INPP4B suppresses HER2-induced mesenchymal transition in HER2+ breast cancer and enhances sensitivity to Lapatinib.

Human epidermal growth factor receptor 2 positive (HER2+) breast cancer (BC) tends to metastasize and has a bad prognosis due to its high malignancy and rapid progression. Inositol polyphosphate 4-phosphatase isoenzymes type II (INPP4B) plays unequal roles in the development of various cancers. However, the function of INPP4B in HER2+ BC has not been elucidated. Here we found that INPP4B expression was significantly lower in HER2+ BC and positively correlated with the prognosis by bioinformatics and tissue immunofluorescence analyses. Overexpression of INPP4B inhibited cell proliferation, migration, and growth of xenografts in HER2+ BC cells. Conversely, depletion of INPP4B reversed these effects and activated the PDK1/AKT and Wnt/ß-catenin signaling pathways to promote epithelial-mesenchymal transition (EMT) progression. Moreover, INPP4B overexpression blocked epidermal growth factor (EGF) -induced cell proliferation, migration and EMT progression, whereas INPP4B depletion antagonized HER2 depletion in reduction of cell proliferation and migration of HER2+ BC cells. Additionally, Lapatinib (LAP) inhibited HER2+ BC cell survival, proliferation and migration, and its effect was further enhanced by overexpression of INPP4B. In summary, our results illustrate that INPP4B suppresses HER2+ BC growth, migration and EMT, and its expression level affects patient outcome, further providing new insights into clinical practice.

Prognostic factors in extensive-stage small cell lung cancer patients with organ-specific metastasis: unveiling commonalities and disparities.

BACKGROUND: This study aimed to identify shared and distinct prognostic factors related to organ-specific metastases (liver, lung, bone, and brain) in extensive-stage small cell lung cancer (ES-SCLC) patients, then construct nomograms for survival prediction. METHODS: Patient data for ES-SCLC were from the Surveillance, Epidemiology, and End Results (SEER) database from 2010 to 2019. Kaplan-Meier analysis was applied to estimate overall survival (OS), and Cox regression was used to identify prognostic factors. A Venn diagram was utilized to distinguish common and unique prognostic factors among the variables assessed. These identified prognostic factors were used to formulate a nomogram, and its predictive accuracy and reliability were evaluated using C-indexes, calibration curves, and receiver operating characteristic (ROC) curves. RESULTS: A total of 24,507 patients diagnosed with ES-SCLC exhibiting metastases to the liver, lung, bone, and brain were included. The 6-month, 1-year, and 2-year OS rates were 46.1%, 19.7%, and 5.0%, respectively. Patients with liver metastasis demonstrated the most unfavorable prognosis, with a 1-year OS rate of 14.5%, while those with brain metastasis had a significantly better prognosis with a 1-year OS rate of 21.6%. The study identified seven common factors associated with a poor prognosis in ES-SCLC patients with organ-specific metastases: older age, male sex, unmarried status, higher T stage, presence of other metastases, and combination radiotherapy and chemotherapy. Furthermore, specific prognostic factors were identified for patients with metastasis to the liver, bone, and brain, including paired tumors, lack of surgical treatment at the primary site, and household income, respectively. To facilitate prognostic predictions, four nomograms were developed and subsequently validated. The performance of these nomograms was assessed using calibration curves, C-indexes, and the area under the curve (AUC), all of which consistently indicated good predictive accuracy and reliability. CONCLUSIONS: Patients diagnosed with ES-SCLC with organ-specific metastases revealed shared and distinct prognostic factors. The nomograms developed from these factors demonstrated good performance and can serve valuable clinical tools to predict the prognosis of ES-SCLC patients with organ-specific metastases.

CCT020312 exerts anti-prostate cancer effect by inducing G1 cell cycle arrest, apoptosis and autophagy through activation of PERK/eIF2α/ATF4/CHOP signaling.

PERK/eIF2α/ATF4/CHOP signaling pathway is one of three major branches of unfolded protein response (UPR) and has been implicated in tumor progression. CCT020312 is a selective PERK activator and may have a potential anti-tumor effect. Here we investigated the anti-prostate cancer effect and its underlying mechanism of CCT020312. Our results showed that CCT020312 inhibited prostate cancer cell viability by inducing cell cycle arrest, apoptosis and autophagy through activation of PERK/eIF2α/ATF4/CHOP signaling. CCT020312 treatment caused cell cycle arrest at G1 phase and increased the levels of cleaved-Caspase3, cleaved-PARP and Bax in prostate cancer C4-2 and LNCaP cells. Moreover, CCT020312 increased LC3II/I, Atg12-Atg5 and Beclin1 levels and induced autophagosome formation. Furthermore, knockdown of CHOP reversed CCT020312-induced cell viability decrease, apoptosis and autophagy. Bafilomycin A1 reversed CCT020312-induced cell viability decrease but had no effect on CCT020312-induced CHOP activation in C4-2 and LNCaP cells. In vivo, CCT020312 suppressed tumor growth in C4-2 cells-derived xenograft mouse model, activated PERK pathway, and induced autophagy and apoptosis. Our study illustrates that CCT020312 exerts an anti-tumor effect in prostate cancer via activating the PERK pathway, thus indicating that CCT020312 may be a potential drug for prostate cancer.

CEP55 as a Promising Immune Intervention Marker to Regulate Tumor Progression: A Pan-Cancer Analysis with Experimental Verification.

CEP55, a member of the centrosomal protein family, affects cell mitosis and promotes the progression of several malignancies. However, the relationship between CEP55 expression levels and prognosis, as well as their role in cancer progression and immune infiltration in different cancer types, remains unclear. We used a combined form of several databases to validate the expression of CEP55 in pan-cancer and its association with immune infiltration, and we further screened its targeted inhibitors with CEP55. Our results showed the expression of CEP55 was significantly higher in most tumors than in the corresponding normal tissues, and it correlated with the pathological grade and age of the patients and affected the prognosis. In breast cancer cells, CEP55 knockdown significantly decreased cell survival, proliferation, and migration, while overexpression of CEP55 significantly promoted breast cancer cell proliferation and migration. Moreover, CEP55 expression was positively correlated with immune cell infiltration, immune checkpoints, and immune-related genes in the tumor microenvironment. CD-437 was screened as a potential CEP55-targeted small-molecule compound inhibitor. In conclusion, our study highlights the prognostic value of CEP55 in cancer and further provides a potential target selection for CEP55 as a potential target for intervention in tumor immune infiltration and related immune genes.

Achieving Ultra-Wideband NIR-II Emission in Cr3+-Doped Li(Sc,In)(Si,Ge)O4 Phosphors Based on Host Composition Engineering.

Realizing ultra-wideband and tunable near-infrared (NIR) emission remains a great challenge in NIR phosphor development. The luminescence of most reported NIR phosphors exhibits a peak wavelength shorter than 1000 nm and the corresponding FWHM is <200 nm. Here, a series of Cr3+-activated Li(Sc,In)(Si,Ge)O4 phosphors with ultra-wideband and tunable NIR-II emission are successfully developed based on the host composition engineering strategy. Significant spectral engineering in the NIR-II region is achieved with a peak wavelength changing from 1110 to 1253 nm. The olivine host structure could provide Cr3+ activator a highly distorted octahedral site with very weak crystal field strength, which results in NIR-II ultra-wideband emission with FWHM > 300 nm. A detailed discussion on the relationship between structural variation, crystal field splitting, and NIR luminescence has been applied. As far as we know, it is the first report about Cr3+ NIR luminescence engineering in such a long wavelength and wide range. The application of these NIR-II phosphors is demonstrated in intensity-based luminescent thermometry with a relative sensitivity of >2.0% K-1 in the physiological temperature range.

Nomograms for predicting overall survival in colorectal cancer patients with metastasis to the liver, lung, bone, and brain.

BACKGROUND: The aim of this study was to identify the heterogeneous and homogeneous prognostic factors associated with distant metastasis to the liver, lung, bone, and brain in colorectal cancer (CRC) patients and then construct nomograms to predict the prognosis. METHODS: CRC patients registered in the surveillance, epidemiology, and end results database between 2010 and 2017 were included. A Cox regression model was used to analyse homogeneous and heterogeneous prognostic factors, and Kaplan‒Meier analysis was performed to estimate overall survival (OS). Predictive nomograms were constructed, and their performance was evaluated with C-indexes, calibration curves and the area under the receiver operating characteristic (ROC) curve (AUC). RESULTS: A total of 37,641 patients with distant metastasis to the liver, lung, bone, and brain were included. The median survival times of patients with liver metastasis, lung metastasis, bone metastasis, and brain metastasis were 12.00 months (95% CI 11.73-12.27 months), 10.00 months (95% CI 9.60-10.41 months), 5.00 months (95% CI 4.52-5.48 months), and 3.00 months (95% CI 2.28-3.72 months), respectively. An older age, higher N stage, elevated carcinoembryonic antigen level, no surgery at the primary site and no/unknown treatment with chemotherapy were identified as homogeneous prognostic factors for the four types of metastases. The calibration curves, C-indexes and AUCs exhibited good performance for predicting the OS of patients with distant metastases to the liver, lung, bone, and brain. CONCLUSIONS: CRC patients with distant metastasis to the liver, lung, bone, and brain exhibited homogeneous and heterogeneous prognostic factors, all of which were associated with shorter survival. The nomograms showed good accuracy and may be used as tools for clinicians to predict the prognosis of CRC patients with distant metastasis.

N76-1, a novel CDK7 inhibitor, exhibits potent anti-cancer effects in triple negative breast cancer.

Emerging evidence suggests that genetically highly specific triple-negative breast cancer (TNBC) possesses a relatively uniform transcriptional program that is abnormally dependent on cyclin-dependent kinase 7 (CDK7). In this study, we obtained an inhibitor of CDK7, N76-1, by attaching the side chain of the covalent CDK7 inhibitor THZ1 to the core of the anaplastic lymphoma kinase inhibitor ceritinib. This study aimed to elucidate the role and underlying mechanism of N76-1 in TNBC and evaluate its potential value as an anti-TNBC drug. The results of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and colony formation assays showed that N76-1 inhibited the viability of TNBC cells. Kinase activity and cellular thermal shift assays showed that N76-1 directly targeted CDK7. Flow cytometry results revealed that N76-1 induced apoptosis and cell cycle arrest in the G2/M phase. N76-1 also effectively inhibited the migration of TNBC cells by high-content detection. The RNA-seq analysis showed that the transcription of genes, especially those related to transcriptional regulation and cell cycle, was suppressed after N76-1 treatment. Moreover, N76-1 markedly inhibited the growth of TNBC xenografts and phosphorylation of RNAPII in tumor tissues. In summary, N76-1 exerts potent anticancer effects in TNBC by inhibiting CDK7 and provides a new strategy and research basis for the development of new drugs for TNBC.

VPS34-IN1 induces apoptosis of ER+ breast cancer cells via activating PERK/ATF4/CHOP pathway.

VPS34-IN1 is a specific selective inhibitor of Class III Phosphatidylinositol 3-kinase (PI3K) and has been shown to exhibit a significant antitumor effect in leukemia and liver cancer. In current study, we focused on the anticancer effect and potential mechanism of VPS34-IN1 in estrogen receptor positive (ER+ ) breast cancer. Our results revealed that VPS34-IN1 inhibited the viability of ER+ breast cancer cells in vitro and in vivo. Flow cytometry and western blot analyses showed that VPS34-IN1 treatment induced breast cancer cell apopotosis. Interestingly, VPS34-IN1 treatment activated protein kinase R (PKR)-like ER kinase (PERK) branch of endoplasmic reticulum (ER) stress. Furthermore, knockdown of PERK by siRNA or inhibition of PERK activity by chemical inhibitor GSK2656157 could attenuate VPS34-IN1-mediated apoptosis in ER+ breast cancer cells. Collectively, VPS34-IN1 has an antitumor effect in breast cancer, and it may result from activating PERK/ATF4/CHOP pathway of ER stress to induce cell apoptosis. These findings broaden our understanding of the anti-breast cancer effects and mechanisms of VPS34-IN1 and provide new ideas and reference directions for the treatment of ER+ breast cancer.

Circular RNAs in the chemoresistance of triple-negative breast cancer: A systematic review.

This study aims to assess studies on circular RNAs (circRNAs) in the chemoresistance of triple-negative breast cancer (TNBC) and provide relevant references for the development of new TNBC chemotherapy sensitivity biomarkers and therapeutic targets. The PubMed, Embase, Web of Knowledge, Cochrane Library, and four Chinese databases were searched up to January 27, 2023, and studies related to TNBC chemoresistance were included. The basic characteristics of the studies and the mechanisms of circRNAs in regulating TNBC chemoresistance were analyzed. A total of 28 studies published between 2018 and 2023 were included, and the chemotherapeutics included adriamycin, paclitaxel, docetaxel, 5-fluorouracil, lapatinib, and so forth. A total of 30 circRNAs were identified, 86.67% (n = 26) of these circRNAs were reported to act as microRNA (miRNA) sponges to regulate chemotherapy sensitivity, while only two circRNAs (circRNA-MTO1 and circRNA-CREIT) interacted with proteins. A total of 14, 12, and 2 circRNAs were reported to be associated with chemoresistance to adriamycin, taxanes, and 5-fluorouracil, respectively. Six circRNAs were found to act as miRNA sponges that promote chemotherapy resistance by regulating the PI3K/Akt signalling pathway. CircRNAs participate in the regulation of TNBC chemoresistance and can be used as biomarkers and therapeutic targets for improving chemotherapy sensitivity. However, further studies are needed to confirm the role of circRNAs in TNBC chemoresistance.

Broadband-excited and green-red tunable emission in Eu2+-sensitized Ca8MnTb(PO4)7 phosphors induced by structural-confined cascade energy transfer.

Novel green-red color-tunable Ca8(Mg,Mn)Tb(PO4)7:Eu2+ phosphors have been synthesized via the traditional solid-state method. Since Tb3+/Mn2+ ions are the parent ions in the lattice, the structural confinement occurs when the sensitizer Eu2+ is introduced into the Ca8(Mg,Mn)Tb(PO4)7:Eu2+ structure. The distance from Eu2+ to Tb3+/Mn2+ is confined in the 5 Å range, which induces a highly efficient energy transfer process. At Eu2+ 350 nm excitation, Ca8MgTb(PO4)7:Eu2+ shows dominant Tb3+ green emission with almost-vanished Eu2+ emission. Red emission is clearly observed as Mn2+ ions doping into Ca8MgTb(PO4)7:Eu2+, and color-tuning from green to red is realized by varying the Mn2+ contents. Eu2+-Tb3+-Mn2+ cascade energy transfer process is in effect due to short Eu2+-Tb3+/Mn2+ and Tb3+-Mn2+ distances, which is verified by PL and decay variations. Meanwhile, the Ca8(Mg,Mn)Tb(PO4)7:Eu2+ phosphor indicates good thermal stability and maintained the 45% emission level at 150 °C, which demonstrates their potential applications in white light LEDs.

Celastrol targets the ChREBP-TXNIP axis to ameliorates type 2 diabetes mellitus.

BACKGROUNDS: Thioredoxin-interacting protein (TXNIP) plays a pivotal role in regulation of blood glucose homeostasis and is an emerging therapeutic target in diabetes and its complications. Celastrol, a pentacyclic triterpene extracted from the roots of Tripterygium wilfordii Hook F, can reduce insulin resistance and improve diabetic complications. PURPOSE: This study aimed to untangle the mechanism of celastrol in ameliorating type 2 diabetes (T2DM) and evaluate its potential benefits as an anti-diabetic agent. METHODS: db/db mice was used to evaluate the hypoglycemic effect of celastrol in vivo; Enzyme-linked immunosorbent assay (ELISA) and 2-NBDG assay were used to detect the effect of celastrol on insulin secretion and glucose uptake in cells; Western blotting, quantitative reverse transcription PCR (RT-qPCR) and immunohistological staining were used to examine effect of celastrol on the expression of TXNIP and the carbohydrate response element-binding protein (ChREBP). Molecular docking, cellular thermal shift assay (CETSA), drug affinity responsive targets stability assay (DARTS) and mass spectrometry were used to test the direct binding between celastrol and ChREBP. Loss- and gain-of-function studies further confirmed the role of ChREBP and TXNIP in celastrol-mediated amelioration of T2DM. RESULTS: Celastrol treatment significantly reduced blood glucose level, body weight and food intake, and improved glucose tolerance in db/db mice. Moreover, celastrol promoted insulin secretion and improved glucose homeostasis. Mechanistically, celastrol directly bound to ChREBP, a primary transcriptional factor upregulating TXNIP expression. By binding to ChREBP, celastrol inhibited its nuclear translocation and promoted its proteasomal degradation, thereby repressing TXNIP transcription and ultimately ameliorating T2DM through breaking the vicious cycle of hyperglycemia deterioration and TXNIP overexpression. CONCLUSION: Celastrol ameliorates T2DM through targeting ChREBP-TXNIP aix. Our study identified ChREBP as a new direct molecular target of celastrol and revealed a novel mechanism for celastrol-mediated amelioration of T2DM, which provides experimental evidence for its possible use in the treatment of T2DM and new insight into diabetes drug development for targeting TXNIP.

Photosensitizers with aggregation-induced far-red/near-infrared emission for versatile visualization and broad-spectrum photodynamic killing of pathogenic microbes.

The exploration of photosensitizers with aggregation-induced emission (AIE PSs) for efficient visualization and broad-spectrum photodynamic killing of pathogenic microbes is a significant task. Herein, two far-red/near-infrared AIE-active PSs (TBTPy and TBTCy) were attained to show efficient Type I and Type II ROS generation, benefiting from the efficient ISC processes. The attained AIE PSs, especially TBTPy with bright emission, showed advantages in discriminating G+ bacteria over G- bacteria, and distinguishing dead E. coli from lived one. Both TBTPy and TBTCy have the capacity of broad-spectrum photodynamic killing of pathogenic microbes in vitro with considerable safety for mammalian cells. Antimicrobial mechanism is found to be changing osmotic pressure of cytoplasm in E. coli, causing cell deformation and destruction of S. aureus and C. albicans. In vivo anti-infection experiment demonstrated AIE PSs can accelerate the healing process of the burned wounds on rats infected by methicillin-resistant S. aureus (MRSA) or E. coli, indicating their potential to treat tertiary burns in clinical application. Therefore, the attained AIE PSs hold great promise as antimicrobial candidates in infective therapeutic application.

The initiation of oxidative stress and therapeutic strategies in wound healing.

When the production of reactive oxygen species (ROS) is overloaded surpassing the capacity of the reductive rheostat, mammalian cells undergo a series of oxidative damage termed oxidative stress (OS). This phenomenon is ubiquitously detected in many human pathological conditions. Wound healing program implicates continuous neovascularization, cell proliferation, and wound remodeling. Increasing evidence indicates that reactive oxygen species (ROS) have profound impacts on the wound healing process through regulating a series of the physiological and pathological program including inflammatory response, cell proliferation, angiogenesis, granulation as well as extracellular matrix formation. In most pathological wound healing processes, excessive ROS exerts a negative role on the wound healing process. Interestingly, the moderate increase of ROS levels is beneficial in killing bacteria at the wound site, which creates a sterile niche for revascularization. In this review, we discussed the physiological rhythms of wound healing and the role of ROS in this progress, aim to explore the potential manipulation of OS as a promising therapeutic avenue.

Proteomics of serum exosomes identified fibulin-1 as a novel biomarker for mild cognitive impairment.

Mild cognitive impairment (MCI) is a prodrome of Alzheimer's disease pathology. Cognitive impairment patients often have a delayed diagnosis because there are no early symptoms or conventional diagnostic methods. Exosomes play a vital role in cell-to-cell communications and can act as promising biomarkers in diagnosing diseases. This study was designed to identify serum exosomal candidate proteins that may play roles in diagnosing MCI. Mass spectrometry coupled with tandem mass tag approach-based non-targeted proteomics was used to show the differentially expressed proteins in exosomes between MCI patients and healthy controls, and these differential proteins were validated using immunoblot and enzyme-linked immunosorbent assays. Correlation of cognitive performance with the serum exosomal protein level was determined. Nanoparticle tracking analysis suggested that there was a higher serum exosome concentration and smaller exosome diameter in individuals with MCI compared with healthy controls. We identified 69 exosomal proteins that were differentially expressed between MCI patients and healthy controls using mass spectrometry analysis. Thirty-nine exosomal proteins were upregulated in MCI patients compared with those in control patients. Exosomal fibulin-1, with an area under the curve value of 0.81, may be a biomarker for an MCI diagnosis. The exosomal protein signature from MCI patients reflected the cell adhesion molecule category. In particular, higher exosomal fibulin-1 levels correlated with lower cognitive performance. Thus, this study revealed that exosomal fibulin-1 is a promising biomarker for diagnosing MCI.

Investigation of isoflavone constituents from tuber of Apios americana Medik and its protective effect against oxidative damage on RIN-m5F cells.

In our previous study, AI-3, a mixture of isoflavones, was obtained from Apios Americana Medik tuber and showed strong protective ability on oxidative damaged RIN-m5F cells. This study aimed to identify the main compounds of AI-3 and elucidate their activities and underlying mechanism. In results, eleven compounds were purified from AI-3. Among them, Compound 8 (2'-Hydroxy, 5-methoxy genistein-7-O-glucoside, HMG) was the most effective compound against H2O2-induced injury in RIN-m5F cells (stronger than positive control α-LA). Further RNA-seq analysis found that compared with H2O2 group, 388 differentially expressed genes (DEGs) were identified in HMG group. The enrichment analyses revealed fluid shear stress and atherosclerosis pathway and hepatocellular carcinoma pathway enriched the most DEGs, in which HOX-1, GST, NQO1, SQSTM, TrxR1 were significantly up-regulated. The finding indicated Keap1-Nrf2-ARE signaling pathway may play essential role in the protective effect of HMG on oxidative damaged RIN-m5F cells.

Cardiovascular Complications in Hematopoietic Stem Cell Transplanted Patients.

Hematopoietic stem cell transplantation (HSCT) is the only curative treatment for many patients suffering from hematologic malignancies, solid tumors, inborn errors of metabolism or genetic disorders. Despite decades of successful HSCT, clinical outcomes are still far from satisfactory due to treatment-related complications, including graft-versus-host disease (GvHD) and cardiovascular complications (CVC). CVC may affect patients in the acute period post-HSCT; however, the occurrence is far higher among long-term survivors. Induction treatment using cardiotoxic treatments, e.g., anthracyclines and radiotherapy, conditioning regimens containing cyclophosphamide, and post-HSCT comorbidities, including GvHD, are factors contributing to CVC. Cardiac function evaluation prior to and post-transplantation is an important strategy for choosing the proper conditioning regimen, HSCT protocol and post-HSCT supportive care. Cardiac systolic function evaluation by echocardiography, in addition to serum cardiac biomarkers, such as troponins and brain natriuretic peptides, is recommended as a routine follow-up for HSCT patients. Angiotensin-converting enzyme inhibitors, angiotensin-II-receptor blockers, and beta-blockers, which are mostly used for the treatment of chemotherapy-induced cardiotoxicity, might be used as treatments for HSCT-related CVC. In summary, the present review reveals the urgent need for further investigations concerning HSCT-related CVC both at the preclinical and clinical levels due to the lack of knowledge about CVC and its underlying mechanisms.

Quercetin Suppresses Human Glioblastoma Migration and Invasion via GSK3ß/ß-catenin/ZEB1 Signaling Pathway.

High invasiveness is a biological and clinical characteristic of glioblastoma and predicts poor prognosis of patients. Quercetin, a natural flavonoid compound, exhibits anticancer activity. However, we have a limited understanding of the possible underlying mechanism of quercetin in glioblastoma. In this study, we investigated the anticancer effect of quercetin in human glioblastoma cells. Our results showed that quercetin markedly suppressed the viability of glioblastoma cells in vitro and in vivo, and significantly inhibited glioblastoma cell migration and invasion. Moreover, quercetin reversed EMT-like mesenchymal phenotype and reduced the expression levels of EMT-related markers. Furthermore, we found that quercetin suppressed GSK-3ß/ß-catenin/ZEB1 signaling in glioblastoma. Taken together, our results demonstrate that quercetin inhibited migration and invasion of human glioma cells by suppressing GSK3ß/ß-catenin/ZEB1 signaling. Our study provides evidence that quercetin is a promising therapeutic natural compound to treat glioblastoma.

Comparison of Changes in Gut Microbiota in Wild Boars and Domestic Pigs Using 16S rRNA Gene and Metagenomics Sequencing Technologies.

Gut microbiota diversity is a result of co-evolution between microorganisms and their hosts. However, there are few studies on the evolution of the gut microbiota of wild boars and domestic pigs. Therefore, this study aimed to analyze the composition and function of the gut microbiota of wild boars and domestic pigs using 16S rRNA gene V3-V4 region sequencing, 16S rRNA gene full-length sequencing, and metagenomic sequencing. This study showed that after a long evolution, as compared to wild boars, the domestic pigs exhibited significantly increased relative abundances of Lactobacillus, Lactobacillus reuteri, Lactobacillus johnsonii, Lactobacillus sp.DJF_WC5, and Lactobacillus; s_uncultured bacterium, while the relative abundances of Bifidobacterium and Methanococcaceae decreased significantly. In addition, the relative abundances of "carbohydrate metabolism", "starch and sucrose metabolism", "valine, leucine, and isoleucine biosynthesis", "lysine biosynthesis", and starch-degrading CAZymes were significantly increased in the domestic pigs, while the relative abundances of "environmental adaptation", "immune system", "fatty acid degradation and synthesis", and cellulose-hemicellulose-degrading CAZymes were significantly increased in the wild boars. Finally, the diversity of ARGs and the "antimicrobial resistance genes" in domestic pigs also increased significantly. This study illustrates that the gut microbiota composition and function of wild boars and domestic pigs changed during the long evolution process. These findings provide a basic research theory for the evolution of gut microbiota and the treatment of health and disease.

Co-Crystal of Rosiglitazone With Berberine Ameliorates Hyperglycemia and Insulin Resistance Through the PI3K/AKT/TXNIP Pathway In Vivo and In Vitro.

Background: Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease characterized by insulin resistance and hyperglycemia. This study examined the effect and elucidated the mechanism of improvement of hyperglycemia and insulin resistance by a co-crystal of rosiglitazone with berberine (RB) in high-sugar high-fat diet (HSHFD)-induced diabetic KKAy mice. Methods: Diabetic KKAy mice were randomly divided into seven groups: KKAy model control group (DM control) treated with 3% sodium carboxymethyl cellulose; RB groups, administered daily with RB 0.7 mg/kg (RB-L), 2.11 mg/kg (RB-M), or 6.33 mg/kg (RB-H); positive control groups, administered daily with rosiglitazone 1.04 mg/kg (RSG), berberine 195 mg/kg (BBR), or combination of 1.04 mg/kg RSG and 1.08 mg/kg BBR (MIX). Test compounds were administered orally for 8 weeks. Non-diabetic C57BL/6J mice were used as normal control (NC). Blood glucose, food intake, body weight, glucose-lipid metabolism, and pathological changes in the pancreas and liver were examined. We further evaluated the mechanism of action of RB in C2C12 and HepG2 cells stimulated with high glucose and palmitate. Results: RB treatment improved glucolipid metabolism and insulin resistance in diabetic KKAy mice. RB reduced blood glucose levels, white fat index, plasma triglyceride (TG), low-density lipoprotein (LDL), gastric inhibitory peptide (GIP), and insulin levels, increased the levels of plasma glucagon-like peptide-1 (GLP-1), high-density lipoprotein (HDL), and glycogen content in the liver and muscle; and improved oral glucose tolerance test (OGTT), insulin tolerance test (ITT), and pathological changes in the pancreas and liver of KKAy mice. Moreover, RB upregulated p-PI3K and p-AKT levels and reduced TXNIP expression in KKAy mice and in HepG2 and C2C12 cells. Conclusion: These data indicate that RB ameliorates insulin resistance and metabolic disorders, and the mechanism might be through regulating the PI3K/AKT/TXNIP signaling pathway . Thus, the co-crystal drug RB may be considered as a potential antidiabetic agent for future clinical therapy.