Self-assembly of PEG-PPS polymers and LL-37 peptide nanomicelles improves the oxidative microenvironment and promotes angiogenesis to facilitate chronic wound healing.

Refractory diabetic wounds are associated with high incidence, mortality, and recurrence rates and are a devastating and rapidly growing clinical problem. However, treating these wounds is difficult owing to uncontrolled inflammatory microenvironments and defective angiogenesis in the affected areas, with no established effective treatment to the best of our knowledge. Herein, we optimized a dual functional therapeutic agent based on the assembly of LL-37 peptides and diblock copolymer poly(ethylene glycol)-poly(propylene sulfide) (PEG-PPS). The incorporation of PEG-PPS enabled responsive or controlled LL-37 peptide release in the presence of reactive oxygen species (ROS). LL-37@PEG-PPS nanomicelles not only scavenged excessive ROS to improve the microenvironment for angiogenesis but also released LL-37 peptides and protected them from degradation, thereby robustly increasing angiogenesis. Diabetic wounds treated with LL-37@PEG-PPS exhibited accelerated and high-quality wound healing in vivo. This study shows that LL-37@PEG-PPS can restore beneficial angiogenesis in the wound microenvironment by continuously providing angiogenesis-promoting signals. Thus, it may be a promising drug for improving chronic refractory wound healing.

Loss of nephric augmenter of liver regeneration facilitates acute kidney injury via ACSL4-mediated ferroptosis.

Ferroptosis, characterized by lipid accumulation in intracellular compartments, is related to acute kidney injury (AKI), but the mechanism remains obscure. In our previous study, the protective effect of augmenter of liver regeneration (ALR) on AKI was not fully clarified. In this study, we established an AKI mouse model by knocking out proximal tubule-specific ALR and an AKI cell model by inducing hypoxia, as well as enrolled AKI patients, to investigate the effects of ALR on ferroptosis and the progression of AKI. We found that ALR knockout aggravated ferroptosis and increased ROS accumulation and mitochondrial damage, whereas ALR overexpression attenuated ferroptosis through clearance of ROS and maintenance of mitochondrial morphology. Mechanistically, we demonstrated that ALR could directly bind to long-chain-fatty-acid-CoA ligase 4 (ACSL4) and further inhibit the expression of ACSL4 by interacting with certain regions. By resolution liquid chromatography coupled with triple quadruple mass spectrometry, we found that ALR could reduce the contents of polyunsaturated fatty acids, especially arachidonic acid. In addition, we showed that ALR binds to ACSL4 and attenuates oxylipin accumulation, exerting a protective effect against ferroptosis in AKI. Therefore, targeting renal ALR can attenuate ferroptosis and can offer a promising strategy for the treatment of AKI.

Optimization of the Solid-State Culture Conditions and Chemical Component Analysis of Poria cocos (Agaricomycetes).

The optimal cultivation conditions and chemical components of Poria cocos fruiting bodies were examined by employing the single factor and response surface methods to screen for optimal conditions for artificial cultivation. The differences in chemical composition among the fruiting bodies, fermented mycelium, and sclerotia of P. cocos were compared using UV spectrophotometry and high-performance liquid chromatography (HPLC). The optimal growth conditions for P. cocos fruiting bodies were 28.5°C temperature, 60% light intensity, and 2.5 g pine sawdust, which resulted in the production of numerous basidiocarps and basidiospores under microscopic examination. Polysaccharides, triterpenoids, and other main active components of P. cocos were found in the fruiting bodies, sclerotia, and fermented mycelium. The triterpenoid components of the fruiting bodies were consistent with those of the sclerotia. The content of pachymic acid in the fruiting bodies was significantly higher than that in the sclerotia, with a value of 33.37 ± 0.1902 mg/g. These findings provide novel insights into the sexual breeding and comprehensive development and utilization of P. cocos.

Clinical features and prognosis of pregnancy-related renal damage and pregnancy after chronic kidney disease.

OBJECTIVE: To explore the clinical features of renal damage related to pregnancy and pregnancy after chronic kidney disease (CKD), providing clinical evidence for the relationship between renal damage and pregnancy. METHODS: A retrospective analysis was performed on patients admitted to our hospital between March 2013 and February 2021 who had both pregnancy and kidney damage. The study collected pathology results from renal biopsies, 24-hour urinary protein quantity, albumin (Alb), serum creatinine (Scr), blood lipids, coagulation function, blood routine, and other indicators during and after pregnancy. RESULTS: This study included 82 cases, with 48 cases in the pregnancy-related renal damage group. Thirty-four cases were in the post-CKD pregnancy group. Of the patients, 30 cases (88.24%) had CKD stage 1-2. Results showed better pregnancy and fetal outcomes in the post-CKD pregnancy group compared to the pregnancy-related renal damage group (Ρ was 0.029 and 0.036, respectively). Renal biopsy pathology revealed that 16 cases (33.33%) in the pregnancy-related renal damage group mainly had focal segmental glomerulosclerosis (FSGS), while the post-CKD pregnancy group was dominated by 14 cases (43.75%) of IgA nephropathy. The first blood test indicators revealed that the pregnancy-related renal damage group had lower estimated glomerular filtration (eGFR) and Alb levels compared to the post-CKD pregnancy group (Ρ was 0.003 and 0.000, respectively). Additionally, 24-hour urinary protein quantity, total cholesterol (Tch), triglyceride (TG), and platelet (PLT) counts were higher in the pregnancy-related renal damage group compared to the post-CKD pregnancy group (Ρ was 0.005, 0.001, 0.008, and 0.031, respectively). The abnormal rate of Scr during pregnancy was 41.67% (20/48) in the pregnancy-related renal damage group and 17.39% (4/23) in the post-CKD pregnancy group, with a statistically significant difference (Ρ was 0.043). CONCLUSION: The pregnancy-related renal damage group is mainly associated with FSGS, while the post-CKD pregnancy group is characterized by IgA nephropathy. Patients with CKD1-2 can have a successful pregnancy after achieving good control of eGFR, albumin, 24-hour urinary protein quantity and other indicators, resulting in better pregnancy and fetal outcomes. Abnormal Scr levels during pregnancy of pregnancy-related renal damage can be improved within 3 months after delivery.

Construction and validation of 3-genes hypoxia-related prognostic signature to predict the prognosis and therapeutic response of hepatocellular carcinoma patients.

BACKGROUND: Previous studies have shown that the hypoxia microenvironment significantly impacted tumor progression. However, the clinical prognostic value of hypoxia-related risk signatures and their effects on the tumor microenvironment (TME) in hepatocellular carcinoma (HCC) remains hazy. This study aimed to conduct novel hypoxia-related prognostic signatures and improve HCC prognosis and treatment. METHODS: Differentially expressed hypoxia-related genes (HGs) were identified with the gene set enrichment analysis (GSEA). Univariate Cox regression was utilized to generate the tumor hypoxia-related prognostic signature, which consists of 3 HGs, based on the least absolute shrinkage and selection operator (LASSO) algorithm. Then the risk score for each patient was performed. The prognostic signature's independent prognostic usefulness was confirmed, and systematic analyses were done on the relationships between the prognostic signature and immune cell infiltration, somatic cell mutation, medication sensitivity, and putative immunological checkpoints. RESULTS: A prognostic risk model of four HGs (FDPS, SRM, and NDRG1) was constructed and validated in the training, testing, and validation datasets. To determine the model's performance in patients with HCC, Kaplan-Meier curves and time-dependent receiver operating characteristic (ROC) curves analysis was implemented. According to immune infiltration analysis, the high-risk group had a significant infiltration of CD4+ T cells, M0 macrophages, and dendritic cells (DCs) than those of the low-risk subtype. In addition, the presence of TP53 mutations in the high-risk group was higher, in which LY317615, PF-562271, Pyrimethamine, and Sunitinib were more sensitive. The CD86, LAIR1, and LGALS9 expression were upregulated in the high-risk subtype. CONCLUSIONS: The hypoxia-related risk signature is a reliable predictive model for better clinical management of HCC patients and offers clinicians a holistic viewpoint when determining the diagnosis and course of HCC treatment.

Composite nanofibrous dressing loaded with Prussian blue and heparin for anti-inflammation therapy and diabetic wound healing.

Diabetic ulcer is a severe complication of diabetes that can lead to amputation due to the overproduction of pro-inflammatory factors and reactive oxygen species (ROS). In this study, a composite nanofibrous dressing was developed by combining Prussian blue nanocrystals (PBNCs) and heparin sodium (Hep) through electrospinning, electrospraying, and chemical deposition. The nanofibrous dressing (PPBDH) was designed to take advantage of the excellent pro-inflammatory factor-adsorbing capability of Hep and the ROS-scavenging capabilities of PBNCs, resulting in synergistic treatment. It is worth noting that the nanozymes were firmly anchored to the fiber surfaces through slight polymer swelling caused by the solvent during electrospinning, thereby guaranteeing the preservation of the enzyme-like activity levels of PBNCs. The PPBDH dressing was found to be effective in reducing intracellular ROS levels, protecting cells from ROS-induced apoptosis, and capturing excessive pro-inflammatory factors, including chemoattractant protein-1 (MCP-1) and interleukin-1ß (IL-1ß). Furthermore, a chronic wound healing evaluation conducted in vivo demonstrated that the PPBDH dressing was able to effectively alleviate the inflammatory response and accelerate wound healing. This research presents an innovative approach to fabricate nanozyme hybrid nanofibrous dressings, which have great potential in accelerating the healing of chronic and refractory wounds with uncontrolled inflammation.

USP33 promotes pancreatic cancer malignant phenotype through the regulation of TGFBR2/TGFß signaling pathway.

Pancreatic cancer (PC) ranked fourth among cancer-related death worldwide with a survival rate less than 5%. The abnormal proliferation and distant metastasis are major obstacles for the diagnosis and treatment of pancreatic cancer, therefore, it is urgent for researchers to uncover the molecular mechanisms underlying the PC proliferation and metastasis. In current study, we found that USP33, a member of deubiquitinating enzyme family, was upregulated among PC samples and cells, meanwhile, the high expression of USP33 correlated with poor prognosis of patients. Function experiments revealed that USP33 overexpression promoted the proliferation, migration and invasion of PC cells while the inhibition of USP33 expression in PC cells exhibited the opposite effect. The mass spectrum and luciferase complementation assay screened TGFBR2 as the potential binding protein of USP33. Mechanistically, USP33 triggered the deubiquitination of TGFBR2 and prevented its degradation by lysosome, therefore promoted TGFBR2 accumulation in cell membrane and eventually contributed to the sustained activation of TGF-ß signaling. Moreover, our results revealed that the activation of TGF-ß targeted gene ZEB1 promoted the transcription of USP33. In conclusion, our study found that USP33 contributed to the proliferation and metastasis of pancreatic cancer through a positive feedback loop with TGF-ß signaling pathway. Moreover, this study suggested that USP33 may serve as a potential prognostic and therapeutic target in PC.

Supervised Attention-Based Bidirectional Long Short-Term Memory Network for Nonlinear Dynamic Soft Sensor Application.

Soft sensors are mathematical methods that describe the dependence of primary variables on secondary variables. A nonlinear characteristic commonly appears in modern industrial process data with increasing complexity and dynamics, which has brought challenges to soft sensor modeling. To solve these issues, a novel supervised attention-based bidirectional long short-term memory (SA-BiLSTM) is first proposed in this paper to handle the nonlinear industrial process modeling with dynamic features. In this SA-BiLSTM model, an attention mechanism is introduced to calculate the correlation between hidden features in each time step, thus avoiding the loss of important information. Furthermore, this approach combines historical quality information and a moving window through a supervised strategy of quality variables. Such manipulation not only extracts and exploits nonlinear dynamic latent information from the process and quality variables but also enhances the model's learning efficiency and overall prediction performance. Finally, two real industrial examples demonstrate the superiority of the proposed method compared to conventional methods.

Predictive Modeling With Multiresolution Pyramid VAE and Industrial Soft Sensor Applications.

In industrial processes, the sampling rates of process variables are discrepant because of the nature of instruments and measuring demands, which forms the challenging issue, that is, the multirate modeling in the data-driven soft sensor development. In this work, a multiresolution pyramid variational autoencoder (MR-PVAE) predictive model is proposed to solve this problem based on the deep feature extraction and feature pyramid augmentation. First, a multirate data filter is designed through a resolution searching strategy to turn the original process data into a multiresolution dataset. Then, the pyramid variational autoencoder (PVAE) is proposed to extract deep nonlinear features from the data with different resolutions. In PVAE, the augmented feature pyramid is constructed layer by layer to fuse extracted features from low resolution to the high. As a consequence, the extracted features with various resolutions are gathered to form the regression model, where the process information contained in data with discrepant sampling rates can be fully utilized. Due to the layer-by-layer enhanced features, the prediction accuracy of the soft sensing model are gradually improved. Meanwhile, an optimized training strategy is established to select the optimal feature pyramid for prediction. A numerical experiment and an industrial soft sensing case are given to validate the effectiveness and superiority of the proposed MR-PVAE model.

A novel necroptosis-related lncRNA signature predicts the prognosis and immune microenvironment of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the malignant tumors with high mortality and a worse prognosis globally. Necroptosis is a programmed death mediated by receptor-interacting Protein 1 (RIP1), receptor-interacting Protein 1 (RIP3), and Mixed Lineage Kinase Domain-Like (MLKL). Our study aimed to create a new Necroptosis-related lncRNAs (NRlncRNAs) risk model that can predict survival and tumor immunity in HCC patients. The RNA expression and clinical data originated from the TCGA database. Pearson correlation analysis was applied to identify the NRlncRNAs. The LASSO-Cox regression analysis was employed to build the risk model. Next, the ROC curve and the area under the Kaplan-Meier curve were utilized to evaluate the accuracy of the risk model. In addition, based on the two groups of risk model, we performed the following analysis: clinical correlation, differential expression, PCA, TMB, GSEA analysis, immune cells infiltration, and clinical drug prediction analysis. Plus, qRT-PCR was applied to test the expression of genes in the risk model. Finally, a prognosis model covering six necroptosis-related lncRNAs was constructed to predict the survival of HCC patients. The ROC curve results showed that the risk model possesses better accuracy. The 1, 3, and 5-years AUC values were 0.746, 0.712, and 0.670, respectively. Of course, we also observed that significant differences exist in the following analysis, such as functional signaling pathways, immunological state, mutation profiles, and medication sensitivity between high-risk and low-risk groups of HCC patients. The result of qRT-PCR confirmed that three NRlncRNAs were more highly expressed in HCC cell lines than in the normal cell line. In conclusion, based on the bioinformatics analysis, we constructed an NRlncRNAs associated risk model, which predicts the prognosis of HCC patients. Although our study has some limitations, it may greatly contribute to the treatment of HCC and medical progression.

Identification and analysis of DNA methylation-driven signatures for prognostic and immune microenvironments evaluation in hepatocellular carcinoma.

Liver cancer is the main reason of cancer deaths globally, with an unfavorable prognosis. DNA methylation is one of the epigenetic modifications and maintains the right adjustment of gene expression and steady gene silencing. We aim to explore the novel signatures for prognosis by using DNA methylation-driven genes. To acquire the DNA methylation-driven genes, we perform the difference analysis from the gene expression data and DNA methylation data in TCGA or GEO databases. And we obtain the 31 DNA methylation-driven genes. Subsequently, consensus clustering analysis was utilized to identify the molecular subtypes based on the 31 DNA methylation-driven genes. So, two molecular subtypes were identified to perform those analyses: Survival, immune cell infiltration, and tumor mutation. Results showed that two subtypes were clustered with distinct prognoses, tumor-infiltrating immune cell and tumor mutation burden. Furthermore, the 31 DNA methylation-driven genes were applied to perform the survival analysis to select the 14 survival-related genes. Immediately, a five methylation-driven genes risk model was built, and the patients were divided into high and low-risk groups. The model was established with TCGA as the training cohort and GSE14520 as the validation cohort. According to the risk model, we perform the systematical analysis, including survival, clinical feature, immune cell infiltration, somatic mutation status, underlying mechanisms, and drug sensitivity. Results showed that the high and low groups possessed statistical significance. In addition, the ROC curve was utilized to measure the accuracy of the risk model. AUCs at 1-year, 3-years, and 5-years were respectively 0.770, 0.698, 0.676 in training cohort and 0.717, 0.649, 0.621 in validation cohort. Nomogram was used to provide a better prediction for patients' survival. Risk score increase the accuracy of survival prediction in HCC patients. In conclusion, this study developed a novel risk model of five methylation-driven genes based on the comprehensive bioinformatics analysis, which accurately predicts the survival of HCC patients and reflects the immune and mutation features of HCC. This study provides novel insights for immunotherapy of HCC patients and promotes medical progress.

Identification and Analysis of Immune-Related Gene Signature in Hepatocellular Carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) originates from the hepatocytes and accounts for 90% of liver cancer. The study intends to identify novel prognostic biomarkers for predicting the prognosis of HCC patients based on TCGA and GSE14520 cohorts. METHODS: Differential analysis was employed to obtain the DEGs (Differentially Expressed Genes) of the TCGA-LIHC-TPM cohort. The lasso regression analysis was applied to build the prognosis model through using the TCGA cohort as the training group and the GSE14520 cohort as the testing group. Next, based on the prognosis model, we performed the following analyses: the survival analysis, the independent prognosis analysis, the clinical feature analysis, the mutation analysis, the immune cell infiltration analysis, the tumor microenvironment analysis, and the drug sensitivity analysis. Finally, the survival time of HCC patients was predicted by constructing nomograms. RESULTS: Through the lasso regression analysis, we obtained a prognosis model of ten genes including BIRC5 (baculoviral IAP repeat containing 5), CDK4 (cyclin-dependent kinase 4), DCK (deoxycytidine kinase), HSPA4 (heat shock protein family A member 4), HSP90AA1 (heat shock protein 90 α family class A member 1), PSMD2 (Proteasome 26S Subunit Ubiquitin Receptor, Non-ATPase 2), IL1RN (interleukin 1 receptor antagonist), PGF (placental growth factor), SPP1 (secreted phosphoprotein 1), and STC2 (stanniocalcin 2). First, we found that the risk score is an independent prognosis factor and is related to the clinical features of HCC patients, covering AFP (α-fetoprotein) and stage. Second, we observed that the p53 mutation was the most obvious mutation between the high-risk and low-risk groups. Third, we also discovered that the risk score is related to some immune cells, covering B cells, T cells, dendritic, macrophages, neutrophils, etc. Fourth, the high-risk group possesses a lower TIDE score, a higher expression of immune checkpoints, and higher ESTIMATE score. Finally, nomograms include the clinical features and risk signatures, displaying the clinical utility of the signature in the survival prediction of HCC patients. CONCLUSIONS: Through the comprehensive analysis, we constructed an immune-related prognosis model to predict the survival of HCC patients. In addition to predicting the survival time of HCC patients, this model significantly correlates with the tumor microenvironment. Furthermore, we concluded that these ten immune-related genes (BIRC5, CDK4, DCK, HSPA4, HSP90AA1, PSMD2, IL1RN, PGF, SPP1, and STC2) serve as novel targets for antitumor immunity. Therefore, this study plays a significant role in exploring the clinical application of immune-related genes.

TRPC6 inhibits renal tubular epithelial cell pyroptosis through regulating zinc influx and alleviates renal ischemia-reperfusion injury.

Canonical transient receptor potential-6 (TRPC6) has been reported to be involved in cell damage after ischemia/reperfusion (I/R) injury in target organs. While the effect and of TRPC6 on pyroptosis in renal I/R injury remain unclear. In our study, we first established the renal I/R mouse model and oxygen-glucose deprivation and re-oxygenation (OGD/R) cell model, and investigated the impacts of TRPC6 on the pyroptosis-related proteins using CCK-8, western blot, ELISA, and immunofluorescence probes. Besides, we also explored the mechanism of TRPC6 in pyroptosis of renal tubular epithelial cells through A20 knockdown or overexpression and zinc chloride (ZnCl2 ) or a zinc ion chelator (TPEN) treatment. Our results indicated that I/R injury could cause downregulation of TRPC6 both in vivo and in vitro. In the I/R injury murine model, TRPC6 inhibition exacerbated tissue damage and upregulated NLRP3, ASC, caspase-1, IL-18, and IL-1ß, which could be alleviated by the administration of ZnCl2 . In the OGD/R cell model, inhibitor of TRPC6 (SAR7334) reduced zinc ion influx, aggravated cell death and upregulated pyroptosis-related protein. The pyroptosis phenotype also could be alleviated by ZnCl2 and intensified by TPEN. Overexpression of A20 reduced the expression of pyroptosis-related protein, increased cell viability in the sh-TRPC6 and TPEN-treated OGD/R cell models, while A20 deficiency impaired the protective effect of zinc ion. Therefore, our results indicate that TRPC6 could promote zinc ion influx in renal tubular epithelial cells, thereby upregulating intracellular A20, inhibiting the activation of inflammasome NLRP3, and ultimately attenuating renal I/R injury.

NAP1L1 Functions as a Novel Prognostic Biomarker Associated With Macrophages and Promotes Tumor Progression by Influencing the Wnt/ß-Catenin Pathway in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is regarded as one of the universal cancers in the world. Therefore, our study is based on clinical, molecular mechanism and immunological perspectives to analyze how NAP1L1 affects the progression of HCC. To begin with, the gene expression datasets and clinical data of GSE14520, GSE76427, ICGC, and TCGA are originated from GEO, ICGC, and TCGA databases. Subsequently, DEG screening was performed on data using R studio, and we finally found that 2,145 overlapping DEGs were screened from four datasets at the end. Then, we used R studio to filter the survival-related genes of the GSE76427 and ICGC datasets, and we screened out 101 survival-related genes. Finally, 33 common genes were screened out from 2,145 overlapping DEGs and 101 survival-related genes. Then, NAP1L1 was screened from 33 common genes using the CytoHubba plug-in in Cytoscape software. Furthermore, ground on GEO, ICGC, and TCGA databases, the survival analysis, clinical feature analysis, univariate/multivariate regression analysis, and multiple GSEA were used to study NAP1L1. The Conclusion claimed that HCC patients with higher expression levels of NAP1L1 had a poorer prognosis than those with lower expression levels. Thus, we believe that NAP1L1 is an independent prognostic factor for HCC. In order to shed light on NAP1L1's molecular mechanism promoting the progression of HCC closely, the GSEA tool was applied to complete the GSEA of the four datasets. Furthermore, the results confirmed that NAP1L1 could promote HCC progression by regulating the G2/M transition of the cell cycle and Wnt signaling pathway. Western blot and flow cytometry were also performed to understand those mechanisms in this study. The result of Western blot showed that NAP1L1 silencing led to downregulation of CDK1 and ß-catenin proteins; the result of flow cytometry showed that cell numbers in the G2 phase were significantly increased when NAP1L1 was silenced. Thus, we claimed that NAP1L1 might promote HCC progression by activating the Wnt signaling pathway and promoting cell cycle G2/M transition. In addition, ground on GSE14520 and GSE76427 datasets, and ICGC and TCGA databases, the correlation between NAP1L1 and immune cells was analyzed in HCC patients. At the same time, the TISIDB online database and the TIMER online database were testified to the association between NAP1L1 and immune cells. Hence, the summary shows that NAP1L1 was connected with a certain amount of immune cells. We can speculate that NAP1L1 may influence macrophages to promote HCC progression through some potential mechanisms.

Integrated Network Pharmacology and Metabolomics Analysis to Reveal the Potential Mechanism of Siwu Paste on Aplastic Anemia Induced by Chemotherapy Drugs.

Purpose: This study aimed to reveal the multicomponent synergy mechanisms of SWP based on network pharmacology and metabolomics for exploring the relationships of active ingredients, biological targets, and crucial metabolic pathways. Materials: Network pharmacology, including TRRUST, GO, and KEGG, enrichment was used to discover the active ingredients and potential regulation mechanisms of SWP. LC-MS and multivariate data analysis method were further applied to analyze serum metabolomics profiling for discovering the potential metabolic mechanisms of SWP on AA induced by Cyclophosphamide (CTX) and 1-Acetyl-2-phenylhydrazine (APH). Results: A total of 27 important bioactive ingredients meeting the ADME (absorption, distribution, metabolism, and excretion) screening criteria from SWP were selected. Interaction networks were constructed and validated based on the 10 associated ingredients with the relevant targets. A total of 125 biomarkers were found by Metabolomics approach, which associated with the development of AA, mainly involved in amino acid metabolism and lipid metabolism. While SWP can reverse the above 12 metabolites changed by AA. Network analysis revealed the synergistic effects of SWP through the 43 crucial pathways, including Sphingolipid signaling pathway, Sphingolipid metabolism, Arginine and proline metabolism, VEGF signaling pathway, Estrogen signaling pathway. Conclusion: The study suggested that SWP is a useful alternative for the treatment of AA induced by CTX + APH. Its potential mechanisms are to improve hematopoietic microenvironment and promote bone marrow hematopoiesis therapies.

TRPC6 ameliorates renal ischemic reperfusion injury by inducing Zn2+ influx and activating autophagy to resist necrosis.

Background: Renal ischemic reperfusion injury (RIRI) is the most hackneyed cause of acute renal injury with high incidence. As a slit diaphragm (SD), TRPC6 (transient receptor potential channel 6) can maintain the structure and function of glomerular podocytes, and its activation has been reported to prominently alleviate ischemia reperfusion (I/R). However, the specific mechanism of TRPC6 in RIRI is uncertain. Methods: The TRPC6 specific shRNA or overexpressing plasmid was used to decrease or increase TRPC6 level in HK-2 cells, respectively. Subsequently, the OGD/R (oxygen-glucose deprivation and re-oxygenation) HK-2 cells and RIRI model rats was established to examine the effect of TRPC6 in RIRI in vitro. After processing, viability was confirmed with MTT; cell necrosis was analyzed with flow cytometry; necrosis and autophagy-related proteins were verified with Western blot; free Zn2+ was tested with an Zn2+ fluorescent probe; and cell autophagy was monitored with MDC (monodansylcadaverine) method. Furthermore, TRPC6 agonist (OGA) or TRPC6 inhibitor (SKF96365) were introduced to increase or inhibit the activity of TRPC6 in RIRI model rats, and the kidney injury was assessed with H&E staining and RIP1 and PARP-1 expressions were examined with IHC (immunohistochemistry) staining. Results: Our results verified TRPC6 could markedly enhance viability, Zn2+ influx, and autophagy, and suppressed necrosis in OGD/R HK-2 cells. In addition, increase of Zn2+ or autophagy activation produced similar results to TRPC6 overexpression in viability, autophagy, and necrosis of OGD/R HK-2 cells. Rescue experiment results also showed TRPC6 could prevent necrosis and facilitate Zn2+ influx and autophagy of OGD/R HK-2 cells by inducing Zn2+ influx and autophagy. Moreover, TRPC6 could ameliorate kidney injury, block necrosis, and enhance autophagy in RIRI model rats by promoting Zn2+ influx and autophagy. Conclusions: TRPC6 could prevent necrosis and induce autophagy to alleviate RIRI by accelerating Zn2+ influx and autophagy. This shows TRPC6/Zn2+ influx/autophagy might be a novel therapeutic strategy for RIRI.

Huxie Huaji Ointment Induced Apoptosis of Liver Cancer Cells In Vivo and In Vitro by Activating the Mitochondrial Pathway.

Huxie Huaji (HXHJ) Ointment is a famous traditional Chinese medicinal prescription and is commonly used for the clinical treatment of hepatocellular carcinoma by boosting immunity and detoxification. However, the scientific evidence for the effect of HXHJ Ointment on hepatocellular carcinoma and the underlying molecular mechanism are lacking. The present study aimed to identify the effects of HXHJ Ointment on hepatocellular carcinoma in vitro and in vivo as well as investigating the mechanistic basis for the anticancer effect of HXHJ ointment. First, liquid chromatography-mass spectrometry was used to verify the composition of HXHJ Ointment and quality control. Second, in vitro, Cell Counting Kit (CCK8) cell viability assay and Hoechst 33342 staining assay were performed to explain the cell apoptosis. The protein levels of tumor suppressor protein (p53), B-cell lymphoma 2 gene (Bcl-2), cytochrome C (Cyt-C), and aspartate proteolytic enzyme-3 (caspase-3) were examined by immunofluorescence. Finally, in vivo, hematoxylin and eosin (H&E) staining was used to observe the pathological changes in hepatocellular carcinoma samples. Western blots and immunohistochemistry were used to detect the anticancer properties of HXHJ ointment. The results in vitro showed that 20% HXHJ Ointment serum could significantly inhibit HepG2 cell proliferation, increased tumor suppressor gene p53, downregulated antiapoptotic protein Bcl-2, promoted the release of mitochondrial Cyt-C, activated caspase-3, and induced HepG2 cell apoptosis. Furthermore, in vivo experiments showed that HXHJ Ointment could effectively inhibit tumor growth in nude mice xenotransplanted with HepG2 cells, changed the morphology of tumor cells, and regulated the expression of apoptosis-related protein pathway p53/Bcl-2/Cyt-C/caspase-3. HXHJ Ointment can significantly inhibit the development of hepatocellular carcinoma, and its mechanism may be related to the regulation of p53/Bcl-2/Cyt-C/caspase-3 signaling pathway to induce cell mitochondrial apoptosis.

Dual Blockade of the Renin-Angiotensin System: A Strategy that Should Be Reconsidered in Cardiorenal Diseases?

Studies on pharmacological mechanisms demonstrated that a strategy of dual renin-angiotensin system (RAS) blockade may have a synergistic effect in the treatment of cardiorenal diseases and may reduce adverse reactions. However, some previous clinical studies reported that dual RAS blockade did not significantly benefit many patients with cardiorenal diseases and increased the risk of hyperkalemia, hypotension and renal function damage. Therefore, the current clinical guidelines suggest that the combined use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) should be used with caution in the clinic. However, these studies enrolled older patients with cardiovascular risk factors, and the results of these trials may not be generalized to the overall population. Some clinical evidence suggests that the combination of low-dose ACEIs and ARBs leads to more effective RAS blockade with few adverse effects. The advent of new RAS inhibitors with superior pharmacological effects provides a more suitable drug choice for individualized therapy for dual RAS blockade. Therefore, the choice of appropriate ARBs/ACEIs for individualized therapy based on patient condition may be a better way to improve the efficiency and safety of the dual RAS blockade strategy.

Research Trends, Hot Spots, and Prospects for Traditional Chinese Medicine in the Field of Ischemia-Reperfusion Injury.

Ischemia-reperfusion (I/R) injury is one of the most common phenomena in ischemic disease or processes that causes progressive disability or even death. It has a major impact on global public health. Traditional Chinese medicine (TCM) has a long history of application in ischemic diseases and has significant clinical effect. Numerous studies have shown that the formulas or single herbs in TCM have specific roles in regulating oxidative stress, anti-inflammatory, inhibiting cell apoptosis, etc., in I/R injury. We used bibliometrics to quantitatively analyze the global output of publications on TCM in the field of I/R injury published in the period 2001-2021 to identify research hotspots and prospects. We included 446 related documents published in the Web of Science during 2001-2021. Visualization analysis revealed that the number of publications related to TCM in the field of I/R injury has increased year by year, reaching a peak in 2020. China is the country with the largest number of publications. Keywords and literature analyses demonstrated that neuroregeneration is likely one of the research hotspots and future directions of research in the field. Taken together, our findings suggest that although the inherent limitations of bibliometrics may affect the accuracy of the literature-based prediction of research hotspots, the results obtained from the included publications can provide a reference for the study of TCM in the field of I/R injury.

Mesenchymal stem cell-derived exosomes for gastrointestinal cancer.

Gastrointestinal (GI) malignancies, a series of malignant conditions originating from the digestive system, include gastric cancer, hepatocellular carcinoma, pancreatic cancer, and colorectal cancer. GI cancers have been regarded as the leading cancer-related cause of death in recent years. Therefore, it is essential to develop effective treatment strategies for GI malignancies. Mesenchymal stem cells (MSCs), a type of distinct non-hematopoietic stem cells and an important component of the tumor microenvironment, play important roles in regulating GI cancer development and progression through multiple mechanisms, such as secreting cytokines and direct interactions. Currently, studies are focusing on the anti-cancer effect of MSCs on GI malignancies. However, the effects and functional mechanisms of MSC-derived exosomes on GI cancer are less studied. MSC-derived exosomes can regulate GI tumor growth, drug response, metastasis, and invasion through transplanting proteins and miRNA to tumor cells to activate the specific signal pathway. Besides, the MSC-derived exosomes are also seen as an important drug delivery system and have shown potential in anti-cancer treatment. This study aims to summarize the effect and biological functions of MSC-derived exosomes on the development of GI cancers and discuss their possible clinical applications for the treatment of GI malignancies.