Post-stroke cognitive impairment: exploring molecular mechanisms and omics biomarkers for early identification and intervention.

Post-stroke cognitive impairment (PSCI) is a major stroke consequence that has a severe impact on patients' quality of life and survival rate. For this reason, it is especially crucial to identify and intervene early in high-risk groups during the acute phase of stroke. Currently, there are no reliable and efficient techniques for the early diagnosis, appropriate evaluation, or prognostication of PSCI. Instead, plenty of biomarkers in stroke patients have progressively been linked to cognitive impairment in recent years. High-throughput omics techniques that generate large amounts of data and process it to a high quality have been used to screen and identify biomarkers of PSCI in order to investigate the molecular mechanisms of the disease. These techniques include metabolomics, which explores dynamic changes in the organism, gut microbiomics, which studies host-microbe interactions, genomics, which elucidates deeper disease mechanisms, transcriptomics and proteomics, which describe gene expression and regulation. We looked through electronic databases like PubMed, the Cochrane Library, Embase, Web of Science, and common databases for each omics to find biomarkers that might be connected to the pathophysiology of PSCI. As all, we found 34 studies: 14 in the field of metabolomics, 5 in the field of gut microbiomics, 5 in the field of genomics, 4 in the field of transcriptomics, and 7 in the field of proteomics. We discovered that neuroinflammation, oxidative stress, and atherosclerosis may be the primary causes of PSCI development, and that metabolomics may play a role in the molecular mechanisms of PSCI. In this study, we summarized the existing issues across omics technologies and discuss the latest discoveries of PSCI biomarkers in the context of omics, with the goal of investigating the molecular causes of post-stroke cognitive impairment. We also discuss the potential therapeutic utility of omics platforms for PSCI mechanisms, diagnosis, and intervention in order to promote the area's advancement towards precision PSCI treatment.

Extrachromosomal circular DNA (eccDNA) characteristics in the bile and plasma of advanced perihilar cholangiocarcinoma patients and the construction of an eccDNA-related gene prognosis model.

Extrachromosomal DNAs (eccDNAs) frequently carry amplified oncogenes. This investigation aimed to examine the occurrence and role of eccDNAs in individuals diagnosed with advanced perihilar cholangiocarcinoma (pCCA) who exhibited distinct prognostic outcomes. Five patients with poor survival outcomes and five with better outcomes were selected among patients who received first-line hepatic arterial infusion chemotherapy from June 2021 to June 2022. The extracted eccDNAs were amplified for high-throughput sequencing. Genes associated with the differentially expressed eccDNAs were analyzed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. The differentially expressed bile eccDNA-related genes were used to construct a prognostic model. Across all 10 patients, a total of 19,024 and 3,048 eccDNAs were identified in bile and plasma, respectively. The concentration of eccDNA detected in the bile was 9-fold higher than that in plasma. The chromosome distribution of the eccDNAs were similar between bile and matched plasma. GO and KEGG pathway analyses showed enrichment in the mitogen-activated protein kinase (MAPK) and Wnt/ß-catenin pathways in patients with poor survival outcomes. According to the prognostic model constructed by eccDNA-related genes, the high-risk group of cholangiocarcinoma patients displayed significantly shorter overall survival (p < 0.001). Moreover, the degree of infiltration of immunosuppressive cells was higher in patients in the high-risk group. In conclusion, EccDNA could be detected in bile and plasma of pCCA patients, with a higher concentration. A prognostic model based on eccDNA-related genes showed the potential to predict the survival and immune microenvironment of patients with cholangiocarcinoma.

Unique features of conventional and nonconventional introns in Euglena gracilis.

BACKGROUND: Nuclear introns in Euglenida have been understudied. This study aimed to investigate nuclear introns in Euglenida by identifying a large number of introns in Euglena gracilis (E. gracilis), including cis-spliced conventional and nonconventional introns, as well as trans-spliced outrons. We also examined the sequence characteristics of these introns. RESULTS: A total of 28,337 introns and 11,921 outrons were identified. Conventional and nonconventional introns have distinct splice site features; the former harbour canonical GT/C-AG splice sites, whereas the latter are capable of forming structured motifs with their terminal sequences. We observed that short introns had a preference for canonical GT-AG introns. Notably, conventional introns and outrons in E. gracilis exhibited a distinct cytidine-rich polypyrimidine tract, in contrast to the thymidine-rich tracts observed in other organisms. Furthermore, the SL-RNAs in E. gracilis, as well as in other trans-splicing species, can form a recently discovered motif called the extended U6/5' ss duplex with the respective U6s. We also describe a novel type of alternative splicing pattern in E. gracilis. The tandem repeat sequences of introns in this protist were determined, and their contents were comparable to those in humans. CONCLUSIONS: Our findings highlight the unique features of E. gracilis introns and provide insights into the splicing mechanism of these introns, as well as the genomics and evolution of Euglenida.

DeTAL: Open-Vocabulary Temporal Action Localization with Decoupled Networks.

Pre-trained visual-language (ViL) models have demonstrated good zero-shot capability in video understanding tasks, where they were usually adapted through fine-tuning or temporal modeling. However, in the task of open-vocabulary temporal action localization (OV-TAL), such adaption reduces the robustness of ViL models against different data distributions, leading to a misalignment between visual representations and text descriptions of unseen action categories. As a result, existing methods often strike a trade-off between action detection and classification. Aiming at this issue, this paper proposes DeTAL, a simple but effective two-stage approach for OV-TAL. DeTAL decouples action detection from action classification to avoid the compromise between them, and the state-of-the-art methods for close-set action localization can be handily adapted to OV-TAL, which significantly improves the performance. Meanwhile, DeTAL can easily tackle the scenario where action category annotations are unavailable in the training dataset. In the experiments, we propose a new cross-dataset setting to evaluate the zero-shot capability of different methods. And the results demonstrate that DeTAL outperforms the state-of-the-art methods for OV-TAL on both THUMOS14 and ActivityNet1.3. Code and data are publicly available at https://github.com/vsislab/DeTAL.

Recent advances of fermented fruits: A review on strains, fermentation strategies, and functional activities.

Fruits are recognized as healthy foods with abundant nutritional content. However, due to their high content of sugar and water, they are easily contaminated by microorganisms leading to spoilage. Probiotic fermentation is an effective method to prevent fruit spoilage. In addition, during fermentation, the probiotics can react with the nutrients in fruits to produce new derived compounds, giving the fruit specific flavor, enhanced color, active ingredients, and nutritional values. Noteworthy, the choice of fermentation strains and strategies has a significant impact on the quality of fermented fruits. Thus, this review provides comprehensive information on the fermentation strains (especially yeast, lactic acid bacteria, and acetic acid bacteria), fermentation strategies (natural or inoculation fermentation, mono- or mixed-strain inoculation fermentation, and liquid- or solid-state fermentation), and the effect of fermentation on the shelf life, flavor, color, functional components, and physiological activities of fruits. This review will provide a theoretical guidance for the production of fermented fruits.

Detection of circulating tumor DNA in plasma of patients with primary CNS lymphoma by digital droplet PCR.

BACKGROUND: Primary central nervous system lymphoma (PCNSL) are rare mature B-cell lymphoproliferative diseases characterized by a high incidence of MYD88 L265P and CD79B Y196 hotspot mutations. Diagnosis of PCNSL can be challenging. The aim of the study was to analyze the detection rate of the MYD88 L265P and CD79B Y196 mutation in cell free DNA (cfDNA) in plasma of patients with PCNSL. METHODS: We analyzed by digital droplet PCR (ddPCR) to determine presence of the MYD88 L265P and CD79B Y196 hotspot mutations in cfDNA isolated from plasma of 24 PCNSL patients with active disease. Corresponding tumor samples were available for 14 cases. Based on the false positive rate observed in 8 healthy control samples, a stringent cut-off for the MYD88 L265P and CD79B Y196 mutation were set at 0.3% and 0.5%, respectively. RESULTS: MYD88 L265P and CD79B Y196 mutations were detected in 9/14 (64%) and 2/13 (15%) tumor biopsies, respectively. In cfDNA samples, the MYD88 L265P mutation was detected in 3/24 (12.5%), while the CD79B Y196 mutation was not detected in any of the 23 tested cfDNA samples. Overall, MYD88 L265P and/or CD79B Y196 were detected in cfDNA in 3/24 cases (12.5%). The detection rate of the combined analysis did not improve the single detection rate for either MYD88 L265P or CD79B Y196. CONCLUSION: The low detection rate of MYD88 L265P and CD79B Y196 mutations in cfDNA in the plasma of PCNSL patients argues against its use in routine diagnostics. However, detection of MYD88 L265P by ddPCR in cfDNA in the plasma could be considered in challenging cases.

Inhibition of GLUD1 mediated by LASP1 and SYVN1 contributes to hepatitis B virus X protein-induced hepatocarcinogenesis.

Glutamate dehydrogenase 1 (GLUD1) is implicated in oncogenesis. However, little is known about the relationship between GLUD1 and hepatocellular carcinoma (HCC). In the present study, we demonstrated that the expression levels of GLUD1 significantly decreased in tumors, which was relevant to the poor prognosis of HCC. Functionally, GLUD1 silencing enhanced the growth and migration of HCC cells. Mechanistically, the upregulation of interleukin-32 through AKT activation contributes to GLUD1 silencing-facilitated hepatocarcinogenesis. The interaction between GLUD1 and AKT, as well as α-ketoglutarate regulated by GLUD1, can suppress AKT activation. In addition, LIM and SH3 protein 1 (LASP1) interacts with GLUD1 and induces GLUD1 degradation via the ubiquitin-proteasome pathway, which relies on the E3 ubiquitin ligase synoviolin (SYVN1), whose interaction with GLUD1 is enhanced by LASP1. In hepatitis B virus (HBV)-related HCC, the HBV X protein (HBX) can suppress GLUD1 with the participation of LASP1 and SYVN1. Collectively, our data suggest that GLUD1 silencing is significantly associated with HCC development, and LASP1 and SYVN1 mediate the inhibition of GLUD1 in HCC, especially in HBV-related tumors.

NLCECA score: a serum inflammatory-tumor biomarker score to predict survival of advanced perihilar cholangiocarcinoma after hepatic arterial infusion chemotherapy.

Prognostic features in advanced perihilar cholangiocarcinoma (pCCA) patients who received first-line hepatic arterial infusion chemotherapy (HAIC) are unknown. The purpose of our study was to develop an applicable score based on serum inflammatory-tumor biomarkers to predict the survival of advanced pCCA patients who received first-line HAIC. In total, 106 advanced pCCA patients were enrolled as the training cohort. The optimal cutoff values of baseline variables were defined by the receiver operating characteristic method or according to previous publications. According to the results of Cox regression analysis, baseline neutrophil-to-lymphocyte ratio (NLR) > 3.19, carcinoembryonic antigen (CEA) > 10 ng/mL, and carbohydrate antigen 19-9 (CA19-9) > 200 U/mL were identified as independent survival predictors, which were used to develop the NLCECA score (NLR, CEA, and CA19-9). When including the NLCECA score in the multivariate analysis, the NLCECA score was the only independent predictor of survival. The risk of survival decreased by 111.9% for each 1-point increase in the NLCECA score. Additionally, the NLCECA score could also predict survival in another 33 patients in the validation cohort (P < 0.001). In summary, the NLCECA score is a potential biomarker system for predicting the survival of advanced pCCA patients who received first-line HAIC.

Passive trapping of biomolecules in hotspots with all-dielectric terahertz metamaterials.

Electromagnetic metamaterials feature the capability of squeezing photons into hotspot regions of high intensity near-field enhancement for strong light-matter interaction, underpinning the next generation of emerging biosensors. However, randomly dispersed biomolecules around the hotspots lead to weak interactions. Here, we demonstrate an all-silicon dielectric terahertz metamaterial sensor design capable of passively trapping biomoleculars into the resonant cavities confined with powerful electric field. Specifically, multiple controllable high-quality factor resonances driven by bound states in the continuum (BIC) are realized by employing longitudinal symmetry breaking. The dielectric metamaterial sensor with nearly 15.2 experimental figure-of-merit enabling qualitative and quantitative identification of different amino acids by delivering biomolecules to the hotspots for strong light-matter interactions. It is envisioned that the presented strategy will enlighten high-performance meta-sensors design from microwaves to visible frequencies, and serve as a potential platform for microfluidic sensing, biomolecular capture, and sorting devices.

Effect of Reduced Graphene Oxide on Microwave Absorbing Properties of Al1.5Co4Fe2Cr High-Entropy Alloys.

The microwave absorption performance of high-entropy alloys (HEAs) can be improved by reducing the reflection coefficient of electromagnetic waves and broadening the absorption frequency band. The present work prepared flaky irregular-shaped Al1.5Co4Fe2Cr and Al1.5Co4Fe2Cr@rGO alloy powders by mechanical alloying (MA) at different rotational speeds. It was found that the addition of trace amounts of reduced graphene oxide (rGO) had a favorable effect on the impedance matching, reflection loss (RL), and effective absorbing bandwidth (EAB) of the Al1.5Co4Fe2Cr@rGO HEA composite powders. The EAB of the alloy powders prepared at 300 rpm increased from 2.58 GHz to 4.62 GHz with the additive, and the RL increased by 2.56 dB. The results showed that the presence of rGO modified the complex dielectric constant of HEA powders, thereby enhancing their dielectric loss capability. Additionally, the presence of lamellar rGO intensified the interfacial reflections within the absorber, facilitating the dissipation of electromagnetic waves. The effect of the ball milling speed on the defect concentration of the alloy powders also affected its wave absorption performance. The samples prepared at 350 rpm had the best wave absorption performance, with an RL of -16.23 and -17.28 dB for a thickness of 1.6 mm and EAB of 5.77 GHz and 5.43 GHz, respectively.

An ultra-broadband frequency-agile terahertz perfect absorber with perturbed MoS2 plasmon modes.

Multidomain dynamic manipulations for terahertz (THz) absorbers usually necessitate the orchestrated actions of several active elements, inevitably complicating the structural design and elongating the modulation time. Herein, we utilize the coupling between the total reflection prism and electrically-driven MoS2 to activate a tight field confinement in a deep-subwavelength interlayer, ultimately achieving frequency-agile absorption adjustments only with a gate voltage. Theoretical and simulation analysis results indicate that the redistributed electric field and susceptible dielectric response are attributed to the limited spatial near-field perturbation of surface plasmon resonances. We also demonstrate that perturbed MoS2 plasmon modes promote the formation of dual-phase singularities, significantly suppressing the attenuation of the absorption amplitude as large-scale frequency shifts, thereby extending the relative tuning range (WRTR) to 175.4%. These findings offer an efficient approach for expanding the horizon of THz absorption applications that require ultra-broadband and swift-response capabilities.

Pathogens in PICU before and during the SARS-CoV-2 pandemic in China: a multicenter retrospective study.

BACKGROUND: Nonpharmacological interventions for COVID-19 could reduce the incidence of children hospitalized in pediatric intensive care units (PICU) and the incidence of children with bacterial infections. This study aimed to evaluate changes in the bacterial profile of children in PICU before and during the COVID-19 pandemics. METHODS: This is a retrospective study, involving clinical data of children with positive bacterial cultures admitted to the PICU respectively in 2019 and 2021. RESULTS: In total 652 children were included in this study. The total number of hospitalized patients and the incidence of bacteria-positive children in 2021 were lower than those in 2019. There were no significant differences in the ratio of Gram-positive bacterial infection, Gram-negative bacteria infection or fungi infection between the two years. The rate of Streptococcus pneumoniae in 2021 was higher than that in 2019(p = 0.127). The incidence of Haemophilus influenzae in hospitalized patients decreased with a downward trend(p = 0.002). The distribution of previous underlying diseases in children admitted to PICU with different outcomes of bacterial infection between the two years were homogeneous (p > 0.05). CONCLUSION: After the implementation of COVID-19 isolation, prevention and control measures, the number of hospitalizations and bacterial infections in PICU decreased, which may be due to changes in population's behavior patterns. Meanwhile, the incidence of Haemophilus influenzae in hospitalized patients decreased with a downward trend.

Hepatitis B virus core protein stabilizes RANGAP1 to upregulate KDM2A and facilitate hepatocarcinogenesis.

PURPOSE: As a vital component of the hepatitis B virus (HBV) nucleocapsid, HBV core protein (HBC) contributes to hepatocarcinogenesis. Here, we aimed to assess the effects of RANGAP1 and KDM2A on tumorigenesis induced by HBC. METHODS: Co-immunoprecipitation (Co-IP) combined with mass spectrometry were utilized to identify the proteins with the capacity to interact with HBC. The gene and protein levels of RANGAP1 and KDM2A in hepatocellular carcinoma (HCC) and HBV-positive HCC tissues were evaluated using different cohorts. The roles of RANGAP1 and KDM2A in HCC cells mediated by HBC were investigated in vitro and in vivo. Co-IP and western blot were used to estimate the interaction of HBC with RANGAP1 and KDM2A and assess RANGAP1 stabilization regulated by HBC. RESULTS: We discovered that HBC could interact with RANGAP1 and KDM2A, the levels of which were markedly elevated in HCC tissues. Relying on RANGAP1 and KDM2A, HBC facilitated HCC cell growth and migration. The increased stabilization of RANGAP1 mediated by HBC was relevant to the disruption of the interaction between RANGAP1 and an E3 ligase SYVN1. RANGAP1 interacted with KDM2A, and it further promoted KDM2A stabilization by disturbing the interaction between KDM2A and SYVN1. HBC enhanced the interaction of KDM2A with RANGAP1 and upregulated the expression of KDM2A via RANGAP1 in HCC cells. CONCLUSIONS: These findings demonstrate a novel mechanism by which HBC facilitates hepatocarcinogenesis. RANGAP1 and KDM2A could act as potential molecular targets for treating HBV-associated malignancy.

A population-based study of transformed marginal zone lymphoma: identifying outcome-related characteristics.

Histological transformation of marginal zone lymphoma (tMZL) into diffuse large B-cell lymphoma is associated with poor outcomes. Clinical characteristics associated with transformation risk and outcome after transformation are largely unknown due to scarcity of data. In this population-based study, competing risk analyses were performed to elucidate clinical characteristics associated with developing transformation among 1793 MZL patients using the Netherlands Cancer Registry. Cox regression analyses were performed to elucidate clinical characteristics associated with risk of relapse and mortality after transformation. Transformation occurred in 75 (4%) out of 1793 MZL patients. Elevated LDH and nodal MZL subtype at MZL diagnosis were associated with an increased risk, and radiotherapy with a reduced risk of developing tMZL. Most tMZL patients received R-(mini)CHOP (n = 53, 71%). Age >60 years and (immuno)chemotherapy before transformation were associated with an increased risk of relapse and mortality after transformation. Two-year progression-free survival (PFS) and overall survival (OS) were 66% (95% CI 52-77%) and 75% (95% CI 62-85%) for R-(mini)CHOP-treated tMZL patients, as compared to a PFS and OS both of 41% (95% CI 19-63%) for patients treated otherwise. Our study offers comprehensive insights into characteristics associated with transformation and survival after transformation, thereby optimizing guidelines and patient counseling.

Genomic profiling of post-transplant lymphoproliferative disorders using cell-free DNA.

Diagnosing post-transplant lymphoproliferative disorder (PTLD) is challenging and often requires invasive procedures. Analyses of cell-free DNA (cfDNA) isolated from plasma is minimally invasive and highly effective for genomic profiling of tumors. We studied the feasibility of using cfDNA to profile PTLD and explore its potential to serve as a screening tool. We included seventeen patients with monomorphic PTLD after solid organ transplantation in this multi-center observational cohort study. We used low-coverage whole genome sequencing (lcWGS) to detect copy number variations (CNVs) and targeted next-generation sequencing (NGS) to identify Epstein-Barr virus (EBV) DNA load and somatic single nucleotide variants (SNVs) in cfDNA from plasma. Seven out of seventeen (41%) patients had EBV-positive tumors, and 13/17 (76%) had stage IV disease. Nine out of seventeen (56%) patients showed CNVs in cfDNA, with more CNVs in EBV-negative cases. Recurrent gains were detected for 3q, 11q, and 18q. Recurrent losses were observed at 6q. The fraction of EBV reads in cfDNA from EBV-positive patients was 3-log higher compared to controls and EBV-negative patients. 289 SNVs were identified, with a median of 19 per sample. SNV burden correlated significantly with lactate dehydrogenase levels. Similar SNV burdens were observed in EBV-negative and EBV-positive PTLD. The most commonly mutated genes were TP53 and KMT2D (41%), followed by SPEN, TET2 (35%), and ARID1A, IGLL5, and PIM1 (29%), indicating DNA damage response, epigenetic regulation, and B-cell signaling/NFkB pathways as drivers of PTLD. Overall, CNVs were more prevalent in EBV-negative lymphoma, while no difference was observed in the number of SNVs. Our data indicated the potential of analyzing cfDNA as a tool for PTLD screening and response monitoring.

Transcriptomic and genomic identification of spliceosomal genes from Euglena gracilis.

Diverse splicing types in nuclear and chloroplast genes of protist Euglena gracilis have been recognized for decades. However, the splicing machinery responsible for processing nuclear precursor messenger RNA introns, including trans-splicing of the 5' terminal outron and spliced leader (SL) RNA, remains elusive. Here, we identify 166 spliceosomal protein genes and two snRNA genes from E. gracilis by performing bioinformatics analysis from a combination of next-generation and full-length transcriptomic RNA sequencing (RNAseq) data as well as draft genomic data. With the spliceosomal proteins we identified in hand, the insensitivity of E. gracilis to some splicing modulators is revealed at the sequence level. The prevalence of SL RNA-mediated trans-splicing is estimated to be more than 70% from our full-length RNAseq data. Finally, the splicing proteomes between E. gracilis and its three evolutionary cousins within the same Excavata group are compared. In conclusion, our study characterizes the spliceosomal components in E. gracilis and provides the molecular basis for further exploration of underlying splicing mechanisms.

Diosgenin Targets CaMKK2 to Alleviate Type II Diabetic Nephropathy through Improving Autophagy, Mitophagy and Mitochondrial Dynamics.

Diabetic nephropathy (DN) is a worldwide health problem with increasing incidence. Diosgenin (DIO) is a natural active ingredient extracted from Chinese yams (Rhizoma dioscoreae) with potential antioxidant, anti-inflammatory, and antidiabetic effects. However, the protective effect of DIO on DN is still unclear. The present study explored the mitigating effects and underlying mechanisms of DIO on DN in vivo and in vitro. In the current study, the DN rats were induced by a high-fat diet and streptozotocin and then treated with DIO and metformin (Mef, a positive control) for 8 weeks. The high-glucose (HG)-induced HK-2 cells were treated with DIO for 24 h. The results showed that DIO decreased blood glucose, biomarkers of renal damage, and renal pathological changes with an effect comparable to that of Mef, indicating that DIO is potential active substance to relieve DN. Thus, the protective mechanism of DIO on DN was further explored. Mechanistically, DIO improved autophagy and mitophagy via the regulation of the AMPK-mTOR and PINK1-MFN2-Parkin pathways, respectively. Knockdown of CaMKK2 abolished AMPK-mTOR and PINK1-MFN2-Parkin pathways-mediated autophagy and mitophagy. Mitophagy and mitochondrial dynamics are closely linked physiological processes. DIO also improved mitochondrial dynamics through inhibiting fission-associated proteins (DRP1 and p-DRP1) and increasing fusion proteins (MFN1/2 and OPA1). The effects were abolished by CaMKK2 and PINK1 knockdown. In conclusion, DIO ameliorated DN by enhancing autophagy and mitophagy and by improving mitochondrial dynamics in a CaMKK2-dependent manner. PINK1 and MFN2 are proteins that concurrently regulated mitophagy and mitochondrial dynamics.

Analysis of secondary failure time responses in studies with response-dependent sampling schemes.

Response-dependent sampling is routinely used as an enrichment strategy in the design of family studies investigating the heritable nature of disease. In addition to the response of primary interest, investigators often wish to investigate the association between biomarkers and secondary responses related to possible comorbidities. Statistical analysis regarding genetic biomarkers and their association with the secondary outcome must address the biased sampling scheme involving the primary response. In this article, we develop composite likelihoods and two-stage estimation procedures for such secondary analyses in which the within-family dependence structure for the primary and secondary outcomes is modeled via a Gaussian copula. The dependence among responses within family members is modeled based on kinship coefficients. Auxiliary data from independent individuals are exploited by augmenting the composite likelihoods to increase precision of marginal parameter estimates and enhance the efficiency of estimators of the dependence parameters. Simulation studies are carried out to evaluate the finite sample performance of the proposed method, and an application to a motivating family study in psoriatic arthritis is given for illustration.

Diosgenin Inhibits ROS Generation by Modulating NOX4 and Mitochondrial Respiratory Chain and Suppresses Apoptosis in Diabetic Nephropathy.

Diosgenin (DIO) is a dietary steroid sapogenin possessing multiple biological functions, such as the amelioration of diabetes. However, the remission effect of DIO on diabetic nephropathy (DN) underlying oxidative stress and cell apoptosis remains unclear. Here, the effect of DIO on ROS generation and its induced cell apoptosis was studied in vitro and in vivo. Renal proximal tubular epithelial (HK-2) cells were treated with DIO (1, 2, 4 µM) under high glucose (HG, 30 mM) conditions. DN rats were induced by a high-fat diet combined with streptozotocin, followed by administration of DIO for 8 weeks. Our data suggested that DIO relieved the decline of HK-2 cell viability and renal pathological damage in DN rats. DIO also relieved ROS (O2- and H2O2) production. Mechanistically, DIO inhibited the expression of NOX4 and restored mitochondrial respiratory chain (MRC) complex I-V expressions. Further, DIO inhibited mitochondrial apoptosis by ameliorating mitochondrial membrane potential (MtMP) and down-regulating the expressions of CytC, Apaf-1, caspase 3, and caspase 9, while up-regulating Bcl2 expression. Moreover, the ER stress and its associated cell apoptosis were inhibited through decreasing PERK, p-PERK, ATF4, IRE1, p-CHOP, and caspase 12 expressions. Collectively, DIO inhibited ROS production by modulating NOX4 and MRC complexes, which then suppressed apoptosis regulated by mitochondria and ER stress, thereby attenuating DN.

The Protective Effect of Heat-Inactivated Companilactobacillus crustorum on Dextran Sulfate Sodium-Induced Ulcerative Colitis in Mice.

Heat-inactivated microorganisms are a typical class of postbiotics with promising potential health effects, as they contain various physiologically active components. Dietary supplementation with Companilactobacillus crustorum MN047 (CC) has been shown to have the potential to alleviate ulcerative colitis (UC). However, it is unclear whether the UC-relieving effect of this strain is partly attributed to its bacterial composition. Therefore, the interventional effects of heat-inactivated CC (HICC) on UC mice were explored. The results showed that the administration of HICC significantly ameliorated the UC-related pathological parameters by (1) alleviating the pathologic lesions of UC (e.g., preventing the increase in disease activity index and the shortening of colon length); (2) ameliorating the colonic inflammation (e.g., inhibiting the expressions of chemokines and pro-inflammatory cytokines, such as Cxcl1, Cxcl5, Ccl7, TNF-α, IL-1ß, IL-6, and MCP-1; (3) attenuating the oxidative damage (e.g., suppressing the increase in myeloperoxidase and malondialdehyde); (4) mitigating the damage of gut barrier (e.g., promoting colonic occludin, ZO-1, and claudin levels); and (5) modulating gut microbiota structure (e.g., increasing the relative abundance of potential probiotics, such as Akkermansia and Lactobacillus). In conclusion, our study suggested that HICC can be effective in preventing UC and has the potential as a dietary supplement to intervene in UC.