Role of pattern recognition receptors in the development of MASLD and potential therapeutic applications.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has become one of the most prevalent liver diseases worldwide, and its occurrence is strongly associated with obesity, insulin resistance (IR), genetics, and metabolic stress. Ranging from simple fatty liver to metabolic dysfunction-associated steatohepatitis (MASH), even to severe complications such as liver fibrosis and advanced cirrhosis or hepatocellular carcinoma, the underlying mechanisms of MASLD progression are complex and involve multiple cellular mediators and related signaling pathways. Pattern recognition receptors (PRRs) from the innate immune system, including Toll-like receptors (TLRs), C-type lectin receptors (CLRs), NOD-like receptors (NLRs), RIG-like receptors (RLRs), and DNA receptors, have been demonstrated to potentially contribute to the pathogenesis for MASLD. Their signaling pathways can induce inflammation, mediate oxidative stress, and affect the gut microbiota balance, ultimately resulting in hepatic steatosis, inflammatory injury and fibrosis. Here we review the available literature regarding the involvement of PRR-associated signals in the pathogenic and clinical features of MASLD, in vitro and in animal models of MASLD. We also discuss the emerging targets from PRRs for drug developments that involved agent therapies intended to arrest or reverse disease progression, thus enabling the refinement of therapeutic targets that can accelerate drug development.

LncRNA GAS5 restrains ISO-induced cardiac fibrosis by modulating mir-217 regulation of SIRT1.

Considering the effect of SIRT1 on improving myocardial fibrosis and GAS5 inhibiting occurrence and development of myocardial fibrosis at the cellular level, the aim of the present study was to investigate whether LncRNA GAS5 could attenuate cardiac fibrosis through regulating mir-217/SIRT1, and whether the NLRP3 inflammasome activation was involved in this process. Isoprenaline (ISO) was given subcutaneously to the male C57BL/6 mice to induce myocardial fibrosis and the AAV9 vectors were randomly injected into the left ventricle of each mouse to overexpress GAS5. Primary myocardial fibroblasts (MCFs) derived from neonatal C57BL/6 mice and TGF-ß1 were used to induce fibrosis. And the GAS5 overexpressed MCFs were treated with mir-217 mimics and mir-217 inhibitor respectively. Then the assays of expression levels of NLRP3, Caspase-1, IL-1ß and SIRT1 were conducted. The findings indicated that the overexpression of GAS5 reduced the expression levels of collagen, NLRP3, Capase-1, IL-1ß and SIRT1 in ISO treated mice and TGF-ß1 treated MCFs. However, this effect was significantly weakened after mir-217 overexpression, but was further enhanced after knockdown of mir-217. mir-217 down-regulates the expression of SIRT1, leading to increased activation of the NLRP3 inflammasome and subsequent pyroptosis. LncRNA GAS5 alleviates cardiac fibrosis induced via regulating mir-217/SIRT1 pathway.

Superior COL7A1 and TGM1 gene expression in difficult-to-transfect skin cell mediated by highly branched poly(ß-amino esters) through stepwise fractionation.

Delivering functional gene into targeted skin cells or tissues to modulate the genes expression, has the potential to treat various hereditary cutaneous disorders. Nevertheless, the lack of safe and effective gene delivery vehicles greatly limits the clinical translation of gene therapy for inherited skin diseases. Herein, we developed a facile elution fractionation strategy to isolate eight HPAEs with Mw ranging from 7.6 to 131.8 kg/mol and D < 2.0 from the one crude HPAE23.7k, and investigated the expression efficiency for TGM1 and COL7A1 plasmids. Gene transfection results revealed that the intermediate MW HPAEs, HPAE20.6k, exhibited the highest gene transfection efficiency (46.4%) and the strongest mean fluorescence intensity (143,032 RLU), compared to other isolated components and the crude product. Importantly, best-performing isolated HPAE effectively delivered COL7A1 (15,974 bp) and TGM1 (7181 bp) plasmids, promoting the efficient expression of type VII collagen (C7) and transglutaminase-1 proteins in cutaneous cells. Our study establishes a straightforward step-by-step elution fractionation strategy for the development of HPAEs gene delivery vectors, expediting their clinical translation in inherited skin diseases.

Clinical analysis of 12 cases of ovarian neuroendocrine carcinoma.

BACKGROUND: Neuroendocrine neoplasms of the female genital tract are rare. AIM: To enhance our clinical understanding of neuroendocrine carcinoma (NEC) of the ovary. METHODS: A retrospective review was conducted on 12 patients diagnosed with NEC of the ovary, analyzing clinicopathological characteristics, treatment modalities, and survival status. RESULTS: The median age at diagnosis was 34.5 years (range: 20 to 62 years). Among the 12 cases, 9 were small cell carcinoma of the ovary and 3 were large cell NEC. Five cases were stage I tumors, one case was stage IV, and six cases were stage III. Eleven patients underwent surgery as part of their treatment. All patients received adjuvant chemotherapy. Among the 12 patients, one patient received radiotherapy, and one patient with a BRCA2 mutation was administered PARP inhibitor maintenance after chemotherapy. The median progression-free survival was 13 months, and the median overall survival was 19.5 months. Four cases remained disease-free, while eight cases experienced tumor recurrence, including three cases that resulted in death due to disease recurrence. CONCLUSION: NEC of the ovary is a rare condition that is more common in women of childbearing age and is associated with aggressive behavior and poor clinical outcomes. Surgical resection remains the mainstay of treatment, with some patients benefiting from adjuvant chemoradiation therapy.

Novel lncRNA 803 related to Marek's disease inhibits apoptosis of DF-1 cells.

RESEARCH HIGHLIGHTS: Differentially expressed lncRNAs in spleens of chickens infected with Marek's disease virus at different stages were identified for the first time.The effects of novel lncRNA 803 on p53 pathway and apoptosis of DF-1 cells were reported for the first time.

Exosomal biomarkers in the differential diagnosis of ovarian tumors: the emerging roles of CA125, HE4, and C5a.

OBJECTIVE: Investigating the utility of serum exosomal markers CA125, HE4, and C5a, both individually and in combination, for distinguishing between benign and malignant ovarian tumors. METHODS: In this study, we selected a total of 234 patients diagnosed with ovarian tumors, including 34 with malignant tumors, 10 with borderline ovarian tumors, and 190 with benign tumors. This study conducted comparisons of exosomal levels of CA125, HE4, and C5a among distinct groups, as well as making comparisons between serum and exosomal levels of CA125 and HE4. Furthermore, the diagnostic performance was assessed through Receiver Operating Characteristic (ROC) curve analysis. The Area Under the Curve (AUC) was computed, and a comparative evaluation of sensitivity and specificity was conducted to ascertain their effectiveness in determining the nature of ovarian tumors across different markers. RESULTS: Serum CA125 and HE4 levels, the ROMA index, exosomal CA125, HE4, C5a levels, and their combined applied value (OCS value) were notably elevated in the ovarian non-benign tumor group compared to the benign tumor group, with statistical significance (P < 0.05). Exosomal and serum levels of CA125 and HE4 exhibited a positive correlation, with concentrations of these markers in serum surpassing those in exosomes. The combined OCS (AUC = 0.871) for CA125, HE4, and C5a in exosomes demonstrated superior sensitivity (0.773) and specificity (0.932) compared to serum tumor markers (CA125, HE4) and the ROMA index. The tumor stage represents an autonomous risk factor influencing the prognosis of individuals with ovarian malignancies. CONCLUSION: The stage of ovarian malignancy is an independent risk factor for its prognosis. The combination of exosomal CA125, HE4 and C5a has a higher clinical value for the identification of the nature of ovarian tumours.

The Pyroptosis-Related Signature Composed of GSDMC Predicts Prognosis and Contributes to Growth and Metastasis of Hepatocellular Carcinoma.

BACKGROUND: Pyroptosis-related genes (PRG) are closely associated with the progression and metastasis of hepatocellular carcinoma (HCC). The predictive power of PRGs could be used to assess the clinical outcomes of HCC. METHODS: The Cancer Genome Atlas (TCGA) RNA-seq data and clinical information from patients with liver hepatocellular carcinoma (LIHC) were used to identify PRG with differentially expressed between HCC and normal samples. Univariate Cox regression, least absolute shrinkage and selection operator (LASSO) Cox method, and multivariate Cox regression analysis were used to develop a prognostic model that included three PRGs. Gene set enrichment analysis (GSEA) was performed to identify differential immune cells and their associated pathways. The expression of Gasdermin C (GSDMC) in the HCC samples was detected by western blotting, and the function of GSDMC in HCC proliferation and metastasis was detected by the Cell Counting Kit-8 (CCK-8), colony formation, cell invasion, and wound healing assays. RESULTS: Of 52 PRGs, GSDMC, Bcl-2 homologusantagonist/ killer 1 (BAK1), and NOD-like receptor thermal protein domain associated protein 6 (NLRP6) were selected to establish a prognostic model. The model successfully differentiated HCC patients with varied survival in the TCGA training and test cohorts, as well as the International Cancer Genome Consortium (ICGC) validation cohorts. The risk score was proven to be an independent prognostic factor. In addition, we also reported a marked upregulation of GSDMC in HCC tissues, which could be induced by CD274 (PD-L1). Overexpression of GSDMC contributes to HCC cells invasion, proliferation, and migration. CONCLUSIONS: The three PRGs signatures containing GSDMC independently predicted HCC prognosis. As a new driver molecule, GSDMC could play a tumor-promoting role by facilitating HCC growth and metastasis.

The novel lncRNA-9802/miR-1646 axis affects cell proliferation of DF-1 by regulating Bax/Bcl-2 signaling pathway.

Marek's disease (MD) is a severe infectious and immunosuppressive neoplastic condition that significantly impacts the global poultry industry. Investigating the role of non-coding RNA in pathogenic mechanisms of MD virus (MDV) offers valuable insights for the effective prevention and management of MD. A higher expression of the novel lncRNA-9802 can be found in spleen tissues of MDV-infected chickens from our prior research, and there is a potential association between lncRNA-9802 and cell proliferation. In this study, we further demonstrated that over-expression of lncRNA-9802 could promote the proliferation of DF-1 cells. It has been established that lncRNA-9802 mediated its effects by binding to miR-1646, and further modulated the expression of the Bax and Bcl-2 genes. Deciphering the role of the recently discovered MD-associated lncRNA-9802/miR-1646 axis provides valuable theoretical basis for decoding the molecular mechanisms underlying MDV pathogenesis.

Identification of potential key genes of TGF-beta signaling associated with the immune response and prognosis of ovarian cancer based on bioinformatics analysis.

Background: TGF-beta signaling is a key regulator of immunity and multiple cellular behaviors in cancer. However, the prognostic and therapeutic role of TGF-beta signaling-related genes in ovarian cancer (OV) remains unexplored. Methods: Data of OV used in the current study were sourced from TCGA and GEO databases. Consensus clustering was applied to classify OV patients into different clusters using TGF-beta signaling-related genes. Differentially expressed genes (DEGs) between different clusters were screened by the "limma" R package. Prognostic genes were screened from DEGs by univariate Cox regression, followed by the construction of the TGF-beta signaling-related score. The prognostic value of TGF-beta signaling-related score was evaluated in both training and testing OV cohorts. Moreover, the immune status, GSEA and therapeutic response between low- and high-score groups were performed to further reveal the potential mechanisms. Results: By consensus clustering, OV patients were classified into two clusters with different tumor immune environments. After differential expression and univariate Cox regression analyses, GMPR, PIEZO1, EMP1, CXCL13, GADD45B, SORCS2, FOSL2, PODN, LYNX1 and SLC38A5 were selected as prognostic genes. Using PCA algorithm, the TGF-beta signaling-related score of OV patients was calculated based on prognostic genes. Then OV patients were divided into low- and high-TGF-beta signaling-related score groups. We observed that the two score groups had significantly different survivals, tumor immune environments and expressions of immune checkpoints. In addition, GSEA results showed that immune-related pathways and biological processes, like chemokine signaling pathway, TNF signaling pathway and T cell migration were significantly enriched in the low-score group. Moreover, patients in the low- and high-score groups had remarkably different sensitivity to chemo- and immunotherapy. Conclusion: For the first time, our study identified ten prognostic genes associated with TGF-beta signaling, constructed a prognostic TGF-beta signaling-related score and investigated the effect of TGF-beta signaling-related score on OV immunity and therapy. These findings may enrich our knowledge of the TGF-beta signaling in OV prognosis and help to improve the prognosis prediction and treatment strategies in OV.

Distinguishable Influence of the Delivery Mode, Feeding Pattern, and Infant Sex on Dynamic Alterations in the Intestinal Microbiota in the First Year of Life.

The delivery mode, the feeding pattern and infant sex significantly influence the development of the infant gut flora. However, the extent to which these factors contribute to the establishment of the gut microbiota at different stages has rarely been studied. The factors that play a dominant role in determining microbial colonization of the infant gut at specific time points are unknown. The purpose of this study was to assess the different contributions of the delivery mode, the feeding pattern and infant sex to the composition of the infant gut microbiome. Here, 213 fecal samples from 55 infants at five ages (0, 1, 3, 6, and 12 months postpartum) were collected, and the composition of the gut microbiota via 16S rRNA sequencing was analyzed. The results showed that the average relative abundances of four genera, Bifidobacterium, Bacteroides, Parabacteroides, and Phascolarctobacterium, were increased in vaginally delivered infants versus cesarean section-delivered infants, while those of ten genera, such as Salmonella and Enterobacter, were reduced. The relative proportions of Anaerococcus and Peptostreptococcaceae were higher in exclusive breastfeeding than in combined feeding, while those of Coriobacteriaceae, Lachnospiraceae and Erysipelotrichaceae were lower. The average relative abundances of two genera, Alistipes and Anaeroglobus, were increased in male infants compared with female infants, whereas those of the phyla Firmicutes and Proteobacteria were reduced. During the first year of life, the average UniFrac distances revealed that the individual difference in the gut microbial composition in vaginally delivered infants was greater than that in cesarean section-delivered infants (P < 0.001) and that infants who received combined feeding had greater individual microbiota differences than exclusively breastfed infants (P < 0.01). The delivery mode, infant sex, and the feeding pattern were the dominant factors determining colonization of the infant gut microbiota at 0 months, from 1 to 6 months, and at 12 months postpartum, respectively. This study demonstrated for the first time that infant sex accounted for the dominant contribution to infant gut microbial development from 1 to 6 months postpartum. More broadly, this study effectively established the extent to which the delivery mode, the feeding pattern and infant sex contribute to the development of the gut microbiota at various time points during the first year of life.

Weierning, a Chinese patent medicine, improves chronic atrophic gastritis with intestinal metaplasia.

ETHNOPHARMACOLOGICAL RELEVANCE: Weierning tablet (WEN) is a traditional Chinese patent medicine widely used in clinical for chronic atrophic gastritis (CAG) therapy for years. However, the underlying mechanisms of WEN on anti-CAG are still unveiled. AIM OF THE STUDY: The present study aimed to elucidate the characteristic function of WEN on anti-CAG and to illuminate its potential mechanism. METHODS: The CAG model was established by gavage rats with a modeling solution (consisting of 2% sodium salicylate and 30% alcohol) with irregular diets and free access to 0.1% ammonia solution for two months on end. An enzyme-linked immunosorbent assay was used to measure the serum levels of gastrin, pepsinogen, and inflammatory cytokines. qRT-PCR was applied to measure mRNA expressions of IL-6, IL-18, IL-10, TNF-α, and γ-IFN in gastric tissue. Pathological changes and the ultrastructure of gastric mucosa were examined by hematoxylin and eosin staining and transmission electron microscopy, respectively. AB-PAS staining was applied to observe the intestinal metaplasia of gastric mucosa. Immunohistochemistry and Western blot were used to measure the expression levels of mitochondria apoptosis-related proteins and Hedgehog pathway-related proteins in gastric tissues. Expressions of Cdx2 and Muc2 protein were determined by immunofluorescent staining. RESULTS: WEN could dose-dependently lower the serum level of IL-1ß and the mRNA expressions of IL-6, IL-8, IL-10, TNF-α, and γ-IFN in gastric tissue. Also, WEN significantly alleviated the collagen deposition in gastric submucosa, regulated the expressions of Bax, Cleaved-caspase9, Bcl2, and Cytochrome c to reduce the apoptosis of gastric mucosa epithelial cells, and maintained the integrity of the gastric mucosal barrier. Moreover, WEN could reduce protein expressions of Cdx2, Muc2, Shh, Gli1, and Smo, and reverse intestinal metaplasia of gastric mucosa to block the progress of CAG. CONCLUSION: This study demonstrated a positive effect of WEN on improving CAG and reverse intestinal metaplasia. These functions were related to the suppression of gastric mucosal cells' apoptosis and the inhibition of Hedgehog pathways' activation.

Excess visceral fat area as an independent risk factor for early postoperative complications in patients with obesity undergoing bariatric surgery.

Background: Few studies have investigated the correlation between visceral fat area (VFA) and early postoperative complications in patients with obesity undergoing bariatric surgery. This study aimed to investigate the relationship between VFA and early postoperative complications in patients with obesity following bariatric surgery. Methods: The study was conducted at a tertiary university hospital. Patients with obesity who underwent laparoscopic sleeve gastrectomy between June 2016 and October 2020 were divided into two groups based on umbilical level VFA: high-VFA group (umbilical level VFA ≥ 100 cm2) and low-VFA group (umbilical level VFA < 100 cm2). Baseline characteristics, intraoperative and postoperative conditions, and early postoperative complications were compared between the groups. The primary outcome was early postoperative complications, and the secondary outcome was postoperative hospital stay. Results: The study included 152 patients, with 82 patients in the low-VFA group and 70 patients in the high-VFA group. The high-VFA group had a higher incidence of early postoperative complications (14.29% vs. 2.44%, P = 0.013) than the low-VFA group. The length of postoperative hospital stay did not differ significantly between the groups. Conclusions: Our study suggests that excess VFA is an independent risk factor for early postoperative complications following bariatric surgery, and VFA may be used in preoperative evaluations.

Relationship between Information Scrambling and Quantum Darwinism.

A quantum system interacting with a multipartite environment can induce redundant encoding of the information of a system into the environment, which is the essence of quantum Darwinism. At the same time, the environment may scramble the initially localized information about the system. Based on a collision model, we mainly investigate the relationship between information scrambling in an environment and the emergence of quantum Darwinism. Our results show that when the mutual information between the system and environmental fragment is a linear increasing function of the fragment size, the tripartite mutual information (TMI) is zero, which can be proved generally beyond the collision model; when the system exhibits Darwinistic behavior, the TMI is positive (i.e., scrambling does not occur); when we see the behavior of an "encoding" environment, the TMI is negative (i.e., scrambling occurs). Additionally, we give a physical explanation for the above results by considering two simple but illustrative examples. Moreover, depending on the nature of system and environment interactions, it is also shown that the single qubit and two-qubit systems behave differently for the emergence of quantum Darwinism, and hence the scrambling, while their relationship is consistent with the above conclusion.

Identification of prognostic miRNA-mRNA regulatory network in the progression of HCV-associated cirrhosis to hepatocellular carcinoma.

Background: Long-term hepatitis C virus (HCV) infection is strongly associated with hepatocellular carcinoma (HCC), yet the mechanisms of the progression process remain unclear. The research is aiming to establish a crucial prognostic model that indicates the risk of HCV-associated cirrhosis evolving into HCC. Methods: Differentially expressed microRNAs (DE-miRNAs) and differentially expressed genes (DEGs) between HCV-associated cirrhosis and HCC were screened from the GSE40744 and GSE6764 datasets, respectively. Downstream target genes of DE-miRNAs were predicted by the miRNet tool and then overlapped with the DEGs to select intersection genes. The GSE15654 was downloaded to establish a prognostic model. Expression levels of risk genes and their corresponding miRNAs were measured in liver tissues of clinical patients. HCC cell lines with UHRF1 knockdown or overexpression were assayed for cell proliferation and migration. Results: Thirty-nine DE-miRNAs and 796 DEGs are identified between HCV-associated cirrhosis and HCC. Main intersection genes and their corresponding miRNAs constitute a miRNA-mRNA regulatory network. PABPC1 (Polyadenylate-binding protein 1), SLC2A9 (solute carrier gene family 2, member 9), and UHRF1 (ubiquitin-like with PHD and ring finger domains 1) form a prognostic model indicating the risk of HCC development among HCV-associated cirrhosis. The genetic mutations of PABPC1, SLC2A9, and UHRF1 in HCC patients are 9%, 0.8%, and 0.6%, respectively. Compared to that in HCV-associated cirrhosis, the expression levels of PABPC1 and UHRF1 are higher while the expression level of SLC2A9 is lower in clinical HCV-associated HCC samples. UHRF1 enhances the proliferation and migration ability of HCC cells. Conclusions: PABPC1, SLC2A9, and UHRF1 and their corresponding miRNAs are involved in the evolution process of HCV-associated cirrhosis into malignant HCC. UHRF1 serves as an oncogene that promotes the proliferation and migration of HCC cells.

Quantum Information Scrambling in Non-Markovian Open Quantum System.

In this paper, we investigate the dynamics of a spin chain whose two end spins interact with two independent non-Markovian baths by using the non-Markovian quantum state diffusion (QSD) equation approach. Specifically, two issues about information scrambling in an open quantum system are addressed. The first issue is that tripartite mutual information (TMI) can quantify information scrambling properly via its negative value in a closed system, whether it is still suitable to indicate information scrambling in an open quantum system. We find that negative TMI is not a suitable quantifier of information scrambling in an open quantum system in some cases, while negative tripartite logarithmic negativity (TLN) is an appropriate one. The second one is that up to now almost all information scrambling in open quantum systems reported were focus on a Markovian environment, while the effect of a non-Markovian environment on information scrambling is still elusive. Our results show that the memory effect of an environment will be beneficial to information scrambling. Moreover, it is found that the environment is generally detrimental for information scrambling in the long-term, while in some cases it will be helpful for information scrambling in the short-term.

Thermal Degradation and Product Analysis of 3-iodo-2-propyl-butylcarbamate as a Wood Preservative.

The thermal degradation kinetics and degradation products of IPBC during the heating process are investigated herein. Experiments were conducted at isothermal conditions from 60 °C to 150 °C. The remaining IPBC content was analyzed by high-performance liquid chromatography (HPLC) at specific time intervals for each test, and the kinetic model of IPBC thermal degradation was established. The thermal degradation products of IPBC were studied by ultra-performance liquid chromatography-mass spectrometry (UPLC-MS/MS). The results showed that thermal degradation of IPBC occurred at 70 °C, and the degradation rate increased significantly from 70 °C to 150 °C. The thermal degradation kinetics of IPBC conformed to the first-order reaction and k=3.47×1012e-111125/RT from 60 °C to 150 °C. Seven degradation products such as prop-2-yn-1-yl ethylcarbamate and methyl N-butylcarbamate were identified and the degradation reaction pathway and the mechanism of IPBC were proposed, which involved deiodination, demethylation, deethynylation, deethylation, and hydroxylation processes.

BCAP31 is involved in modulating colorectal cancer cell proliferation via the Emerin/ß-catenin axis.

Understanding the mechanisms of colorectal cancer (CRC) progression is critical for developing innovative treatment strategies. As an endoplasmic reticulum-located protein, B cell receptor-associated protein 31 (BCAP31) has been identified to be highly expressed in multiple cancers. However, its function and molecular mechanism in CRC remain not fully understood. In the present study, BCAP31 expression and its correlation with the clinical stage were analyzed based on TCGA database. We demonstrated that loss of BCAP31 suppressed CRC cell proliferation in vitro and tumor growth in vivo. Mechanistically, we demonstrated that Emerin was an interaction partner and downstream molecule of BCAP31. Knockdown of BCAP31 promoted the nuclear envelope localization of Emerin, leading to a reduction of ß-catenin accumulation in the nucleus, which resulted in downregulation of Wnt/ß-catenin downstream target genes, including c-Myc, cyclin D1, Survivin, and Mcl-1. Moreover, downregulation of Emerin partially restored the BCAP31 depletion-mediated ß-catenin protein level and tumor suppressive effects in CRC cells.Our data highlights the pivotal role of BCAP31 depletion in inhibiting cell proliferation in CRC cells, and mechanistically via Emerin/ß-catenin signaling, which may serve as a promising target for CRC treatment.

TRX2/Rab35 Interaction Impairs Exosome Secretion by Inducing Rab35 Degradation.

Given that exosomes mediate intercellular communication by delivering cellular components to recipient cells or tissue, they have the potential to be engineered to deliver therapeutic payloads. However, the regulatory mechanism of exosome secretion is poorly understood. In addition, mitochondrial components have been found in exosomes, suggesting communication between mitochondria and exosomes. However, the molecular mechanism of the mitochondria and vesicle interaction remains unclear. Here, we showed that mitochondrial thioredoxin 2 (TRX2) decreased exosome concentrations and inhibited HCT116 cell migration. Coimmunoprecipitation/mass spectrometry (Co-IP/MS) showed that TRX2 interacted with Rab35. TRX2 and Rab35 bound to each other at their N-terminal motifs and colocalized on mitochondria. Furthermore, TRX2 induced Rab35 degradation, resulting in impaired exosome secretion. Additionally, Rab35 mediated the suppressive effects of TRX2 on cell migration, and TRX2 suppressed cell migration through exosomes. Taken together, this study first found an interaction between TRX2 and Rab35. These results revealed a new role for TRX2 in the regulation of exosome secretion and cell migration and explained the upstream regulatory mechanism of Rab35. Furthermore, these findings also provide new molecular evidence for communication between mitochondria and vesicles.

SND1 acts as a functional target of miR-330-5p involved in modulating the proliferation, apoptosis and invasion of colorectal cancer cells.

MicroRNAs (miRNAs) play a crucial role in cancer progression due to their capability to modulate the expression of various target genes. However, given the heterogeneity of tumor cells, miRNAs have been confirmed to exert different regulatory effects. Here, bioinformatic analysis results indicated that expression of miR-330-5p is decreased in colorectal cancer (CRC) tissues and inversely correlated with SND1 expression. Notably, ectopic expression of miR-330-5p restrained tumor cell proliferation, migration, and enhance the sensitivity of CRC cells to 5-FU. Moreover, similar phenotypes were substantiated after inhibition of SND1 expression using RNA interference. Conversely, overexpression of SND1 facilitated the malignant phenotypes of CRC cells and restored miR-330-5p-mediated tumor-suppressive activities in CRC cells. Mechanistically, miR-330-5p directly binds to SND1-3'-untranslated region (3'-UTR), thus involving in inhibiting CRC cells proliferation and invasion and promoting apoptosis. Taken together, miR-330-5p may act as a tumor suppressor by targeting the expression of SND1, suggesting that the miR-330-5p/SND1 axis may be a meaningful regulator for CRC intervention.

Pre-Administration of Berberine Exerts Chemopreventive Effects in AOM/DSS-Induced Colitis-Associated Carcinogenesis Mice via Modulating Inflammation and Intestinal Microbiota.

Inflammatory activation and intestinal flora imbalance play an essential role in the development and progression of colorectal cancer (CRC). Berberine (BBR) has attracted great attention in recent years due to its heath-related benefits in inflammatory disorders and tumors, but the intricate mechanisms have not been fully elucidated. In this study, the effects and the mechanism of BBR on colon cancer were investigated in an azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colitis-associated carcinogenesis mice model. Our results showed that pre-administration of BBR showed a decrease in weight loss, disease activity index (DAI) score, and the number of colon tumors in mice, compared with the model group. The evidence from pathological examination indicated that the malignancy of intestinal tumors was ameliorated after pre-administration of BBR. Additionally, pre-administration with BBR suppressed the expression of pro-inflammatory factors (interleukin (IL)-6, IL-1ß, cyclooxygenase (COX)-2 and tumor necrosis factor (TNF)-α) and the cell-proliferation marker Ki67, while expression of the tight junction proteins (ZO-1 and occludin) were increased in colon tissue. Moreover, the levels of critical pathway proteins involved in the inflammatory process (p-STAT3 and p-JNK) and cell cycle regulation molecules (ß-catenin, c-Myc and CylinD1) exhibited lower expression levels. Besides, 16S rRNA sequence analysis indicated that pre-administration of BBR increased the ratio of Firmicutes/Bacteroidetes (F:M) and the relative abundance of potentially beneficial bacteria, while the abundance of cancer-related bacteria was decreased. Gavage with Lactobacillus rhamnosus can improve the anti-tumor effect of BBR. Overall, pre-administration of BBR exerts preventive effects in colon carcinogenesis, and the mechanisms underlying these effects are correlated with the inhibition of inflammation and tumor proliferation and the maintenance of intestinal homeostasis.