Interventional therapy combined with tyrosine kinase inhibitors with or without immune checkpoint inhibitors as initial treatment for hepatocellular carcinoma with portal vein tumor thrombosis: a systematic review and meta-analysis.

BACKGROUND: Interventional therapy, in conjunction with tyrosine kinase inhibitors (TKIs), has shown promising outcomes for treating hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT). With the advent of immunotherapy, the combined use of immune checkpoint inhibitors (ICIs) has attracted great attention due to their potential effectiveness in advanced HCC. This study aims to compare the efficacy and safety of a triple therapy regimen (Interventional therapy, TKIs and ICIs, IT-TKI-ICI) with a dual therapy regimen (Interventional therapy and TKIs, IT-TKI) in the treatment of HCC and PVTT (HCC-PVTT). METHODS: A comprehensive search was carried out in PubMed, Web of Science, Embase, Scopus, and the Cochrane Library databases. Primary outcome measures were overall survival (OS) and progression-free survival (PFS), while secondary outcomes included tumor response rate, adverse event incidence as well as downstaging surgery rate. Statistical analysis was conducted using Revman 5.4 software. RESULTS: The meta-analysis finally included 6 cohort studies. The triple therapy group demonstrated significantly prolonged OS and PFS compared to the dual therapy group. Meanwhile, the former exhibited significantly higher rates of objective response rate (ORR), disease control rate (DCR) and better downstaging effects with a higher salvage surgery rate without significantly increasing adverse events. CONCLUSION: In comparison to dual therapy, the triple therapy with interventional therapy, TKIs, and ICIs demonstrates superior efficacy and equivalent safety for HCC-PVTT.

Huaier Polysaccharide Alleviates Dextran Sulphate Sodium Salt-Induced Colitis by Inhibiting Inflammation and Oxidative Stress, Maintaining the Intestinal Barrier, and Modulating Gut Microbiota.

The incidence of ulcerative colitis (UC) is increasing annually, and UC has a serious impact on patients' lives. Polysaccharides have gained attention as potential drug candidates for treating ulcerative colitis (UC) in recent years. Huaier (Trametes robiniophila Murr) is a fungus that has been used clinically for more than 1000 years, and its bioactive polysaccharide components have been reported to possess immunomodulatory effects, antitumour potential, and renoprotective effects. In this study, we aimed to examine the protective effects and mechanisms of Huaier polysaccharide (HP) against UC. Based on the H2O2-induced oxidative stress model in HT-29 cells and the dextran sulphate sodium salt (DSS)-induced UC model, we demonstrated that Huaier polysaccharides significantly alleviated DSS-induced colitis (weight loss, elevated disease activity index (DAI) scores, and colonic shortening). In addition, HP inhibited oxidative stress and inflammation and alleviated DSS-induced intestinal barrier damage. It also significantly promoted the expression of the mucin Muc2. Furthermore, HP reduced the abundance of harmful bacteria Escherichia-Shigella and promoted the abundance of beneficial bacteria Muribaculaceae_unclassified, Anaerotruncus, and Ruminococcaceae_unclassified to regulate the intestinal flora disturbance caused by DSS. Nontargeted metabolomics revealed that HP intervention would modulate metabolism by promoting levels of 3-hydroxybutyric acid, phosphatidylcholine (PC), and phosphatidylethanolamine (PE). These results demonstrated that HP had the ability to mitigate DSS-induced UC by suppressing oxidative stress and inflammation, maintaining the intestinal barrier, and modulating the intestinal flora. These findings will expand our knowledge of how HP functions and offer a theoretical foundation for using HP as a potential prebiotic to prevent UC.

Pan-cancer analysis of Sushi domain-containing protein 4 (SUSD4) and validated in colorectal cancer.

Sushi domain-containing protein 4 (SUSD4) is a complement regulatory protein whose primary function is to inhibit the complement system, and it is involved in immune regulation. The role of SUSD4 in cancer progression has largely remained elusive. SUSD4 was studied across a variety of cancer types in this study. According to the results, there is an association between the expression level of SUSD4 and prognosis in multiple types of cancer. Further analysis demonstrated that SUSD4 expression level was related to immune cell infiltration, immune-related genes, tumor heterogeneity, and multiple cancer pathways. Additionally, we validated the function of SUSD4 in colorectal cancer cell lines and found that knockdown of SUSD4 inhibited cell growth and impacted the JAK/STAT pathway. By characterizing drug sensitivity in organoids, we found that the expression of SUSD4 showed a positive correlation trend with IC50 of Selumetinib, YK-4-279, and Piperlongumine. In conclusion, SUSD4 is a valuable prognostic indicator for diverse types of cancer, and it has the potential to be a target for cancer therapy.

Turtle peptide and its derivative peptide ameliorated DSS-induced ulcerative colitis by inhibiting inflammation and modulating the composition of the gut microbiota.

Ulcerative colitis (UC) is a recurrent intestinal disease with an increasing incidence worldwide that seriously affects the life of patients. Turtle peptide (TP) is a bioactive peptide extracted from turtles that has anti-inflammatory, antioxidant and anti-aging properties. However, studies investigating the effect of TP on the progression of UC are lacking. The aim of this study was to investigate effects and underlying mechanisms of TP and its derivative peptide GPAGPIGPV (GP-9) in alleviating UC in mice. The results showed that 500 mg/kg TP treatment significantly ameliorated colitis symptoms and oxidative stress in UC mice. TP alleviated intestinal barrier damage in UC mice by promoting mucosal repair and increasing the expression of tight junction proteins (ZO1, occludin and claudin-1). TP also modulated the composition of the gut microbiota by increasing the abundance of the beneficial bacteria Anaerotignum, Prevotellaceae_UCG-001, Alistipes, and Lachno-spiraceae_NK4A136_group and decreasing the abundance of the harmful bacteria Prevotella_9 and Parasutterella. Furthermore, we characterized the peptide composition of TP and found that GP-9 ameliorated the symptoms of dextran sodium sulfate (DSS)-induced colitis in mice by inhibiting the TLR4/NF-κB signaling pathway. In conclusion, TP and its derivative peptides ameliorated DSS-induced ulcerative colitis by inhibiting the expression of inflammatory factors and modulating the composition of the intestinal microbiota; this study provides a theoretical basis for the application of TP and its derivative peptides for their anti-inflammatory activity.

ALTA: a simple nutritional prognostic score for patients with hepatitis B virus-related acute-on-chronic liver failure.

Background: Malnutrition, despite being a common complication, is often neglected in patients with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF). The objective of this study was to develop a simplified nutritional prognostic score to accurately predict mortality in HBV-ACLF patients. Methods: In this multicenter retrospective study, clinical data from 530 HBV-ACLF patients were used to create a new prognostic score, which was then validated in two external cohorts (n = 229 and 248). Results: Four independent factors were significantly associated with 28-day mortality in HBV-ACLF patients, forming a novel prognostic score (ALTA score = 0.187 × age-0.849 × lymphocyte count-2.033 × total cholesterol-0.148 × albumin-0.971). Notably, the AUROC of ALTA score for 28/90-day mortality (0.950/0.967) were significantly higher than those of three other ACLF prognostic scores (COSSH-ACLF II, 0.864/0.734; MELD, 0.525/0.488; MELD-Na, 0.546/0.517; all P < 0.001), and three known nutritional scores (CONUT, 0.739/0.861; OPNI, 0.279/0.157; NRS-2002, 0.322/0.286; all P < 0.001). The prediction error rates of ALTA score for 28-day mortality were significantly lower than COSSH-ACLF II (7.3%), MELD (14.4%), MELD-Na (12.7%), CONUT (9.0%), OPNI (30.6%), and NRS2002 (34.1%) scores. Further classifying ALTA score into two strata, the hazard ratios of mortality at 28/90 days were notably increased in the high-risk groups compared to the low-risk group (15.959 and 5.740). These results were then validated in two external cohorts. Conclusion: ALTA, as a simplified nutritional prognostic score for HBV-ACLF, demonstrates superiority over the COSSH-ACLF II and other scores in predicting short-term mortality among HBV-ACLF patients. Therefore, it may be used to guide clinical management, particularly in primary care settings.

Lipopolysaccharide promotes cancer cell migration and invasion through METTL3/PI3K/AKT signaling in human cholangiocarcinoma.

Purpose: As a major structural component of the outer membrane of Gram-negative bacteria, lipopolysaccharide (LPS) has been detected in the blood circulation and tissues in patients with chronic diseases and cancers, which plays a critical role in the tumor formation and progression. However, the biological role of LPS in human intrahepatic cholangiocarcinoma remains unclear. The aims of this study were to investigate the role of LPS in the malignant progression of intrahepatic cholangiocarcinoma. Methods: The cell migration and invasion capacities of cholangiocarcinoma cell lines were evaluated by Boyden chamber assays. Expression levels of the key molecules involved in the PI3K/AKT signaling and METTL3 were detected by qPCR and western blot. The molecular mechanism by which LPS promotes the malignant behaviors was investigated by using siRNAs, plasmids and small molecule inhibitors. Results: In vitro experiments showed that exogenous LPS treatment promoted cell migration and invasion capacities in both QBC939 and HUCCT1 cell lines, while did not affect cell proliferation and apoptosis. Mechanistically, exogenous LPS treatment had been proved to induce the increased expression of METTL3 and activate the downstream PI3K/AKTsignaling pathway. In addition, suppression of METTL3 expression reduced cell proliferation, migration and invasion capacities in both cell lines. Furthermore, inhibition of METTL3 expression or inhibition of PI3K/AKT signaling decreased LPS-induced cell migration and invasion capacities. Moreover, knockdown of METTL3 or inhibition of METTL3 significantly inhibited LPS-induced activation of the PI3K/AKT signaling. Conclusion: In general, these results suggest that the LPS-METTL3-PI3K/AKT signal axis promotes cell migration and invasion in ICC, which contributes to a reduced overall survival in patients with ICC. It may broaden the horizon of cancer therapy with potential therapeutic targets.

Depletion and Downregulation of Hydrogen Sulfide Using an Activatable Probe for Promoting Photothermal Therapy toward Colorectal Cancers.

Since hydrogen sulfide (H2S) is an important endogenous gaseous mediator, therapeutic manipulation of H2S is promising for anticancer treatment. In this work, we develop a novel theranostic nanoplatform with H2S-specific and photocontrolled synergistic activation for imaging-guided H2S depletion and downregulation along with promoted photothermal therapy. Such a nanoplatform is fabricated by integration of a H2S-responsive molecule probe that can generate a cystathionine-ß-synthase (CBS) inhibitor AOAA and a photothermal transducer into an NIR-light-responsive container. Our nanoplatform can turn on NIR fluorescence specifically in H2S-rich cancers, guiding further laser irradiation. Furthermore, prominent conversion of photoenergy into heat guarantees special container melting with controllable AOAA release for H2S-level downregulation. This smart regulation of the endogenous H2S level amplifies the PTT therapeutic effect, successfully suppressing colorectal tumor in living mice under NIR fluorescence imaging guidance. Thus, we believe that this nanoplatform may provide a powerful tool toward H2S-concerned cancer treatment with an optimized diagnostic and therapeutic effect.

Tracking SO2 plumes from the Tonga volcano eruption with multi-satellite observations.

The Hunga Tonga-Hunga Ha'apai (HTHH) volcano eruption received worldwide attention due to its magnitude and potential effects on environment and climate. However, the operational sulfur dioxide (SO2) products mis-estimated SO2 emissions under volcanic conditions due to large uncertainties in the assumptions of SO2 plume altitude. That might have occurred in previous volcanic eruptions and misled understanding of the evolution of sulfate aerosols in the atmosphere and their impact on global climate. Here, we simultaneously retrieved the volcanic SO2 and its plume altitude from the Troposphere Monitoring Instrument (TROPOMI) and the Environment Monitoring Instrument-2 (EMI-2), exploring the SO2 burden, distribution, and evolution from January 14 to 17. We captured multiple eruptions with the second eruption emitting far more SO2 than the first. Total emissions exceeded 900 kt, significantly higher than those from operational products. Our inferred emission fluxes and injection heights offer valuable references for climate modeling and submarine volcano studies.

Three-Dimensional Virtual Reconstruction of External Nasal Defects Based on Facial Mesh Generation Network.

(1) Background: In digital-technology-assisted nasal defect reconstruction methods, a crucial step involves utilizing computer-aided design to virtually reconstruct the nasal defect's complete morphology. However, current digital methods for virtual nasal defect reconstruction have yet to achieve efficient, precise, and personalized outcomes. In this research paper, we propose a novel approach for reconstructing external nasal defects based on the Facial Mesh Generation Network (FMGen-Net), aiming to enhance the levels of automation and personalization in virtual reconstruction. (2) Methods: We collected data from 400 3D scans of faces with normal morphology and combined the structured 3D face template and the Meshmonk non-rigid registration algorithm to construct a structured 3D facial dataset for training FMGen-Net. Guided by defective facial data, the trained FMGen-Net automatically generated an intact 3D face that was similar to the defective face, and maintained a consistent spatial position. This intact 3D face served as the 3D target reference face (3D-TRF) for nasal defect reconstruction. The reconstructed nasal data were extracted from the 3D-TRF based on the defective area using reverse engineering software. The '3D surface deviation' between the reconstructed nose and the original nose was calculated to evaluate the effect of 3D morphological restoration of the nasal defects. (3) Results: In the simulation experiment of 20 cases involving full nasal defect reconstruction, the '3D surface deviation' between the reconstructed nasal data and the original nasal data was 1.45 ± 0.24 mm. The reconstructed nasal data, constructed from the personalized 3D-TRF, accurately reconstructed the anatomical morphology of nasal defects. (4) Conclusions: This paper proposes a novel method for the virtual reconstruction of external nasal defects based on the FMGen-Net model, achieving the automated and personalized construction of the 3D-TRF and preliminarily demonstrating promising clinical application potential.

Quantum Implementation of the SAND Algorithm and Its Quantum Resource Estimation for Brute-Force Attack.

The SAND algorithm is a family of lightweight AND-RX block ciphers released by DCC in 2022. Our research focuses on assessing the security of SAND with a quantum computation model. This paper presents the first quantum implementation of SAND (including two versions of SAND, SAND-64 and SAND-128). Considering the depth-times-width metric, the quantum circuit implementation of the SAND algorithm demonstrates a relatively lower consumption of quantum resources than that of the quantum implementations of existing lightweight algorithms. A generalized Grover-based brute-force attack framework was implemented and employed to perform attacks on two versions of the SAND algorithm. This framework utilized the g-database algorithm, which considered different plaintext-ciphertext pairs in a unified manner, reducing quantum resource consumption. Our findings indicate that the SAND-128 algorithm achieved the NIST security level I, while the SAND-64 algorithm fell short of meeting the requirements of security level I.

Self-reported perceptions of ethical and professional expectations of medical students in China and the influence of voluntary work during the COVID-19: a survey on "Five Characteristics".

In the post-pandemic era, there is a need for medical professionals with creativity, clinical expertise, and social responsibility. The Chinese government issued a directive to enhance the "Five Characteristics" perceptions of medical students, incorporating moral integrity and adeptness in saving lives and aiding the injured, embracing a compassionate approach to medical practice, possessing the knowledge essential for academic distinction, mastering technical expertise, and the artistry of applying scientific methodologies. The purpose of this study was to investigate the opinions related to ethics and professional behaviors of medical students at one Chinese medical school using a validated 19-item survey instrument and analyze its influencing factors. We conducted a survey in a medical university in Anhui Province, China, and collected 1966 valid questionnaires using the "Five Characteristics Rating Scale". The results indicated high perceptions of "Five Characteristics" among Chinese medical students (85.42 ± 8.727). Lower-grade-year medical students (86.59 ± 7.888) had higher "Five Characteristics" perceptions than upper-grade-year medical students (84.29 ± 9.327, P < 0.05). In addition, medical students experiencing voluntary work during the COVID-19 pandemic showed higher perceptions (86.21 ± 8.357) than those without such experience (85.13 ± 8.842, P < 0.05). Grade year and voluntary work experience during the COVID-19 pandemic were influencing factors of "Five Characteristics" perceptions. Our research offers a theoretical foundation for governments and medical schools to cultivate doctors with high ethical standards and professional expectations.

CGA alleviates LPS-induced inflammation and milk fat reduction in BMECs through the NF-κB signaling pathway.

Mastitis is an easy clinical disease in dairy cows, which seriously affects the milk yield and quality of dairy cows. Chlorogenic acid (CGA), a polyphenolic substance, is abundant in Eucommia ulmoides leaves and has anti-inflammatory and anti-oxidative stress effects. Here, we explore whether CGA attenuated lipopolysaccharide (LPS)-induced inflammation and decreased milk fat in bovine mammary epithelial cells (BMECs). 10 µg/mL LPS was used to induce mastitis in BMECs. QRT-PCR, Western blotting, oil red O staining, and triglyceride (TG) assay were used to examine the effects of CGA on BMECs, including inflammatory response, oxidative stress response, and milk fat synthesis. The results showed that CGA repaired LPS-induced inflammation in BMECs. The expression of IL-6, IL-8, TNF-α, IL-1ß, and iNOS was decreased, and the expression levels of CHOP, XCT, NRF2, and HO-1 were increased, which reduced the oxidative stress level of cells and alleviated the reduction of milk fat synthesis. In addition, the regulation of P65 phosphorylation by CGA suggests that CGA may exert its anti-inflammatory and anti-oxidative effects through the NF-κB signaling pathway. Our study showed that CGA attenuated LPS-induced inflammation and oxidative stress, and restored the decrease in milk fat content in BMECs by regulating the NF-κB signaling pathway.

Integrated Transcriptome and Metabolome Analyses Reveal Bamboo Culm Color Formation Mechanisms Involved in Anthocyanin Biosynthetic in Phyllostachys nigra.

Phyllostachys nigra has green young culms (S1) and purple black mature culms (S4). Anthocyanins are the principal pigment responsible for color presentation in ornamental plants. We employ a multi-omics approach to investigate the regulatory mechanisms of anthocyanins in Ph. nigra. Firstly, we found that the pigments of the culm of Ph. nigra accumulated only in one to four layers of cells below the epidermis. The levels of total anthocyanins and total flavonoids gradually increased during the process of bamboo culm color formation. Metabolomics analysis indicated that the predominant pigment metabolites observed were petunidin 3-O-glucoside and malvidin O-hexoside, exhibiting a significant increase of up to 9.36-fold and 13.23-fold, respectively, during pigmentation of Ph. nigra culm. Transcriptomics sequencing has revealed that genes involved in flavonoid biosynthesis, phenylpropanoid biosynthesis, and starch and sucrose metabolism pathways were significantly enriched, leading to color formation. A total of 62 differentially expressed structural genes associated with anthocyanin synthesis were identified. Notably, PnANS2, PnUFGT2, PnCHI2, and PnCHS1 showed significant correlations with anthocyanin metabolites. Additionally, certain transcription factors such as PnMYB6 and PnMYB1 showed significant positive or negative correlations with anthocyanins. With the accumulation of sucrose, the expression of PnMYB6 is enhanced, which in turn triggers the expression of anthocyanin biosynthesis genes. Based on these findings, we propose that these key genes primarily regulate the anthocyanin synthesis pathway in the culm and contribute to the accumulation of anthocyanin, ultimately resulting in the purple-black coloration of Ph. nigra.

Discovery of novel ß-elemene hybrids with hydrogen sulfide-releasing moiety possessing cardiovascular protective activity for the treatment of atherosclerosis.

Herein, a series of novel ß-elemene hybrids with different types of hydrogen sulfide (H2S) donors was designed and synthesized for the first time. In addition, all compounds were tested for H2S release in phosphate buffer solution assay, among which the derivatives with 5-p-hydroxyphenyl-3H-1,2-dithiole-3-thione (ADT-OH) as the H2S donor released the best level. The results of the isolated vasodilation assay revealed that all the compounds exhibited a degree of vasodilatory effect, and the representative compound "ß-elemene-H2S gas donor" hybrid L13-2h produced more than 50% vasodilatory activity at a concentration of 20 µM. Furthermore, L13-2h possessed good concentration dependence and significantly better vasodilatory activity than the lead compound L13. In the RAW 264.7 cellular lipid inhibition against oxidized low-density lipoprotein (ox-LDL) stimulation assay, eight compounds, including L13-2g and L13-2h, produced significant cellular lipid-lowering activity. The results of the further antioxidant activity study showed that the representative compounds L13-2g and L13-2h improved H2O2-induced oxidative damage in HUVEC cells and compound L13-2h exhibited excellent antioxidant damage protection activity compared to the positive control. Moreover, none of the target compounds appeared to be significantly cytotoxic at the tested concentrations. These results suggest that the hybridization of hydrogen sulfide donors with ß-elemene provides a promising approach for the discovery of novel anti-atherosclerotic drugs from natural products.

Preoperative systemic inflammation response index: Clinicopathologic predictor of pathological complete response in HER2-positive breast cancer patients receiving neoadjuvant systemic therapy.

BACKGROUND: Multiple pretreatment systemic inflammatory markers (SIMs) have been reported as predictors of pathological complete response (pCR) after neoadjuvant systemic therapy (NST) in patients with breast cancer (BC). However, the most significant SIM remains to be conclusively identified, and variations among different molecular subtypes remain unknown. The objective of the study was to identify the most significant SIM in patients with human epidermal growth factor receptor 2 (HER2) positive BC, to construct a pCR-predictive nomogram combining it with other clinicopathologic factors, and to evaluate its prognostic value on survival. METHODS: We retrospectively reviewed the findings for 240 patients with stage I-III HER2-positive BC who underwent NST and subsequent surgery at Kaohsiung and Taichung Veterans General Hospital from 2011 to 2021. Clinicopathologic factors were analyzed by stepwise logistic regression with backward selection. The data were used to construct a nomogram plot for determining the pCR probability. Kaplan-Meier curves and log-rank test were used to evaluate disease-free survival (DFS) and overall survival (OS). RESULTS: Among the pretreatment SIMs, only the systemic inflammation response index (SIRI) was significantly related to pCR, with an optimal cutoff value of 1.27 × 10 9 /L. Stepwise logistic analyses indicated that clinical N stage, HER2 immunohistochemistry score, hormone receptor status, targeted therapy regimen, and SIRI were independent predictors of pCR, with an area under the curve of 0.722. The Hosmer-Lemeshow test and calibration curve revealed that the predictive ability was a good fit to actual observations. A nomogram was constructed based on the logistic model. The external validation of the model also revealed satisfactory discrimination and calibration. Kaplan-Meier analysis showed that patients with SIRI <1.27 had longer DFS and OS. CONCLUSION: Pretreatment SIRI <1.27 is predictive of pCR, DFS, and OS in HER2-positive BC. Our nomogram could efficiently predict pCR and facilitate clinical decision-making before neoadjuvant treatment.

Establishment and multicenter external validation of a risk prediction model for de novo intracranial aneurysms based on a systematic review and meta-analysis of 19 cohorts.

OBJECTIVE: A de novo intracranial aneurysm (IA) is a second, new IA that develops in patients with IAs distant from where the initial IA was detected. This study aimed to identify risk factors for de novo IA formation and establish and externally validate a multicenter risk prediction model for de novo IAs. METHODS: A systematic review and meta-analysis of existing de novo IA cohorts was conducted to form the derivation cohort. The risk ratios and 95% CIs of each risk factor were calculated. In addition, risk scores included in the model were calculated based on the statistically significant risk factors with their weightings. Then the model was validated in a multicenter external cohort of Chinese patients, and receiver operating characteristic and calibration curves, decision curve analysis, and Kaplan-Meier curves were used to evaluate the model. RESULTS: Nineteen studies with 9351 patients, of whom 304 patients (3.25%) developed de novo IAs, were included in the derivation cohort. These patients developed de novo IAs at 2.5-18.5 years during a total follow-up of 3.3-18.8 years. The statistically significant risk factors were age < 60 years, female sex, smoking history, family history of IAs, multiple IAs at initial diagnosis, and initial IAs in the middle cerebral artery, with risk scores of 4, 5, 2, 6, 3, and 3, respectively. Then, a multicenter external cohort comprising 776 patients, of whom 45 patients (5.80%) developed de novo IAs, was included in the validation cohort. De novo IAs formed in these patients at a mean of 5.25 years during a mean follow-up of 6.19 years. The area under the curve of the model was 0.804, with a sensitivity of 0.667 and specificity of 0.900, at a cutoff value of 13. The calibration curve, decision curve analysis, and Kaplan-Meier curves also indicated good performance of the model. CONCLUSIONS: This prediction model is a convenient and intuitive tool for identifying high-risk patients with de novo IAs. Reasonable use of the model can not only aid in clinical decision-making but also play a positive role in the prevention of aneurysmal subarachnoid hemorrhage to a certain extent.

Targeted Degradation of PCSK9 In Vivo by Autophagy-Tethering Compounds.

Proprotein convertase subtilisin/kexin type-9 (PCSK9), a secreted protein that is synthesized and spontaneously cleaved in the endoplasmic reticulum, has become a hot lipid-lowering target chased by pharmaceutical companies in recent years. Autophagosome-tethering compounds (ATTECs) represent a new strategy to degrade targeted biomolecules. Here, we designed and synthesized PCSK9·ATTECs that are capable of lowering PCSK9 levels via autophagy in vivo, providing the first report of the degradation of a secreted protein by ATTECs. OY3, one of the PCSK9·ATTECs synthesized, shows greater potency to reduce plasma low-density lipoprotein cholesterol (LDL-C) levels and improve atherosclerosis symptoms than treatment with the same dose of simvastatin. OY3 also significantly reduces the high expression of PCSK9 caused by simvastatin administration in atherosclerosis model mice and subsequently increases the level of low-density lipoprotein receptor, promoting simvastatin to clear plasma LDL-C and alleviate atherosclerosis symptoms. Thus, we developed a new candidate compound to treat atherosclerosis that could also promote statin therapy.

Visible-Light-Mediated Annulation/Thiolation of 2-Isocyanobiaryls with Disulfides to Organoylthiophenanthridines Derivatives.

A visible-light-induced annulation/thiolation of 2-isocyanobiaryls with dialkyl(aryl)disulfides has been established, delivering a sustainable and atom-economic route to 6-organoylthiophenanthridines with wild functional group tolerance and good to excellent yields under oxidant-, base-, and transition-metal-free conditions.

Oat Peptides Alleviate Dextran Sulfate Sodium Salt-Induced Colitis by Maintaining the Intestinal Barrier and Modulating the Keap1-Nrf2 Axis.

The prevalence of inflammatory bowel disease (IBD) is progressively rising each year, emphasizing the significance of implementing rational dietary interventions for disease prevention. Oats, being a staple agricultural product, are abundant in protein content. This study aimed to investigate the protective effects and underlying mechanisms of oat peptides (OPs) in a mouse model of acute colitis induced by dextran sulfate sodium salt (DSS) and a Caco-2 cell model. The findings demonstrated that intervention with OPs effectively mitigated the symptoms associated with DSS-induced colitis. The physicochemical characterization analysis demonstrated that the molecular weight of the OPs was predominantly below 5 kDa, with a predominant composition of 266 peptides. This study provides further evidence of the regulatory impact of OPs on the Keap1-Nrf2 signaling axis and elucidates the potential role of WGVGVRAERDA as the primary bioactive peptide responsible for the functional effects of OPs. Ultimately, the results of this investigation demonstrate that OPs effectively mitigate DSS-induced colitis by preserving the integrity of the intestinal barrier and modulating the Keap1-Nrf2 axis. Consequently, these findings establish a theoretical foundation for the utilization of OPs as dietary supplements to prevent the onset of IBD.

Association between gut microbiota and NAFLD/NASH: a bidirectional two-sample Mendelian randomization study.

Background: Recent studies have suggested a relationship between gut microbiota and non-alcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH). However, the nature and direction of this potential causal relationship are still unclear. This study used two-sample Mendelian randomization (MR) to clarify the potential causal links. Methods: Summary-level Genome-Wide Association Studies (GWAS) statistical data for gut microbiota and NAFLD/NASH were obtained from MiBioGen and FinnGen respectively. The MR analyses were performed mainly using the inverse-variance weighted (IVW) method, with sensitivity analyses conducted to verify the robustness. Additionally, reverse MR analyses were performed to examine any potential reverse causal associations. Results: Our analysis, primarily based on the IVW method, strongly supports the existence of causal relationships between four microbial taxa and NAFLD, and four taxa with NASH. Specifically, associations were observed between Enterobacteriales (P =0.04), Enterobacteriaceae (P =0.04), Lachnospiraceae UCG-004 (P =0.02), and Prevotella9 (P =0.04) and increased risk of NAFLD. Dorea (P =0.03) and Veillonella (P =0.04) could increase the risks of NASH while Oscillospira (P =0.04) and Ruminococcaceae UCG-013 (P=0.005) could decrease them. We also identified that NAFLD was found to potentially cause an increased abundance in Holdemania (P =0.007) and Ruminococcus2 (P =0.002). However, we found no evidence of reverse causation in the microbial taxa associations with NASH. Conclusion: This study identified several specific gut microbiota that are causally related to NAFLD and NASH. Observations herein may provide promising theoretical groundwork for potential prevention and treatment strategies for NAFLD and its progression to NASH in future.