The mechanisms of ferroptosis in the pathogenesis of kidney diseases.

The pathological features of acute and chronic kidney diseases are closely associated with cell death in glomeruli and tubules. Ferroptosis is a form of programmed cell death characterized by iron overload-induced oxidative stress. Ferroptosis has recently gained increasing attention as a pathogenic mechanism of kidney damage. Specifically, the ferroptosis signaling pathway has been found to be involved in the pathological process of acute and chronic kidney injury, potentially contributing to the development of both acute and chronic kidney diseases. This paper aims to elucidate the underlying mechanisms of ferroptosis and its role in the pathogenesis of kidney disease, highlighting its significance and proposing novel directions for its treatment.

SARS-CoV-2 NSP2 as a Potential Delivery Vehicle for Proteins.

The development of biomolecule delivery systems is essential for the treatment of various diseases such as cancer, immunological diseases, and metabolic disorders. For the first time, we found that SARS-CoV-2-encoded nonstructural protein 2 (NSP2) can be secreted from the cells, where it is synthesized. Brefeldin A and H89, inhibitors of ER/Golgi secretion pathways, did not inhibit NSP2 secretion. NSP2 is likely secreted via an unconventional secretory pathway. Moreover, both secreted and purified NSP2 proteins were able to traverse the plasma membrane barrier and enter both immortalized human umbilical vein endothelial cells and tumor cell lines. After entry, the NSP2 protein was localized in only the cytoplasm. Cytochalasin D, a potent inhibitor of actin polymerization, inhibited the entry of NSP2. NSP2 can carry other molecules into cells. Burkholderia lethal factor 1, a monomeric toxin from the intracellular pathogen Burkholderia pseudomallei, has demonstrated antitumor activity by targeting host eukaryotic initiation translation factor 4A. An NSP2-BLF1 fusion protein was translocated across the cellular membranes of Huh7 cells and mediated cell killing. By using different approaches, including protein purification, chemical inhibition, and cell imaging, we confirm that NSP2 is able to deliver heterologous proteins into cells. NSP2 can act as a potential delivery vehicle for proteins.

Temperature-adaptive rooftop covering with synergetic modulation of solar and thermal radiation for maximal energy saving.

The energy consumption for maintaining desired indoor temperature accounts for 20% of primary energy use worldwide. Passive rooftop modulation of solar/thermal radiation without external energy input has a great potential in building energy saving. However, existing passive rooftop modulation techniques failed to simultaneously modulate solar/thermal radiation in response to rooftop surface temperature which is closely related to the building thermal loads, leading to limited or even counter-productive overall energy saving. Here, we report the development of a surface temperature-adaptive rooftop covering with synergetic solar and thermal modulations. The covering, made of a scalable metalized polyethylene film, demonstrated excellent solar absorptance modulation (72.5%) and thermal emissivity modulation (79%) in response to its temperature change from 22°C (indoor heating setpoint) to 25°C (indoor cooling setpoint), and vice versa. Building energy simulations demonstrate that the proposed rooftop covering can achieve all-season energy savings across all climate regions.

The tumor microenvironment and prognostic role of autophagy- and immune-related genes in bladder cancer.

BACKGROUND: Autophagy-related genes and immune-related genes contribute significantly to the initiation and prognosis of bladder cancer (BLCA). OBJECTIVE: We aimed to explore differentially expressed autophagy-related genes (DEARGs) and immune-related genes (DEIRGs) in BLCA to create a prognostic risk assessment model and gain some insights into BLCA's molecular underpinnings. METHODS: The prognostic DEARGs and DEIRGs were evaluated for BLCA through The Cancer Genome Atlas (TCGA) database (n= 399) and GSE13507 dataset (n= 165). The BLCA risk model was constructed and verified. The immune score, stromal score, and estimate score in different risk groups were calculated by the ESTIMATE algorithm. Immune infiltration levels were assessed by a single sample gene set enrichment analysis (GSEA) algorithm. RESULTS: In the risk model, AURKA, ACTC1, MYLK, PDGFD, PDGFRA and TNC were significantly associated with the overall survival. The pathways in cancer, T cell receptor signaling pathway and B cell receptor signaling pathway were significantly gathered in the high-risk group. Moreover, the risk score was significantly correlated with infiltrating immune cells, expression of critical immune checkpoints and mismatch repair genes including MSH6, MLH1, and MSH2. CONCLUSIONS: In this study, three DEARGs (AURKA, ACTC1, MYLK) and three DEIRGs (PDGFD, PDGFRA, TNC) were demonstrated to be potential prognostic biomarkers for BLCA patients through bioinformatics methods, which might be novel therapeutic targets and prognostic markers for BLCA, in follow up studies, we will combine experiments to verify this.

Exosomal long noncoding RNA HOXD-AS1 promotes prostate cancer metastasis via miR-361-5p/FOXM1 axis.

Development of distant metastasis is the main cause of deaths in prostate cancer (PCa) patients. Understanding the mechanism of PCa metastasis is of utmost importance to improve its prognosis. The role of exosomal long noncoding RNA (lncRNA) has been reported not yet fully understood in the metastasis of PCa. Here, we discovered an exosomal lncRNA HOXD-AS1 is upregulated in castration resistant prostate cancer (CRPC) cell line derived exosomes and serum exosomes from metastatic PCa patients, which correlated with its tissue expression. Further investigation confirmed exosomal HOXD-AS1 promotes prostate cancer cell metastasis in vitro and in vivo by inducing metastasis associated phenotype. Mechanistically exosomal HOXD-AS1 was internalized directly by PCa cells, acting as competing endogenous RNA (ceRNA) to modulate the miR-361-5p/FOXM1 axis, therefore promoting PCa metastasis. In addition, we found that serum exosomal HOXD-AS1 was upregulated in metastatic PCa patients, especially those with high volume disease. And it is correlated closely with Gleason Score, distant and nodal metastasis, Prostatic specific antigen (PSA) recurrence free survival, and progression free survival (PFS). This sheds a new insight into the regulation of PCa distant metastasis by exosomal HOXD-AS1 mediated miR-361-5p/FOXM1 axis, and provided a promising liquid biopsy biomarker to guide the detection and treatment of metastatic PCa.

GPR40 Agonist Ameliorate Pathological Neuroinflammation of Alzheimer's Disease via the Modulation of Gut Microbiota and Immune System, a Mini-Review.

Alzheimer's disease (AD) is a central disease with high incidence, and its pathological process is closely associated with changes of some biological indicators in the periphery. Among them, the intestinal flora mainly causes a series of pathological changes such as inflammation through the immune system, which may contribute to the pathological process of AD. In this paper, we mainly focused the relationship between gut microbiota and immune system disorder in the neuropathology of AD, underlining the significance of the advanced mechanism of inflammatory response and providing a new direction for the treatment of AD.

miR­583 inhibits the proliferation and invasion of prostate cancer cells by targeting JAK1.

Prostate cancer (PCa) is a leading cause for death in men and the most commonly diagnosed malignancy globally. MicroRNA (miR)­583 expression levels have been discovered to be downregulated in recurrent PCa samples compared with non­recurrent cases. However, the precise functions and pathogenic mechanism of miR­583 in the development of PCa are vague, thus the aim of the present study was to investigate these. The expression levels of miR­583 and Janus kinase 1 (JAK1) in PCa tissues and cell lines were analyzed using reverse transcription­quantitative PCR and western blotting. The protein expression levels of phosphorylated (p)­STAT3 and STAT3 in PCa cell lines were also analyzed using western blotting. The effects of miR­583 and JAK1 on the proliferation and invasion of PCa cell lines cell lines were determined using MTT and Transwell assays, respectively. The binding interaction between miR­583 and the 3'­untranslated region of JAK1 were predicted by TargetScan, and further validated using dual luciferase reporter assays in PCa cell lines. The results revealed that the expression levels of miR­583 were downregulated, while those of JAK1 were upregulated in PCa tissues and cell lines (DU145 and PC3). The transfection with the miR­583 mimic inhibited the proliferation and invasion, as well as downregulating JAK1 and p­STAT3 protein expression levels in DU145 and PC3 cell lines. These effects were partially abolished following the overexpression of JAK1. Moreover, JAK1 was identified to be a target gene for miR­583 in DU145 and PC3 cell lines and the expression levels of miR­583 were revealed to be negatively correlated with JAK1 expression levels in PCa tissues. In conclusion, the findings of the present study suggested that miR­583 may inhibit the proliferation and invasion of PCa cells by targeting JAK1, thus providing a novel therapeutic target for patients with PCa.

LINC00992 contributes to the oncogenic phenotypes in prostate cancer via targeting miR-3935 and augmenting GOLM1 expression.

BACKGROUND: Accumulating evidence has revealed the critical role of long non-coding RNAs (lncRNAs) in cellular processes during tumor progression. As documented in cancer-related literatures, LINC00992 expression is associated with cancer progression, whereas its function in tumors including prostate cancer has not been characterized yet. METHODS: Data from GEPIA database suggested LINC00992 expression in prostate cancer tissues. The expression levels of RNAs were monitored via qRT-PCR. Western blot evaluated the levels of proteins. The proliferation, apoptosis and migration of prostate cancer cells were assessed by CCK-8, EdU, TUNEL, Transwell and wound healing assays. Luciferase reporter, RNA pull down and RIP assays were applied to detect the interplays among LINC00992, miR-3935 and GOLM1. RESULTS: Elevated levels of LINC00992 and GOLM1 were detected in prostate cancer tissues and cells. LINC00992 exerted facilitating functions in prostate cancer cell proliferation and migration. Mechanically, LINC00992 interacted with and negatively regulated miR-3935 to elevate GOLM1 expression in prostate cancer cells. In addition, the in vitro suppressive effect of silenced LINC00992 on prostate cancer cell proliferation and migration was reversed by GOLM1 upregulation. Likewise, LINC00992 depletion restrained tumor growth in vivo was offset by enhanced GOLM1 expression. CONCLUSIONS: LINC00992 competitively bound with miR-3935 to elevate GOLM1 expression and therefore facilitate the oncogenic phenotypes of prostate cancer cells, implying a potential LINC00992-targeted therapy for prostate cancer.

Dual CNN for Relation Extraction with Knowledge-Based Attention and Word Embeddings.

Relation extraction is the underlying critical task of textual understanding. However, the existing methods currently have defects in instance selection and lack background knowledge for entity recognition. In this paper, we propose a knowledge-based attention model, which can make full use of supervised information from a knowledge base, to select an entity. We also design a method of dual convolutional neural networks (CNNs) considering the word embedding of each word is restricted by using a single training tool. The proposed model combines a CNN with an attention mechanism. The model inserts the word embedding and supervised information from the knowledge base into the CNN, performs convolution and pooling, and combines the knowledge base and CNN in the full connection layer. Based on these processes, the model not only obtains better entity representations but also improves the performance of relation extraction with the help of rich background knowledge. The experimental results demonstrate that the proposed model achieves competitive performance.

Reduced Glycolysis Contributed to Inhibition of Testis Spermatogenesis in Rats After Chronic Methamphetamine Exposure.

BACKGROUND Previous reports suggested that methamphetamine (METH) exposure could lead to inhibition of rat testis spermatogenesis. Glycolysis and glucose metabolism as well as oxidative stress have been implicated in testis spermatogenesis. Here we explored the underlying mechanism of local metabolism and glycolysis of testis after METH exposure. MATERIAL AND METHODS METH was intraperitoneally injected into rats with different doses and duration of METH exposure to establish short-term and chronic exposure models. The serum 8-hydroxy-2 deoxyguanosine (8-OHdG) level of rats was detected by enzyme-linked immunosorbent assay. Untargeted gas chromatography-mass spectrometry analysis was applied to identify differential metabolites and metabolic signature. The mRNA expression of hypoxia inducible factor 1alpha (HIF1alpha), glucose transporter 1 (GLUT1), hexokinase 1 (HK1) and lactate dehydrogenase C (LDHC) in rat testes were detected by polymerase chain reaction. Further, we determined the 4 proteins with western blotting and immunohistochemistry. RESULTS Decreased testes index and sperm counts were showed in the chronic METH group. The metabolome revealed that the main differential metabolites impacted were associated with glycolysis and glucose metabolism. The mRNA and protein expression of GLUT1, HK1, and LDHC were reduced in the chronic METH group but elevated in the short-term METH group, whereas HIF1alpha was upregulated in the short-term METH group but remained at baseline in the chronic METH group. CONCLUSIONS Overall, glucose metabolism was regulated by HIF1alpha after short-term METH exposure. Reduced glycolysis in the testis led to impaired spermatogenesis after chronic METH exposure.

The mediation of interleukin-17 and chemokine ligand 2 in pelvic pain of experimental autoimmune prostatitis.

The present study aimed to determine the expression and mediation of interleukin-17 (IL-17) and chemokine ligand 2 (CCL2) in a rat model with experimental autoimmune prostatitis (EAP). A total of 44 Sprague Dawley (SD) rats were used in the present study. Of these, a total of 20 two-month-old SD rats were randomly divided into a normal control (n=10) and a model group (EAP group, n=10). The remaining 24 two-month old SD rats were treated in the same way as EAP rats and subsequently randomly divided into a tacrolimus group (n=8), a celecoxib group (n=8) and a normal saline (NS) control group (n=8). Rats in the EAP and normal control groups underwent the Von Frey filaments behavioral test; rats in the tacrolimus, celecoxib and normal saline groups received a pain test following intervention treatment. Prostate tissues of SD rats in each group were harvested for reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis to observe the expression of IL-17 and CCL2. In the pain-reaction test, the occurrence of abnormal pain in the EAP group was significantly higher compared with the control group (P<0.001). The celecoxib group experienced a significant decrease in pain at day 10 compared with the NS group (P<0.01), while the decrease in pain experienced by the tacrolimus group was only significant at day 30 (P<0.001) and the pain experienced by the NS group decreased slightly over this same period. Results of RT-qPCR and western blot analysis indicated that, compared with the control group, the expression of IL-17 and CCL2 in the prostate tissue of EAP rats was significantly upregulated 50 days following modeling (P<0.05). On day 30 following intervention, the expression of IL-17 and CCL2 in the prostate of rats in the tacrolimus and celecoxib groups was significantly downregulated compared with the NS group (P<0.05). Therefore, the results of the current study demonstrate that IL-17 and CCL2 serve a vital role in the morbidity of the experimental autoimmune prostatitis and may also have a mediation effect on pelvic pain associated with chronic prostatitis.

[Expression of Type 3 Acid Sensitive Ion Channels in Bladder of OAB Rat Model].

OBJECTIVE: To investigate the expression of type 3 acid-sensing ion channels (ASIC3) in bladder tissue of over active bladder (OAB) rat model. METHODS: Sixty adult female rats were randomly divided into control group (intraperitoneal injection of 0.9% sodium chloride), GAB group (intraperitoneal injection of cyclophosphamide) and the intervention group (OAB rats treated with ASIC3 inhibitor amiloride). The rats underwent urodynamic testing. The bladder tissues were collected for pathological examination, while the expressions of ASIC3 were measured by the methods of immunohistochemistry, RT-PCR and Western blot. RESULTS: Urodynamic study found that the rats in control group had no significant contraction instability in both storage and voiding stages. Compared with the control group, OAB group and intervention group showed instability of visible contraction in urine storage stage, with shorter micturition interval (P < 0.01) and increased frequency of urination (P < 0.01). Compared with the OAB group, the intervention group showed significantly prolonged micturition interval (P < 0.05) and reduced frequency of urination (P < 0.05). Pathologic examination showed rat bladder mucosal damage in both OAB group and intervention group. Immunohistochemistry found the expression of ASIC3 on bladder mucosa. RT-PCR and Western blot showed significantly higher expression of ASIC3 in OAB group (P < 0.01), but the expression of ASIC3 decreased in intervention group after adding ASIC3 inhibitor. CONCLUSION ASIC3 expresses mainly on bladder mucosa. The gene and protein expression of ASIC3 in rat bladder tissue of OAB rats is higher, which can be significantly decreased by ASIC inhibitor. The symptoms of OAB reduce after intervention, which demonstrates the increased expression of ASIC3 in bladder tissue is closely related to bladder detrusor.

MicroRNA-200 Family Profile: A Promising Ancillary Tool for Accurate Cancer Diagnosis.

Cancer is one of the most threatening diseases in the world and great interests have been paid to discover accurate and noninvasive methods for cancer diagnosis. The value of microRNA-200 (miRNA-200, miR-200) family has been revealed in many studies. However, the results from various studies were inconsistent, and thus a meta-analysis was designed and performed to assess the overall value of miRNA200 in cancer diagnosis. Relevant studies were searched electronically from the following databases: PubMed, Embase, Web of Science, the Cochrane Library, and Chinese National Knowledge Infrastructure. Keyword combined with "miR-200," "cancer," and "diagnosis" in any fields was used for searching relevant studies. Then, the pooled sensitivity, specificity, area under the curve (AUC), and partial AUC were calculated using the random-effects model. Heterogeneity among individual studies was also explored by subgroup analyses. A total of 28 studies from 18 articles with an overall sample size of 3676 subjects (2097 patients and 1579 controls) were included in this meta-analysis. The overall sensitivity and specificity with 95% confidence intervals (95% CIs) are 0.709 (95% CI: 0.657-0.755) and 0.667 (95% CI: 0.617-0.713), respectively. Additionally, AUC and partial AUC for the pooled data is 0.735 and 0.627, respectively. Subgroup analyses revealed that using miRNA-200 family for cancer diagnosis is more effective in white than in Asian ethnic groups. In addition, cancer diagnosis by miRNA using circulating specimen is more effective than that using noncirculating specimen. Finally, miRNA is more accurate in diagnosing endometrial cancer than other types of cancer, and some miRNA family members (miR-200b and miR-429) have superior diagnostic accuracy than other miR-200 family members. In conclusion, the profiling of miRNA-200 family is likely to be a valuable tool in cancer detection and diagnosis.