Hspb1 protects against severe acute pancreatitis by attenuating apoptosis and ferroptosis via interacting with Anxa2 to restore the antioxidative activity of Prdx1.

Acute pancreatitis (AP) is a common abdominal disease that typically resolves on its own, but the mortality rate dramatically increases when it progresses to severe acute pancreatitis (SAP). In this study, we investigated the molecular mechanism underlying the development of SAP from AP. We utilized two SAP models induced by pancreatic duct ligation and caerulein administration. Transcriptomic and proteomic analyses were subsequently performed to determine the mRNA and protein expression profiles of pancreatic samples from SAP and AP model and normal mice. To explore the role of Hspb1 in SAP, we used Hspb1 knockout (KO) mice, a genetically engineered chronic pancreatitis strain (T7D23A), Anxa2 KO mice, and acinar cell-specific Prdx1 knockout mice. Additionally, various in vivo and in vitro assays were performed to elucidate the molecular events and direct targets of Hspb1 in acinar cells. We found that Hspb1 expression was upregulated in AP samples but significantly reduced in acinar cells from SAP samples. KO or inhibition of Hspb1 worsened AP, while AAV8-Hspb1 administration mitigated the severity of SAP and reduced remote organ damage in mice. Furthermore, AAV8-Hspb1 treatment prevented the development of chronic pancreatitis. We found that KO or inhibition of Hspb1 promoted acinar cell death through apoptosis and ferroptosis but not necroptosis or autophagy by increasing reactive oxygen species (ROS) and lipid ROS levels. Mechanistically, Hspb1 directly interacted with Anxa2 to decrease its aggregation and phosphorylation, interact with the crucial antioxidant enzyme Prdx1, and maintain its antioxidative activity by decreasing Thr-90 phosphorylation. Notably, the overexpression of Hspb1 did not have a protective effect on acinar-specific Prdx1 knockout mice. In summary, our findings shed light on the role of Hspb1 in acinar cells. We showed that targeting Hspb1/Anxa2/Prdx1 could serve as a potential therapeutic strategy for SAP.

Chronic exposure to BDE-47 aggravates acute pancreatitis and chronic pancreatitis by promoting acinar cell apoptosis and inflammation.

The effect of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47), a persistent environmental pollutant commonly used as a flame retardant in various consumer products, on pancreatitis has not been clearly elucidated, although it has been reported to be toxic to the liver, nervous system, and reproductive system. Acute pancreatitis (AP) and chronic pancreatitis (CP) models were induced in this study by intraperitoneal injection of caerulein. The aim was to investigate the impact of BDE-47 on pancreatitis by exposing the animals to acute (1 week) or chronic (8 weeks) doses of BDE-47 (30 mg/kg in the low-concentration group and 100 mg/kg in the high-concentration group). Additionally, BDE-47 was utilized to stimulate mouse bone marrow-derived macrophages, pancreatic primary stellate cells, and acinar cells in order to investigate the impact of BDE-47 on pancreatitis. In vivo experiments conducted on mice revealed that chronic exposure to BDE-47, rather than acute exposure, exacerbated the histopathological damage of AP and CP, leading to elevated fibrosis in pancreatic tissue and increased infiltration of inflammatory cells in the pancreas. In vitro experiments showed that BDE-47 can promote the expression of the inflammatory cytokines Tnf-α and Il-6 in M1 macrophages, as well as promote acinar cell apoptosis through the activation of the PERK and JNK pathways via endoplasmic reticulum stress. The findings of this study imply chronic exposure to BDE-47 may exacerbate the progression of both AP and CP by inducing acinar cell apoptosis and dysregulating inflammatory responses.

The unique salt bridge network in GlacPETase: a key to its stability.

The extensive accumulation of polyethylene terephthalate (PET) has become a critical environmental issue. PET hydrolases can break down PET into its building blocks. Recently, we identified a glacial PET hydrolase GlacPETase sharing less than 31% amino acid identity with any known PET hydrolases. In this study, the crystal structure of GlacPETase was determined at 1.8 Å resolution, revealing unique structural features including a distinctive N-terminal disulfide bond and a specific salt bridge network. Site-directed mutagenesis demonstrated that the disruption of the N-terminal disulfide bond did not reduce GlacPETase's thermostability or its catalytic activity on PET. However, mutations in the salt bridges resulted in changes in melting temperature ranging from -8°C to +2°C and the activity on PET ranging from 17.5% to 145.5% compared to the wild type. Molecular dynamics simulations revealed that these salt bridges stabilized the GlacPETase's structure by maintaining their surrounding structure. Phylogenetic analysis indicated that GlacPETase represented a distinct branch within PET hydrolases-like proteins, with the salt bridges and disulfide bonds in this branch being relatively conserved. This research contributed to the improvement of our comprehension of the structural mechanisms that dictate the thermostability of PET hydrolases, highlighting the diverse characteristics and adaptability observed within PET hydrolases.IMPORTANCEThe pervasive problem of polyethylene terephthalate (PET) pollution in various terrestrial and marine environments is widely acknowledged and continues to escalate. PET hydrolases, such as GlacPETase in this study, offered a solution for breaking down PET. Its unique origin and less than 31% identity with any known PET hydrolases have driven us to resolve its structure. Here, we report the correlation between its unique structure and biochemical properties, focusing on an N-terminal disulfide bond and specific salt bridges. Through site-directed mutagenesis experiments and molecular dynamics simulations, the roles of the N-terminal disulfide bond and salt bridges were elucidated in GlacPETase. This research enhanced our understanding of the role of salt bridges in the thermostability of PET hydrolases, providing a valuable reference for the future engineering of PET hydrolases.

Harnessing Pseudomonas putida in bioelectrochemical systems.

Bioelectrochemical systems (BESs), a group of promising integrated systems that combine the advantages of biotechnology and electrochemical techniques, offer new opportunities to address environmental and energy challenges. Exoelectrogens capable of extracellular electron transfer (EET) are the critical factor enabling electrocatalytic activity in BESs. Pseudomonas putida, an aerobe widely used in environmental bioremediation, the biosynthesis of valuable chemicals, and energy bioproduction, has attracted much attention due to its unique application potential in BESs. This review provides a comprehensive understanding of the working principles, key factors, and applications of BESs using P. putida as the exoelectrogen. The challenges and perspectives for the development of BESs with P. putida as the exoelectrogen are also proposed and discussed.

Association of dietary inflammatory index with risk of gestational diabetes mellitus and preeclampsia: a systematic review and meta-analysis.

Findings from observational studies have suggested a possible association between dietary inflammatory index (DII) and risk of gestational diabetes mellitus (GDM) and preeclampsia (PE). However, the results of these studies were inconclusive. A systematic review and meta-analysis was carried out to illuminate this association. Systematic literature search was conducted in PubMed, Web of Science, Cochrane Library, EMBASE, Scopus and other databases from inception until January 2023. The qualities of included studies were assessed using the Newcastle-Ottawa scale. Nine studies (seven cohort, two case-control) were included in the meta-analysis, including 11 423 participants from five different countries. The meta-analysis indicated that a 1-unit increase in the DII score, representing pro-inflammatory diet, was associated with 13 % higher risk of GDM (OR = 1·13; 95 % CI 1·02, 1·25, I2 = 68·4 %, P = 0·004) and 24 % higher risk of PE (OR = 1·24; 95 % CI 1·14, 1·35, I2 = 52·0 %, P = 0·125). Subgroup analysis found that this association was evident among studies with Chinese populations (OR = 1·16; 95 % CI 1·06, 1·28) and studies with mid pregnancy (OR = 1·20; 95 % CI 1·07, 1·34). The findings indicate that pro-inflammatory diet can increase the risk of GDM and PE. Considering some limitations in this study, more studies are needed to verify this association.

Integration of Glutamate Dehydrogenase and Nanoporous Gold for Electrochemical Detection of Glutamate.

Glutamate, a non-essential amino acid produced by fermentation, plays a significant role in disease diagnosis and food safety. It is important to enable the real-time monitoring of glutamate concentration for human health and nutrition. Due to the challenges in directly performing electrochemical oxidation-reduction reactions of glutamate, this study leverages the synergistic effect of glutamate dehydrogenase (GLDH) and nanoporous gold (NPG) to achieve the indirect and accurate detection of glutamate within the range of 50 to 700 µM by measuring the generated quantity of NADH during the enzymatic reaction. The proposed biosensor demonstrates remarkable performance characteristics, including a detection sensitivity of 1.95 µA mM-1 and a limit of detection (LOD) of 6.82 µM. The anti-interference tests indicate an average recognition error ranging from -3.85% to +2.60%, spiked sample recovery rates between 95% and 105%, and a relative standard deviation (RSD) of less than 4.97% for three replicate experiments. Therefore, the GLDH-NPG/GCE biosensor presented in this work exhibits excellent accuracy and repeatability, providing a novel alternative for rapid glutamate detection. This research contributes significantly to enhancing the precise monitoring of glutamate concentration, thereby offering more effective guidance and control for human health and nutrition.

The Most Popular Commercial Weight Management Apps in the Chinese App Store: Analysis of Quality, Features, and Behavior Change Techniques.

BACKGROUND: Many smartphone apps designed to assist individuals in managing their weight are accessible, but the assessment of app quality and features has predominantly taken place in Western countries. Nevertheless, there is a scarcity of research evaluating weight management apps in China, which highlights the need for further investigation in this area. OBJECTIVE: This study aims to conduct a comprehensive search for the most popular commercial Chinese smartphone apps focused on weight management and assess their quality, behavior change techniques (BCTs), and content-related features using appropriate evaluation scales. Additionally, the study sought to investigate the associations between the quality of various domains within weight management apps and the number of incorporated BCTs and app features. METHODS: In April 2023, data on weight management apps from the iOS and Android app stores were downloaded from the Qimai Data platform. Subsequently, a total of 35 weight management apps were subjected to screening and analysis by 2 researchers. The features and quality of the apps were independently assessed by 6 professionals specializing in nutrition management and health behavioral change using the Mobile Application Rating Scale (MARS). Two registered dietitians, who had experience in app development and coding BCTs, applied the established 26-item BCT taxonomy to verify the presence of BCTs. Mean (SD) scores and their distributions were calculated for each section and item. Spearman correlations were used to assess the relationship between an app's quality and its technical features, as well as the number of incorporated BCTs. RESULTS: The data set included a total of 35 apps, with 8 available in the Android Store, 10 in the Apple Store, and 17 in both. The overall quality, with a mean MARS score of 3.44 (SD 0.44), showed that functionality was the highest scoring domain (mean 4.18, SD 0.37), followed by aesthetics (mean 3.43, SD 0.42), engagement (mean 3.26, SD 0.64), and information (mean 2.91, SD 0.52), which had the lowest score. The mean number of BCTs in the analyzed apps was 9.17 (range 2-18 BCTs/app). The most common BCTs were "prompt review of behavioral goals" and "provide instruction," present in 31 apps (89%). This was followed by "prompt self-monitoring of behavior" in 30 apps (86%), "prompt specific goal setting" in 29 apps (83%), and "provide feedback on performance" in 27 apps (77%). The most prevalent features in the analyzed apps were the need for web access (35/35, 100%), monitoring/tracking (30/35, 86%), goal setting (29/35, 83%), and sending alerts (28/35, 80%). The study also revealed strong positive correlations among the number of BCTs incorporated, app quality, and app features. This suggests that apps with a higher number of BCTs tend to have better overall quality and more features. CONCLUSIONS: The study found that the overall quality of weight management apps in China is moderate, with a particular weakness in the quality of information provided. The most prevalent BCTs in these apps were reviewing behavioral goals, providing guidance, self-monitoring of behavior, goal setting, and offering performance feedback. The most common features were the need for web access, monitoring and tracking, goal setting, and sending alerts. Notably, higher-quality weight management apps in China tended to incorporate more BCTs and features. These findings can be valuable for developers looking to improve weight management apps and enhance their potential to drive behavioral change in weight management.

Clinical utility of the pan-immune-inflammation value in breast cancer patients.

Background: The newly discovered pan-immune-inflammation value (PIV) has been illustrated to have good prognostic value for cancer patient prognosis. However, the prognostic usefulness of PIV in breast cancer patients is unknown. As a result, to aid the clinic in providing a distinctive and trustworthy biomarker to better assess breast cancer patient's prognosis, we conducted this meta-analysis to investigate the relationship between PIV and the survival of breast cancer patients. Methods: We conducted a systematic search of Pubmed, Embase, the Cochrane Library, and the CNKI databases to screen for eligible studies published up to April 2023. Outcomes included overall survival (OS), progression-free survival (PFS), and pathological complete response (pCR). The hazard ratio (HR) and the corresponding 95% confidence interval (CI) were used as the indicators. STATA 15.0 software was used to perform meta-analysis, sensitivity analysis, and publication bias analysis. Results: A total of eight articles, involving 2953 patients, met the inclusion criteria and were included in this meta-analysis. The results showed that patients with higher PIV levels had a significantly shorter OS (HR: 2.045, 95% CI: 1.355-3.086, P = 0.001) and PFS (HR: 1.466, 95% CI: 1.163-1.848, P = 0.001). Besides, the PIV value was negatively correlated with the efficacy of neoadjuvant chemotherapy. Sensitivity analysis showed that the results of this study were reliable and stable. Conclusions: PIV has a good prognostic value in breast cancer patients and is expected to be a prognostic biomarker for breast cancer.

Glacier as a source of novel polyethylene terephthalate hydrolases.

Polyethylene terephthalate (PET) is a major component of microplastic contamination globally, which is now detected in pristine environments including Polar and mountain glaciers. As a carbon-rich molecule, PET could be a carbon source for microorganisms dwelling in glacier habitats. Thus, glacial microorganisms may be potential PET degraders with novel PET hydrolases. Here, we obtained 414 putative PET hydrolase sequences by searching a global glacier metagenome dataset. Metagenomes from the Alps and Tibetan glaciers exhibited a higher relative abundance of putative PET hydrolases than those from the Arctic and Antarctic. Twelve putative PET hydrolase sequences were cloned and expressed, with one sequence (designated as GlacPETase) proven to degrade amorphous PET film with a similar performance as IsPETase, but with a higher thermostability. GlacPETase exhibited only 30% sequence identity to known active PET hydrolases with a novel disulphide bridge location and, therefore may represent a novel PET hydrolases class. The present work suggests that extreme carbon-poor environments may harbour a diverse range of known and novel PET hydrolases for carbon acquisition as an environmental adaptation mechanism.

The anoikis-related gene signature predicts survival accurately in colon adenocarcinoma.

Colon adenocarcinoma (COAD) is a serious public health problem, the third most common cancer and the second most deadly cancer in the world. About 9.4% of cancer-related deaths in 2020 were due to COAD. Anoikis is a specialized form of programmed cell death that plays an important role in tumor invasion and metastasis. The presence of anti-anoikis factors is associated with tumor aggressiveness and drug resistance. Various bioinformatic methods, such as differential expression analysis, and functional annotation analysis, machine learning, were used in this study. RNA-sequencing and clinical data from COAD patients were obtained from the Gene expression omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. Construction of a prognostic nomogram for predicting overall survival (OS) using multivariate analysis and Lasso-Cox regression. Immunohistochemistry (IHC) was our method of validating the expression of seven genes that are linked to anoikis in COAD. We identified seven anoikis-related genes as predictors of COAD survival and prognosis, and confirmed their accuracy in predicting colon adenocarcinoma prognosis by KM survival curves and ROC curves. A seven-gene risk score consisting of NAT1, CDC25C, ATP2A3, MMP3, EEF1A2, PBK, and TIMP1 showed strong prognostic value. Meanwhile, we made a nomogram to predict the survival rate of COAD patients. The immune infiltration assay showed T cells. CD4 memory. Rest and macrophages. M0 has a higher proportion in COAD, and 11 genes related to tumor immunity are important. GDSC2-based drug susceptibility analysis showed that 6 out of 198 drugs were significant in COAD. Anoikis-related genes have potential value in predicting the prognosis of COAD and provide clues for developing new therapeutic strategies for COAD. Immune infiltration and drug susceptibility results provide important clues for finding new personalized treatment options for COAD. These findings also suggest possible mechanisms that may affect prognosis. These results are the starting point for planning individualized treatment and managing patient outcomes.

Kinesin family member 11 promotes progression of hepatocellular carcinoma via the OCT4 pathway.

Hepatocellular carcinoma (HCC) is the tumor with the second highest mortality rate worldwide. Recent research data show that KIF11, a member of the kinesin family (KIF), plays an important role in the progression of various tumors. However, its expression and molecular mechanism in HCC remain elusive. Here, we evaluated the potential role of KIF11 in HCC. The effect of KIF11 was evaluated using the hepatocellular carcinoma cell lines, LM3 and Huh7, after genetic or pharmacological treatment. Evaluating the role of KIF11 in the xenograft animal models using its specific inhibitor. The role of KIF11 was systematically evaluated using specimens obtained from the aforementioned animal and cell models after various in vivo and in vitro experiments. The clinicopathological analysis showed that KIF11 was expressed at high levels in patients with hepatocellular carcinoma. Cell experiments in vitro showed that KIF11 deficiency significantly slowed the proliferation of liver tumor cells. And in the experiment using liver cancer cells overexpressing OCT4, overexpression of OCT4 substantially increased the proliferation of tumor cells compared with tumor cells with KIF11 knockdown alone. Both in vitro cell experiment and in vivo xenotransplantation tumor experiment showed that monastrol, an inhibitor of KIF11, could effectively delay the proliferation and migration of tumor cells. Based on these results, KIF11 is expressed at high levels in hepatocellular carcinoma and promotes tumor proliferation in an OCT4-dependent manner. KIF11 may become a therapeutic target for hepatocellular carcinoma, and its inhibitor monastrol may become a clinical antitumor drug.

New insight of obesity-associated NAFLD: Dysregulated "crosstalk" between multi-organ and the liver?

Obesity plays a crucial role in the development of non-alcoholic fatty liver disease (NAFLD). However, the underlying mechanism for the pathogenesis of obesity-associated NAFLD remains largely obscure. Although the "multiple hit" theory provides a more accurate explanation of NAFLD pathogenesis, it still cannot fully explain precisely how obesity causes NAFLD. The liver is the key integrator of the body's energy needs, receiving input from multiple metabolically active organs. Thus, recent studies have advocated the "multiple crosstalk" hypothesis, highlighting that obesity-related hepatic steatosis may be the result of dysregulated "crosstalk" among multiple extra-hepatic organs and the liver in obesity. A wide variety of circulating endocrine hormones work together to orchestrate this "crosstalk". Of note, with deepening understanding of the endocrine system, the perception of hormones has gradually risen from the narrow sense (i.e. traditional hormones) to the broad sense of hormones as organokines and exosomes. In this review, we focus on the perspective of organic endocrine hormones (organokines) and molecular endocrine hormones (exosomes), summarizing systematically how the two types of new hormones mediate the dialogue between extra-hepatic organs and liver in the pathogenesis of obesity-related NAFLD.

Integrative proteomics, phosphoproteomics and acetylation proteomics analyses of acute pancreatitis in rats.

Acute pancreatitis (AP) is a common acute abdominalgia of the digestive tract. When the disease progresses to severe acute pancreatitis (SAP), the complications and mortality rate greatly increase. Determining the key factors and pathways underlying AP and SAP will help elucidate the pathological processes involved in disease progression and will be beneficial for identifying potential therapeutic targets. We conducted an integrative proteomics, phosphoproteomics and acetylation proteomics analysis of pancreas samples collected from normal, AP and SAP rat models. We identified 9582 proteins, 3130 phosphorylated modified proteins, and 1677 acetylated modified proteins across all samples. The differentiated expression proteins and KEGG pathway analysis suggested the pronounced enrichment of key pathways based on the following group comparisons: AP versus normal, SAP versus normal, and SAP versus AP. Integrative proteomics and phosphoproteomics analyses revealed 985 jointly detected proteins in the comparison of AP and normal samples, 911 proteins in the comparison of SAP and normal samples, and 910 proteins in the comparison of SAP and AP samples. Based on proteomics and acetylation proteomics analyses, we found that 984 proteins were jointly detected in the comparison of AP and normal samples, 990 proteins in SAP and normal samples, and 728 proteins in SAP and AP samples. Thus, our study offers a valuable resource to understand the proteomic and protein modification atlas in AP.

IL-37 alleviates TNF-α-induced pyroptosis of rheumatoid arthritis fibroblast-like synoviocytes by inhibiting the NF-κB/GSDMD signaling pathway.

OBJECTIVE: Pyroptosis is crucial to rheumatoid arthritis (RA) by inducing and aggravating inflammation. TNF-α is abundant in fibroblast-like synoviocytes of RA (RA-FLSs) and plays a key role in pyroptosis by inducing nuclear factor (NF)-κB activation. Additionally, interleukin (IL)-37 is involved in autoimmune diseases as an anti-inflammatory cytokine and innate and acquired immune response inhibitor. However, the effect of IL-37 on pyroptosis in RA-FLSs remains unclear. Therefore, this study investigated the effects and mechanism of IL-37 on RA-FLS pyroptosis induced by TNF-α. METHODS: In this study, the serum cytokines in patients with RA and healthy controls were detected using ELISA. The RA-FLSs were then cultured with TNF-α, with or without various IL-37 concentrations, to test the cytokine levels in the cell supernatant. 5-Ethynyl-2'-Deoxyuridine (EdU) assay assessed the effects of IL-37 on RA FLS proliferation. RA-FLS apoptosis was assessed using flow cytometry and mitochondrial membrane potential (MMP) measurement. In addition, transmission electron microscopy (TEM) was used to examine cell pyroptosis. We selected the optimal concentration for the following experiments and detected the signal pathway of IL-37 on pyroptosis of RA FLSs by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and Western blotting. Finally, we validated the therapeutic effects of IL-37 on CIA rat model in vivo. RESULTS: IL-37 inhibited inflammation in vitro and in vivo and reduced pyroptosis-related protein expression in RA FLSs. Furthermore, we determined that nuclear factor κB (NF-κB) signaling is required for GSDMD-mediated pyroptosis in RA FLSs. CONCLUSION: IL-37 alleviates TNF-α-induced pyroptosis of RA FLSs by inhibiting NF-κB/GSDMD signaling. Additionally, our data revealed a novel mechanism for IL-37 in RA FLSs, suggesting a new potential therapy for IL-37 to treat RA.

Effects of Torulaspora delbrueckii co-fermented with Saccharomyces cerevisiae on physicochemical and aromatic profiles of blueberry fermented beverage.

To investigate the effects of mixed fermentation with T. delbrueckii on aroma profiles of blueberry fermented beverage, five fermentations were conducted: monoculture of T. delbrueckii and S. cerevisiae, respectively; co-inoculation of two strains; sequential inoculation of two strains at time intervals of 24 h and 48 h, respectively. Compared with pure S. cerevisiae fermentation, ethanol level was decreased by up to 1.1% vol., while total anthocyanins were increased by 27.7%-85.0% in mixed fermentations. Marker aroma compounds in different fermentations with relative odor activity values higher than 1were identified. T. delbrueckii significantly decreased volatile acid content (especially acetic acid) by 22.2%-83.3%. Ethyl 3-methylbutanoate, ethyl hexanoate and ethyl octanoate, in pure T. delbrueckii fermentation were significantly decreased, while their concentrations were increased by 1.6-4.4 folds in sequential fermentations. Besides, linalool, rose oxide, benzeneacetaldehyde were significantly increased by sequential fermentation, which was associated with the enhancement of fruity and sweet notes.

Exosomal microRNAs and Progression of Nonalcoholic Steatohepatitis (NASH).

Nonalcoholic fatty liver disease (NAFLD)/metabolic associated fatty liver disease (MAFLD) is becoming a public health problem worldwide. Steatosis as the simple form and nonalcoholic steatohepatitis (NASH) as its progression form are commonly seen in liver biopsy specimens from patients with obesity, diabetes, hyperlipidemia, hypertension, and the use of certain drugs. Patients with NASH and advanced fibrosis were associated with increased risks of liver-related complications, including hepatocellular carcinoma (HCC). However, the mechanisms regarding the progression from simple steatosis to NASH fibrosis remain incompletely understood. Because NASH-caused liver injury is a complex process and multiple cell types are involved, intercellular communication is likely mediated by extracellular vesicles. Exosomes are a type of small extracellular vesicles and contain various cellular molecules, including proteins, messenger RNAs (mRNAs), and microRNAs (miRNAs). MiRNAs are short, non-coding RNA species that are important post-transcriptional regulators of gene expression and may play an important role in the pathogenesis of NALFD/NASH. In this article, we review the articles about NASH and exosomal miRNAs published in the most recent English literature through PubMed search and discuss the most recent criteria for histological diagnosis, pathogenesis from steatosis to NASH, roles of exosomal miRNAs in NASH pathogenesis and progression, as well as their potential in future clinical diagnosis and treatment for patients with NASH.

Andrographolide elevates tumor necrosis factor-related apoptosis-inducing ligand lethality through reactive oxygen species accumulation and gasdermin E cleavage in breast cancer cells.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is selectively lethal to cancer cells and harmless to normal cells, making it a potential agent for cancer therapy. However, some breast cancer cells are resistant to TRAIL. This study revealed that andrographolide (Andro), an extract from Andrographis paniculate, a natural compound, sensitized breast cancer cells to TRAIL-induced tumor suppression; it identified apoptosis-associated protein regulation, reactive oxygen species accumulation, mitochondria membrane potential disruption, caspase cascade activation, and gasdermin-E cleavage to be involved in the tumor lethality mediated by Andro combined with TRAIL treatment. The flow cytometry results showed the combination of Andro and TRAIL repressed breast cancer cells by cell death induction, and the assessment of combined index indicated that the combined treatment with Andro and TRAIL repressed breast cancer cells synergistically. Blotting results displayed Andro and TRAIL combination elevated TRAIL-associated receptors, death receptors 4 and 5, at protein levels. These results provided critical insight into breast cancer patients' therapy and exploration direction for TRAIL clinical application.

Elevation of effective p53 expression sensitizes wild-type p53 breast cancer cells to CDK7 inhibitor THZ1.

BACKGROUND: The cyclin-dependent kinase 7 (CDK7) inhibitor THZ1 represses multiple cancer cells. However, its tumor-repressive efficiency in wild-type p53 breast cancer cells remains controversial. METHODS: We conducted various assays, including CCK8, colony formation, flow cytometry, western blotting, and lactate dehydrogenase release detection, to clarify whether p53 elevation sensitizes breast cancer cells to THZ1. RESULTS: We found that upregulating functional p53 contributes to the increased sensitivity of breast cancer cells to THZ1. Increased THZ1 sensitivity requires active p53 and an intact p53 pathway, which was confirmed by introducing exogenous wild-type p53 and the subsequent elevation of THZ1-mediated tumor suppression in breast cancer cells carrying mutant p53. We confirmed that p53 accumulates in the nucleus and mitochondria during cell death. Furthermore, we identified extensive transcriptional disruption, rather than solely CDK7 inhibition, as the mechanism underlying the nutlin-3 and THZ1-induced death of breast cancer cells. Finally, we observed the combined nutlin-3 and THZ1 treatment amplified gasdermin E cleavage. CONCLUSION: Enhanced sensitivity of breast cancer cells to THZ1 can be achieved by increasing effective p53 expression. Our approach may serve as a potential treatment for patients with breast cancer resistant to regular therapies. Video Abstract.