-C and pro-inflammatory cytokines within mouse serum or liver tissue. The expression of key proteins of PPARα, fatty acid β oxidation-related protein, PI3K/Akt and TLR4/JNK signaling pathway was detected by western blot. EbSe significantly downregulated body weight, liver weight and liver lipid accumulation in NAFLD mice and downregulated ALT, AST, TG, TC, LDL-C and increased HDL-C serum levels. EbSe upregulated the expression levels of PPARα and fatty acid β oxidation-associated proteins CPT1α, ACOX1, UCP2 and PGC1α. EbSe promoted Akt and PI3K phosphorylation, and inhibited TLR4 expression and JNK phosphorylation. EbSe can upregulate PPARα to promote fatty acid β-oxidation and improve hepatic lipid metabolism. Meanwhile, EbSe also activated PI3K/Akt and inhibited TLR4/JNK signaling pathway. EbSe is predicted to be an effective therapeutic drug for treating NAFLD.

Functional evaluation of pure natural edible Ferment: protective function on ulcerative colitis.

To investigate the therapeutic efficiency of a novel drink termed "Ferment" in cases of ulcerative colitis (UC) and its influence on the gut microbiota. In this study, we developed a complex of mixed fruit juice and lactic acid bacteria referred to as Ferment. Ferment was fed to mice for 35 days, before inducing UC with Dextran Sulfate Sodium Salt. We subsequently investigated the gut microbiome composition using 16S rRNA sequencing. After Ferment treatment, mouse body weight increased, and animals displayed less diarrhea, reduced frequency of bloody stools, and reduced inflammation in the colon. Beneficial bacteria belonging to Ileibacterium, Akkermansia, and Prevotellacea were enriched in the gut after Ferment treatment, while detrimental organisms including Erysipelatoclostridium, Dubosiella, and Alistipes were reduced. These data place Ferment as a promising dietary candidate for enhancing immunity and protecting against UC.

Nesfatin-1 regulates the phenotype transition of cavernous smooth muscle cells by activating PI3K/AKT/mTOR signaling pathway to improve diabetic erectile dysfunction

ObjectiveThis study aims to explore the impact of Nesfatin-1 on type 2 diabetic erectile dysfunction (T2DMED) and its underlying mechanism in regulating the phenotypic switching of corpus cavernosum smooth muscle cells (CCSMCs). MethodsTwenty-four 4-week-old male C57 wild-type mice were randomly assigned to the control group, model group, and Nesfatin-1 treatment group. Monitoring included body weight, blood glucose levels, and penile cavernous pressure (ICP). Histochemistry and Western blot analyses were conducted to assess the expressions of α-SMA, OPN, and factors related to the PI3K/AKT/mTOR signaling pathway. CCSMCs were categorized into the control group, high glucose and high oleic acid group (GO group), Nesfatin-1 treatment group (GO + N group), sildenafil positive control group (GO + S group), and PI3K inhibitor group (GO + N + E group). Changes in phenotypic markers, cell morphology, and the PI3K/AKT/mTOR signaling pathway were observed in each group. Results(1) Nesfatin-1 significantly ameliorated the body size, body weight, blood glucose, glucose tolerance, and insulin resistance in T2DMED mice. (2) Following Nesfatin-1 treatment, the ICP/MSBP ratio and the peak of the ICP curve demonstrated a significant increase. (3) Nesfatin-1 significantly enhanced smooth muscle and reduced collagen fibers in the corpus cavernosum. (4) Nesfatin-1 notably increased α-SMA expression and decreased OPN expression in CCSMCs. (5) Nesfatin-1 elevated PI3K, p-AKT/AKT, and p-mTOR/mTOR levels in penile cavernous tissue. ConclusionsNesfatin-1 not only effectively improves body weight and blood glucose levels in diabetic mice but also enhances erectile function and regulates the phenotypic switching of corpus cavernosum smooth muscle. The potential mechanism involves Nesfatin-1 activating the PI3K/AKT/mTOR signaling pathway to induce the conversion of CCSMCs to a contractile phenotype.

Sucralose triggers insulin resistance leading to follicular dysplasia in mice

Sucralose, the extensively utilized sweetener, might lead to metabolic disorders with prolonged consumption, but it remains uncertain if sucralose has any impact on female reproductive health. We incorporated sucralose into drinking water and observed food intake, body weight, estrous cycle, follicular development, serum hormones, and insulin sensitivity of mice. The mice did not experience any changes in their food intake or body weight after consuming sucralose. However, they displayed irregularities in the estrous cycle, marked by a reduced count of primordial, primary, and secondary follicles, coupled with a significant increase in the number of antral follicles. There was a decline in follicle-stimulating hormone (FSH), estradiol (E2), and progesterone (P4) levels, while testosterone (T) and luteinizing hormone (LH) levels surged, leading to a notable elevation in the LH / FSH ratio. Sucralose also induced insulin resistance, as evidenced by elevated insulin levels and impaired insulin tolerance, which responded to an increase in bacterial-derived serum endotoxin. By eliminating insulin resistance with rosiglitazone (RSG), eradicating intestinal flora-derived endotoxins with neomycin (NEO), or enhancing intestinal barrier function with indole-3-carbinol (I3C), the abnormalities in estrous cycle, disruptions in follicular development, hormonal imbalances and elevation in serum endotoxins induced by sucralose were successfully reversed. The present study indicates that sucralose-induced follicular dysplasia in mice is probably related to impaired intestinal permeability, infiltration of endotoxins, initiation of systemic inflammation, and insulin resistance.

Design of a Fibroblast Activation Protein-Targeted Radiopharmaceutical Therapy with High Tumor-to-Healthy-Tissue Ratios.

Because of upregulated expression on cancer-associated fibroblasts, fibroblast activation protein (FAP) has emerged as an attractive biomarker for the imaging and therapy of solid tumors. Although many FAP ligands have already been developed for radiopharmaceutical therapies (RPTs), most suffer from inadequate tumor uptake, insufficient tumor residence times, or off-target accumulation in healthy tissues, suggesting a need for further improvements. Methods: A new FAP-targeted RPT with a novel ligand (FAP8-PEG3-IP-DOTA) was designed by combining the desirable features of several previous ligand-targeted RPTs. Uptake and retention of [111In]In or [177Lu]Lu-FAP8-PEG3-IP-DOTA were assessed in KB, HT29, MDA-MB-231, and 4T1 murine tumor models by radioimaging or ex vivo biodistribution analyses. Radiotherapeutic potencies and gross toxicities were also investigated by monitoring tumor growth, body weight, and tissue damage in tumor-bearing mice. Results: FAP8-PEG3-IP-DOTA exhibited high affinity (half-maximal inhibitory concentration, 1.6 nM) and good selectivity for FAP relative to its closest homologs, prolyl oligopeptidase (half-maximal inhibitory concentration, ∼14.0 nM) and dipeptidyl peptidase-IV (half-maximal inhibitory concentration, ∼860 nM). SPECT/CT scans exhibited high retention in 2 different solid tumor models and minimal uptake in healthy tissues. Quantitative biodistribution analyses revealed tumor-to-healthy-tissue ratios of more than 5 times for all major organs, and live animal studies demonstrated 65%-93% suppression of tumor growth in all 4 models tested, with minimal or no evidence of systemic toxicity. Conclusion: We conclude that [177Lu]Lu-FAP8-PEG3-IP-DOTA constitutes a promising and safe RPT candidate for FAPα-targeted radionuclide therapy of solid tumors.

Network Pharmacology and Bioinformatics Analysis identify potential therapeutic effects of Berberine on Colon Cancer complicated with Radiation Enteritis

Background: Patients with colon adenocarcinoma (COAD) who undergo radiation therapy develop radiation enteritis (RE). The predictive value of RE in COAD is yet to be established. Berberine, an active compound derived from the traditional Chinese medicinal plant, Coptis chinensis, has notable anti-inflammatory properties and offers protection to the intestinal mucosa. This study aimed to evaluate the possible therapeutic effect and mechanism of berberine as a treatment for COAD complicated with RE (COAD&amp;RE). Methods: Relevant genetic features of diverse COAD&amp;RE populations were analyzed using bioinformatics and the Cox proportional hazards regression model. The therapeutic targets of berberine were predicted using network pharmacology and molecular docking. In vivo and in vitro experiments were conducted to validate the core genes identified using molecular docking. Results: RE has a certain impact on the prognosis of COAD and berberine may play an important role in the treatment of COAD&amp;RE. In addition, we identified five core therapeutic targets of berberine by network pharmacology and molecular docking: CCND1, MYC, AR, LEP, and CYP19A1. In vivo experiments showed that berberine increased short-term survival rate, body weight, and intestinal epithelial cell recovery in mice after radiation. In an in vitro study, berberine promoted the proliferation of human intestinal epithelial cells and enhanced the radiosensitivity of HT29 cells after radiation, and the relative mRNA expression levels of CCND1 and MYC closely correlated with these effects. Conclusions: This study predicted the potential therapeutic effects of berberine on COAD&amp;RE and verified the relevant mechanisms, which may provide insights and suggestions for the clinical treatment of COAD&amp;RE.

Improvement effects of a novel Chinese herbal formula in imiquimod and IL-23-stimulated mouse models of psoriasis

BackgroundPsoriasis is a long-term inflammatory skin disease. A novel herbal formula containing nine Chinese herbal medicines, named Inflammation Skin Disease Formula (ISDF), has been prescribed in clinics for decades.AimsTo investigate the efficacy and action mechanisms of ISDF on psoriasis using imiquimod (IMQ) and Interleukin-23 (IL-23)-induced models in mice and reveal the pharmacokinetics profile of ISDF in rats.MethodsTopical administration of IMQ and intradermal injection with IL-23 respectively induced skin lesions like psoriasis on the dorsal area of Balb/c and C57 mice. The mice's body weight, skin thickness, and psoriasis area and severity index (PASI) were assessed weekly. SD rats were used in the pharmacokinetics study and the contents of berberine and baicalin were determined.ResultsThe PASI scores and epidermal thickness of mice were markedly decreased after ISDF treatment in both models. ISDF treatment significantly decreased the contents of IL-17A and IL-22 in the serum of IMQ- and IL-23-treated mice. Importantly, ISDF markedly downregulated IL-4, IL-6, IL-1β, and tumor necrosis factor α (TNF-α) gene expression, and the phosphorylation of NF-κB p65, JNK, ERKs and MAPK p38 in IMQ-treated mice. The protein phosphorylation of Jak1, Jak2, Tyk2 and Stat3 was significantly mitigated in the ISDF-treated groups. The absorption of baicalin and berberine of ISDF through the gastrointestinal tract of rats was limited, and their distribution and metabolism in rats were also very slow, which suggested ISDF could be used in the long-term application.ConclusionsISDF has a strong anti-psoriatic therapeutic effect on mouse models induced with psoriasis through IMQ and IL-23, which is achieved by inhibiting the activation of the Jak/Stat3-activated IL-23/Th17 axis and the downstream NF-κB signalling and MAPK signalling pathways. ISDF holds great potential to be a therapy for psoriasis and should be further developed for this purpose.