Mito-LND and (E)-Akt inhibitor-IV: novel compounds inducing endoplasmic reticulum stress and ROS accumulation against hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality. Although multi-kinase inhibitors can prolong the overall survival of late-stage HCC patients, the emergence of drug resistance diminishes these benefits, ultimately resulting in treatment failure. Therefore, there is an urgent need for novel and effective drugs to impede the progression of liver cancer. METHODS: This study employed a concentration gradient increment method to establish acquired sorafenib or regorafenib-resistant SNU-449 cells. Cell viability was assessed using the cell counting kit-8 assay. A library of 793 bioactive small molecules related to metabolism screened compounds targeting both parental and drug-resistant cells. The screened compounds will be added to both the HCC parental cells and the drug-resistant cells, followed by a comprehensive assessment. Intracellular adenosine triphosphate (ATP) levels were quantified using kits. Flow cytometry was applied to assess cell apoptosis and reactive oxygen species (ROS). Real-time quantitative PCR studied relative gene expression, and western blot analysis assessed protein expression changes in HCC parental and drug-resistant cells. A xenograft model in vivo evaluated Mito-LND and (E)-Akt inhibitor-IV effects on liver tumors, with hematoxylin and eosin staining for tissue structure and immunohistochemistry staining for endoplasmic reticulum stress protein expression. RESULTS: From the compound library, we screened out two novel compounds, Mito-LND and (E)-Akt inhibitor-IV, which could potently kill both parental cells and drug-resistant cells. Mito-LND could significantly suppress proliferation and induce apoptosis in HCC parental and drug-resistant cells by upregulating glycolytic intermediates and downregulating those of the tricarboxylic acid (TCA) cycle, thereby decreasing ATP production and increasing ROS. (E)-Akt inhibitor-IV achieved comparable results by reducing glycolytic intermediates, increasing TCA cycle intermediates, and decreasing ATP synthesis and ROS levels. Both compounds trigger apoptosis in HCC cells through the interplay of the AMPK/MAPK pathway and the endoplasmic reticulum stress response. In vivo assays also showed that these two compounds could significantly inhibit the growth of HCC cells and induce endoplasmic reticulum stress. CONCLUSION: Through high throughput screening, we identified that Mito-LND and (E)-Akt inhibitor-IV are two novel compounds against both parental and drug-resistant HCC cells, which could offer new strategies for HCC patients.

Achieving dendrite-free growth of Zn anode by electrodepositing on zincophilic gold-furnished mesh for aqueous zinc-ion batteries.

Here, we report a gold-furnished mesh as the current collector for Zn electrodeposition, which is used as the anode in aqueous zinc-ion batteries. The anode exhibits excellent cycling performance without obvious dendrite growth, and the full cell shows an outstanding specific capacity and long-term durability, surpassing those of bare Zn.

The SGLT2 inhibitor empagliflozin inhibits skeletal muscle fibrosis in naturally aging male mice through the AMPKα/MMP9/TGF-ß1/Smad pathway.

ABSTACT: With advancing age, the incidence of sarcopenia increases, eventually leading to a cascade of adverse events. However, there is currently a lack of effective pharmacological treatment for sarcopenia. Sodium-glucose co-transporter 2 inhibitor (SGLT2i) empagliflozin demonstrates anti-fibrotic capabilities in various organs. This study aims to determine whether empagliflozin can improve skeletal muscle fibrosis induced by sarcopenia in naturally aging mice. A natural aging model was established by feeding male mice from 13 months of age to 19 months of age. A fibrosis model was created by stimulating skeletal muscle fibroblasts with TGF-ß1. The Forelimb grip strength test assessed skeletal muscle function, and expression levels of COL1A1, COL3A1, and α-SMA were analyzed by western blot, qPCR, and immunohistochemistry. Additionally, levels of AMPKα/MMP9/TGFß1/Smad signaling pathways were examined. In naturally aging mice, skeletal muscle function declines, expression of muscle fibrosis markers increases, AMPKα expression is downregulated, and MMP9/TGFß1/Smad signaling pathways are upregulated. However, treatment with empagliflozin reverses this phenomenon. At the cellular level, empagliflozin exhibits similar anti-fibrotic effects, and these effects are attenuated by Compound C and siAMPKα. Empagliflozin exhibits anti-fibrotic effects, possibly associated with the AMPK/MMP9/TGFß1/Smad signaling pathways.

Compositional and temporal division of labor modulates mixed sugar fermentation by an engineered yeast consortium.

Synthetic microbial communities have emerged as an attractive route for chemical bioprocessing. They are argued to be superior to single strains through microbial division of labor (DOL), but the exact mechanism by which DOL confers advantages remains unclear. Here, we utilize a synthetic Saccharomyces cerevisiae consortium along with mathematical modeling to achieve tunable mixed sugar fermentation to overcome the limitations of single-strain fermentation. The consortium involves two strains with each specializing in glucose or xylose utilization for ethanol production. By controlling initial community composition, DOL allows fine tuning of fermentation dynamics and product generation. By altering inoculation delay, DOL provides additional programmability to parallelly regulate fermentation characteristics and product yield. Mathematical models capture observed experimental findings and further offer guidance for subsequent fermentation optimization. This study demonstrates the functional potential of DOL in bioprocessing and provides insight into the rational design of engineered ecosystems for various applications.

Downregulation of miR-182-5p by NFIB promotes NAD+ salvage synthesis in colorectal cancer by targeting NAMPT.

Nuclear factor I B (NFIB) plays an important role in tumors. Our previous study found that NFIB can promote colorectal cancer (CRC) cell proliferation in acidic environments. However, its biological functions and the underlying mechanism in CRC are incompletely understood. Nicotinamide adenine dinucleotide (NAD+) effectively affects cancer cell proliferation. Nevertheless, the regulatory mechanism of NAD+ synthesis in cancer remains to be elucidated. Here we show NFIB promotes CRC proliferation in vitro and growth in vivo, and down-regulation of NFIB can reduce the level of NAD+. In addition, supplementation of NAD+ precursor NMN can recapture cell proliferation in CRC cells with NFIB knockdown. Mechanistically, we identified that NFIB promotes CRC cell proliferation by inhibiting miRNA-182-5p targeting and binding to NAMPT, the NAD+ salvage synthetic rate-limiting enzyme. Our results delineate a combination of high expression of NFIB and NAMPT predicted a clinical poorest prognosis. This work provides potential therapeutic targets for CRC treatment.

Spatially resolved transcriptomics revealed local invasion-related genes in colorectal cancer.

Objective: Local invasion is the first step of metastasis, the main cause of colorectal cancer (CRC)-related death. Recent studies have revealed extensive intertumoral and intratumoral heterogeneity. Here, we focused on revealing local invasion-related genes in CRC. Methods: We used spatial transcriptomic techniques to study the process of local invasion in four CRC tissues. First, we compared the pre-cancerous, cancer center, and invasive margin in one section (S115) and used pseudo-time analysis to reveal the differentiation trajectories from cancer center to invasive margin. Next, we performed immunohistochemical staining for RPL5, STC1, AKR1B1, CD47, and HLA-A on CRC samples. Moreover, we knocked down AKR1B1 in CRC cell lines and performed CCK-8, wound healing, and transwell assays to assess cell proliferation, migration, and invasion. Results: We demonstrated that 13 genes were overexpressed in invasive clusters, among which the expression of CSTB and TM4SF1 was correlated with poor PFS in CRC patients. The ribosome pathway was increased, while the antigen processing and presentation pathway was decreased along CRC progression. RPL5 was upregulated, while HLA-A was downregulated along cancer invasion in CRC samples. Pseudo-time analysis revealed that STC1, AKR1B1, SIRPA, C4orf3, EDNRA, CES1, PRRX1, EMP1, PPIB, PLTP, SULF2, and EGFL6 were unpregulated along the trajectories. Immunohistochemic3al staining showed the expression of STC1, AKR1B1, and CD47 was increased along cancer invasion in CRC samples. Knockdown of AKR1B1 inhibited CRC cells' proliferation, migration, and invasion. Conclusions: We revealed the spatial heterogeneity within CRC tissues and uncovered some novel genes that were associated with CRC invasion.

Recent progress in the biology and physiology of BMP-8a.

PURPOSE: BMP-8a is a member of bone morphogenetic proteins (BMPs) and plays a regulatory role in human growth and development as a transcription regulator. This review aims to summarize the current research on the impact and mechanism of BMP-8a in female and male reproduction, formation and eruption of teeth, bone and cartilage development, tissue differentiation, disease occurrence, progression and prognosis. METHODS: The phrases "BMP-8a," "BMPs," "regulator," "mechanism," "osteoblast," "cartilage," "cancer," "disease," and "inflammation" were searched in the PubMed database. The abstracts were evaluated, and a series of original publications and reviews were examined. RESULTS: According to the search, BMP-8a affects the development of the uterus by inhibiting luteinization and plays an important role in late spermatogenesis. It is highly expressed in osteogenesis and differentially expressed in chondrogenesis. Furthermore, BMP-8a has a significant impact on the occurrence, development and prognosis of various diseases. CONCLUSIONS: BMP-8a regulates important factors and pathways, such as SMAD2/3 and SMAD1/5/8, to promote or inhibit the developmental processes of human reproductive organs. BMP-8a is also a member of the BMP family of proteins that regulates chondrogenesis and osteogenesis. In addition to its osteoinductive capabilities, BMP-8a is involved in the progression of diverse cancers.

Transcriptional regulation of NDUFA4L2 by NFIB induces sorafenib resistance by decreasing reactive oxygen species in hepatocellular carcinoma.

Sorafenib is one a first-line therapeutic drugs for advanced hepatocellular carcinoma (HCC). However, only 30% of patients benefit from sorafenib due to drug resistance. We and other groups have revealed that nuclear factor I B (NFIB) regulates liver regeneration and carcinogenesis, but its role in drug resistance is poorly known. We found that NFIB was more upregulated in sorafenib-resistant SMMC-7721 cells compared to parental cells. NFIB knockdown not only sensitized drug-resistant cells to sorafenib but also inhibited the proliferation and invasion of these cells. Meanwhile, NFIB promoted the proliferation and invasion of HCC cells in vitro and facilitated tumor growth and metastasis in vivo. Knocking down NFIB synergetically inhibited tumor growth with sorafenib. Mechanically, gene expression profiling and subsequent verification experiments proved that NFIB could bind with the promoter region of a complex I inhibitor NDUFA4L2 and promote its transcription. Transcriptional upregulation of NDUFA4L2 by NFIB could thus inhibit the sorafenib-induced reactive oxygen species accumulation. Finally, we found that NFIB was highly expressed in HCC tissues, and high NFIB expression level was associated with macrovascular invasion, advanced tumor stage, and poor prognosis of HCC patients (n = 156). In summary, we demonstrated that NFIB could transcriptionally upregulate NDUFA4L2 to enhance both intrinsic and acquired sorafenib resistance of HCC cells by reducing reactive oxygen species induction.

A classification framework for identifying bronchitis and pneumonia in children based on a small-scale cough sounds dataset.

Bronchitis and pneumonia are the common respiratory diseases, of which pneumonia is the leading cause of mortality in pediatric patients worldwide and impose intense pressure on health care systems. This study aims to classify bronchitis and pneumonia in children by analyzing cough sounds. We propose a Classification Framework based on Cough Sounds (CFCS) to identify bronchitis and pneumonia in children. Our dataset includes cough sounds from 173 outpatients at the West China Second University Hospital, Sichuan University, Chengdu, China. We adopt aggregation operation to obtain patients' disease features because some cough chunks carry the disease information while others do not. In the stage of classification in our framework, we adopt Support Vector Machine (SVM) to classify the diseases due to the small scale of our dataset. Furthermore, we apply data augmentation to our dataset to enlarge the number of samples and then adopt Long Short-Term Memory Network (LSTM) to classify. After 45 random tests on RAW dataset, SVM achieves the best classification accuracy of 86.04% and standard deviation of 4.7%. The precision of bronchitis and pneumonia is 93.75% and 87.5%, and their recall is 88.24% and 93.33%. The AUC of SVM and LSTM classification models on the dataset with pitch-shifting data augmentation reach 0.92 and 0.93, respectively. Extensive experimental results show that CFCS can effectively classify children into bronchitis and pneumonia.

[Research on competency building standards of institutions of schistosomiasis prevention and control in Hubei Province I Investigation of institution management].

OBJECTIVE: To investigate the current situation of management of institutions of schistosomiasis prevention and control in Hubei Province, so as to explore the probable competency building standards for these institutions at the county and township levels. METHODS: By using a combination of quantitative and qualitative methods, the institutions of schistosomiasis prevention and control at county and township levels were investigated for the institutional setup, staffing and fulfillment functions since the reform of 2004. RESULTS: Among 63 schistosomiasis endemic counties (cities, districts) of Hubei Province, there were 26 independent schistosomiasis control institutions (41.27%), there were 24 institutions which were incorporated into CDC (38.10%), and there were no institutions in 13 counties (20.63%). Among 518 endemic towns, there were 299 institutions (57.72%). The total staffing size were 1 932, but there were 1 586 (82.09%) people actually working in the post, and therefore there were 346 (17.91%) empty positions. The average rates of carrying out the six functions were 91.48%-71.19%, but only 19.23% of the institutions participated in the comprehensive schistosomiasis control management project and its effect assessment. CONCLUSION: According to the management model for schistosomiasis control institutions under the current institutional mechanisms, we need a rigorous industry standard to constrain, guide and standardize the management and capacity-building of the institutions in different historical periods.

[Research on competency building standards of institutions of schistosomiasis prevention and control in Hubei Province. II. Investigation of human resources].

OBJECTIVE: To understand the human resources of the grassroots institutions of schistosomiasis control and prevention, so as to provide the evidence for formulating the standards of institutional capacity-building. METHODS: By using the combination of quantitative and qualitative methods, the hierarchy of schistosomiasis control institution workers, structural features of workers, and benefits of workers were investigated and the results were analyzed statistically after the 2004 reform. RESULTS: The constituent ratios of personnel ≤ 30 years old, 30 to 45 years old, and ≥ 45 years old were 6.8%, 64.0% and 29.2% respectively, with an average age of 43.1 years. For education levels, 61.35% of the personnel had secondary or high school levels. At the city level, the structural proportion of the senior professional; medium professional and primary professional titles was 1.4 : 5.6 : 3.0, and at the county level, the proportion was 0.5 : 6.1 : 3.4. There was 14 200 yuan per capita at the township schistosomiasis control institutions. CONCLUSION: The technology of the personnel in schistosomiasis institutions of Hubei Province is weak, the average age of personnel is old, and the salary is low.