(S)-10-Hydroxycamptothecin Inhibits EMT-evoked Osteosarcoma Cell Growth and Metastasis by Activating the HIPPO Signaling Pathway.

BACKGROUND: Osteosarcoma is the most common primary bone cancer in children and adolescents with high metastatic ability. AIM: This study aimed to explore the inhibitory effects of (S)-10-hydroxycamptothecin (HCPT) on osteosarcoma cell growth and metastasis as well as the underlying mechanism. METHOD: The osteosarcoma cells of 143B and U-2 OS (U-2), treated with HCPT (20, 100, or 300 nM), underwent detections, such as CCK-8, flow cytometry, Transwell, wound healing, and immunoblotting. EMT-related key proteins, like N-cadherin, Snail, and Vimentin, were found to be down-regulated, while E-cadherin was up-regulated dose-dependently in HCPT-exposed 143B and U-2 cells. Additionally, incubation of 143B and U-2 cells with HCPT for 3 hours dosedependently reduced the expression ratios of p-LATS1/LATS1, p-MST1/MST1, p-YAP/YAP, and p-TAZ/TAZ. RESULT: Taken together, our study has demonstrated HCPT to inhibit osteosarcoma growth and metastasis potentially by activating the HIPPO signaling pathway and reversing EMT. CONCLUSION: HCPT might be a candidate agent for the prevention and treatment of osteosarcoma.

Retinitis pigmentosa with or without skeletal abnormalities due to homozygous mutations in the CWC27 gene: A case report.

RATIONALE: Retinitis pigmentosa with or without skeletal abnormalities (RPSKA) is an autosomal recessive disorder caused by mutations in the CWC27 gene. Skeletal dysplasia and non-syndromic retinitis pigmentosa are typical manifestations, and most patients present with retinopathy such as retinitis pigmentosa and limited visual field. Its clinical manifestations are complex and diverse, often involving multiple systems. Examples include short finger deformities, peculiar facial features, short stature, and neurodevelopmental abnormalities, and it is easy to misdiagnose clinically, and early diagnosis is crucial for prognosis. PATIENT CONCERNS: A 2-year and 2-month-old female child was admitted to the hospital due to "unsteady walking alone and slow reaction for more than half a year." After admission, the child was found to have delayed motor development, accompanied by special face, abnormal physical examination of the nervous system, cranial MRI Dandy-Walker malformation, considering developmental delay. DIAGNOSES: Whole exome sequencing of the family line revealed the presence of a c.617(exon7)C>A pure mutation in the CWC27 gene in the affected child (this locus has been reported in the clinical literature); the final diagnosis is RPSKA. INTERVENTIONS: Unfortunately, there is no specific drug for the disease; we give children rehabilitation training treatment. OUTCOMES: During follow-up process we found that children's condition is better than before. LESSONS SUBSECTIONS AS PER STYLE: We reported a case of RPSKA caused by mutations in the CWC27 gene. This study adds to our understanding of the clinical phenotype of TBL1XR1 mutations and provides a realistic and reliable basis for clinicians.

Integrated Transcriptome and Metabolomics to Reveal the Mechanism of Adipose Mesenchymal Stem Cells in Treating Liver Fibrosis.

Liver fibrosis (LF) is a late-stage process observed in various chronic liver diseases with bile and retinol metabolism closely associated with it. Adipose-derived mesenchymal stem cells (ADMSCs) have shown significant therapeutic potential in treating LF. In this study, the transplantation of ADMSCs was applied to a CCl4-induced LF model to investigate its molecular mechanism through a multi-omics joint analysis. The findings reveal that ADMSCs effectively reduced levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), gamma-glutamyltransferase (GGT), Interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and α-Smooth muscle actin (α-SMA), thereby mitigating liver lesions, preventing liver parenchymal necrosis, and improving liver collagen deposition. Furthermore, 4751 differentially expressed genes (DEGs) and 270 differentially expressed metabolites (DMs) were detected via transcriptome and metabolomics analysis. Conjoint analysis showed that ADMSCs up-regulated the expression of Cyp7a1, Baat, Cyp27a1, Adh7, Slco1a4, Aldh1a1, and Adh7 genes to promote primary bile acids (TCDCA: Taurochenodeoxycholic acid; GCDCA: Glycochenodeoxycholic acid; GCA: glycocholic acid, TCA: Taurocholic acid) synthesis, secretion and retinol metabolism. This suggests that ADMSCs play a therapeutic role in maintaining bile acid (BA) homeostasis and correcting disturbances in retinol metabolism.

RNF6 promotes gastric cancer progression by regulating CCNA1/CREBBP transcription.

Ring finger protein 6 (RNF6) is a member of the E3 ubiquitin ligase family. Previous studies have reported the involvement of RNF6 as a ubiquitin ligase in the progression of gastric cancer (GC). However, this study found that RNF6 has a clear localization in the nucleus of GC, indicating a role other than ubiquitin ligase. Further chromatin immunoprecipitation sequencing (ChIP-seq) analysis revealed that RNF6 has DNA binding and transcriptional regulatory effects and is involved in important pathways such as tumor cell cycle and apoptosis. Cyclin A1 (CCNA1) and CREB binding protein (CREBBP) are downstream targets for RNF6 transcription regulation in GC. RNF6 binds to the promoter region of CCNA1/CREBBP and is actively regulating their expression in GC cells. Silencing CCNA1/CREBBP partially reversed the promoting effect of RNF6 overexpression on the biological function of GC cells. Our study suggests that RNF6 promotes the progression of GC by regulating CCNA1/CREBBP transcription.

Exogenous tannic acid relieves imidacloprid-induced oxidative stress in tea tree by activating antioxidant responses and the flavonoid biosynthetic pathway.

Pesticide stress on plants is receiving increased scrutiny due to its effect on plant secondary metabolism and nutritional quality. Tannic acid (TA) is a natural polyphenolic compound showing excellent antioxidant properties and is involved in alleviating stress. The present study thoroughly investigated the effects and mechanism of exogenous TA on relieving imidacloprid (IMI) stress in tea plants. Our research found that TA(10 mg/L) activated the antioxidant defense system, enhanced the antioxidant ability, reduced the accumulation of ROS and membrane peroxidation, and notably promoted tea plant tolerance to imidacloprid stress. Additionally, TA boosted photosynthetic capacity, strengthened the accumulation of nutrients. regulated detoxification metabolism, and accelerated the digestion and metabolism of imidacloprid in tea plants. Furthermore, TA induced significant changes in 90 important metabolites in tea, targeting 17 metabolic pathways through extensively targeted metabolomics. Specifically, TA activated the flavonoid biosynthetic pathway, resulting in a 1.3- to 3.1-fold increase in the levels of 17 compounds and a 1.5- to 63.8-fold increase in the transcript level of related genes, such as ANR, LAR and CHS in this pathway. As a potential tea health activator, TA alleviates the oxidative damage caused by imidacloprid and improves the yield and quality of tea under pesticide stress.

RNA Fluorescence In Situ Hybridization for Long Non-Coding RNA Localization in Human Osteosarcoma Cells.

The important roles of long non-coding RNAs (lncRNAs) in cancer have been studied, such as regulating the proliferation, epithelial-mesenchymal transition (EMT), migration, infiltration, and autophagy of cancer cells. Localization detection of lncRNAs in cells can provide insight into their functions. By designing the lncRNA-specific antisense chain sequence followed by labeling with fluorescent dyes, RNA fluorescence in situ hybridization (FISH) can be applied to detect the cellular localization of lncRNAs. Together with the development of microscopy, the RNA FISH techniques now even allow for visualization of the poorly expressed lncRNAs. This method can not only detect the localization of lncRNAs alone, but also detect the colocalization of other RNAs, DNA, or proteins by using double-color or multicolor immunofluorescence. Here, we have included the detailed experimental operation procedure and precautions of RNA FISH by using lncRNA small nucleolar RNA host gene 6 (SNHG6) in human osteosarcoma cells (143B) as an example, to provide a reference for researchers who want to perform RNA FISH experiments, especially lncRNA FISH.

A meta-analysis: the clinical value of PD-1 inhibitor or protein tyrosine kinase inhibitors in the treatment of advanced osteosarcoma.

Backgrounds: PD-1 inhibitors and TKIs have been used to treat advanced osteosarcoma, but there is still a lack of intuitive data for the comparison of their efficacy. We conducted a meta-analysis to evaluate their therapeutic benefits. Methods: A systematic methodological search of five primary electronic databases was performed. Studies with a randomized design of any type about PD-1 inhibitors or TKIs for the treatment of advanced osteosarcoma were included. The primary outcomes mainly included CBR, PFS, OS and ORR, The CR, PR, SD and AEs were the secondary outcomes. The survival period (months) of patients was taken as the main analysis data. Random-effects models were used for meta-analysis. Results: Eight immunocheckpoint inhibitors in 327 patients from 10 clinical trials were finally evaluated. For OS, TKIs [11.67 months (95% CI, 9.32-14.01)] show more obvious advantages than PD-1 inhibitors [6.37 months (95% CI, 3.96-8.78)]. For PFS, TKIs [4.79 months (95% CI, 3.33-6.24)] are longer than PD-1 inhibitors [1.46 months (95% CI, 1.23-1.69)]. Although there was no fatal event, attention should still be paid, especially during the combined application of PD-1 inhibitors with TKIs since their obvious AEs. Conclusions: The findings of this study suggest that patients with advanced osteosarcoma, TKIs may be more beneficial than PD-1 inhibitors. TKIs combined with PD-1 inhibitors has a bright future in the treatment of advanced osteosarcoma, but we should always pay attention to the strong side effects.

Residue Levels and Dietary Intake Risk Assessments of 139 Pesticides in Agricultural Produce Using the m-PFC Method Based on SBA-15-C18 with GC-MS/MS.

A survey was designed to investigate the pesticide residues in agricultural produce and to estimate their potential intake risks to inhabitants. A total of 314 samples of nine types of fruits and vegetables were collected from the supermarkets and vegetable markets of Shandong Province (China) from October 2020 to February 2022. An accurate and reliable multi-residue method, based on GC-MS/MS detection, as well as the multiplug filtration cleanup method, based on SBA-15-C18, was prepared by a solution chemical reaction. Additionally, an in situ co-condensation method was established for the quantification of 139 pesticide residues. Residues that contained no pesticides were detected in 66.5% of the 314 samples. Moreover, of the samples, 30.6% were at or below the MRLs, and 2.9% were above the MRLs. Residues of procymidone were found to be the one that most often exceeded the MRLs (1.3% of the samples). Tebuconazole was found most frequently in 22.0% of the samples analyzed. Consumer exposure to the 139 pesticides did not exceed 100% ADI and ARfD. This led to a consideration that these pesticide residues in the nine commodities may not raise the health risk of the consumers in the long and short term. The highest value of chronic dietary intake was obtained from spirodiclofen, which resulted in a 24.1% of ADI. Furthermore, the highest exposure levels in the short term were obtained from the consumption of leeks with procymidone (58.3% ARfD).

Adipose-derived mesenchymal stem cells secrete extracellular vesicles: A potential cell-free therapy for canine renal ischaemia-reperfusion injury.

BACKGROUND: Adipose-derived mesenchymal stem cells (ADMSCs) and their extracellular vesicles (EVs) are a promising source of therapies for ischaemia-reperfusion (IR) because of their potent anti-inflammatory and immunomodulatory properties. OBJECTIVES: The aims of this study were to explore the therapeutic efficacy and potential mechanism of ADMSC-EVs in canine renal IR injury. METHODS: Mesenchymal stem cells (MSCs) and EVs were isolated and characterised for surface markers. A canine IR model administered with ADMSC-EVs was used to evaluate therapeutic effects on inflammation, oxidative stress, mitochondrial damage and apoptosis. RESULTS: CD105, CD90 and beta integrin ITGB were positively expressed in MSCs, while CD63, CD9 and intramembrane marker TSG101 were positively expressed in EVs. Compared with the IR model group, there was less mitochondrial damage and reduction in quantity of mitochondria in the EV treatment group. Renal IR injury led to severe histopathological lesions and significant increases in biomarkers of renal function, inflammation and apoptosis, which were attenuated by the administration of ADMSC-EVs. CONCLUSIONS: Secretion of EVs by ADMSCs exhibited therapeutic potential in renal IR injury and may lead to a cell-free therapy for canine renal IR injury. These findings revealed that canine ADMSC-EVs potently attenuate renal IR injury-induced renal dysfunction, inflammation and apoptosis, possibly by reducing mitochondrial damage.

Identification and vitro verification of the potential drug targets of active ingredients of Chonglou in the treatment of lung adenocarcinoma based on EMT-related genes.

Lung adenocarcinoma (LUAD) is the main histological type of lung cancer with an unfavorable survival rate. Metastasis is the leading LUAD-related death with Epithelial-Mesenchymal Transition (EMT) playing an essential role. The anticancer efficacies of the active ingredients in Chonglou have been widely reported in various cancers. However, the potential therapeutic targets of the Chonglou active ingredients in LUAD patients remain unknown. Here, the network pharmacology and bioinformatics were performed to analyze the associations of the clinical characteristics, immune infiltration factors and m6A-related genes with the EMT-related genes associated with LUAD (EMT-LUAD related genes), and the molecular docking, STRING, GO, and KEGG enrichment for the drug targets of Chonglou active ingredients associated with EMT (EMT-LUAD-Chonglou related genes). And, cell viability analysis and cell invasion and infiltration analysis were used to confirm the theoretical basis of this study. A total of 166 EMT-LUAD related genes were identified and a multivariate Cox proportional hazards regression model with a favorable predictive accuracy was constructed. Meanwhile, the immune cell infiltration, immune cell subsets, checkpoint inhibitors and the expression of m6A-related genes were significantly associated with the risk scores for EMT-LUAD related genes with independent significant prognostic value of all included LUAD patients. Furthermore, 12 EMT-LUAD-Chonglou related genes with five core drug targets were identified, which participated in LUAD development through extracellular matrix disassembly, collagen metabolic process, collagen catabolic process, extracellular matrix organization, extracellular structure organization and inflammatory response. Moreover, we found that the active ingredients of Chonglou could indeed inhibit the progression of lung adenocarcinoma cells. These results are oriented towards EMT-related genes to achieve a better understanding of the role of Chonglou and its targets in osteosarcoma development and metastasis, thus guiding future preclinical studies and facilitating clinical translation of LUAD treatment.

Angiotensin-converting enzyme inhibitor promotes angiogenesis through Sp1/Sp3-mediated inhibition of notch signaling in male mice.

Angiogenesis is a critical pathophysiological process involved in organ growth and various diseases. Transcription factors Sp1/Sp3 are necessary for fetal development and tumor growth. Sp1/Sp3 proteins were downregulated in the capillaries of the gastrocnemius in patients with critical limb ischemia samples. Endothelial-specific Sp1/Sp3 knockout reduces angiogenesis in retinal, pathological, and tumor models and induced activation of the Notch1 pathway. Further, the inactivation of VEGFR2 signaling by Notch1 contributes to the delayed angiogenesis phenotype. Mechanistically, endothelial Sp1 binds to the promoter of Notch1 and inhibits its transcription, which is enhanced by Sp3. The proangiogenic effect of ACEI is abolished in Sp1/Sp3-deletion male mice. We identify USP7 as an ACEI-activated deubiquitinating enzyme that translocated into the nucleus binding to Sp1/Sp3, which are deacetylated by HDAC1. Our findings demonstrate a central role for endothelial USP7-Sp1/Sp3-Notch1 signaling in pathophysiological angiogenesis in response to ACEI treatment.

Pyrotinib combining with radiotherapy on breast cancer with brain metastasis.

With the extensive application of anti-human epidermal growth factor receptor-2 (HER2) targeted therapy, the prognosis of HER2-positive breast cancer brain metastasis (BCBM) has been improved greatly. Due to the lack of prospective randomized controlled studies; however, the treatment of active brain metastasis (BM) remains a difficulty in clinic. Based upon the retrospective studies, an effective approach of radiotherapy combined with pyrotinib in HER2-positive BCBM treatment was investigated in present research. In all, 29 patients who had active BM in HER2-positive breast cancer (BC) and underwent whole-brain radiotherapy (WBRT) combined with pyrotinib from January 2019 to May 2021 were enrolled. The progression-free survival (PFS), overall survival (OS), clinical benefit rate (CBR), objective response rate (ORR), and drug-related adverse events (AEs) were analyzed among patients undergoing WBRT combined with concurrent or sequence pyrotinib + capecitabine. After the systematic treatments using WBRT combined with pyrotinib + capecitabine, the mPFS and mOS of BM patients were 6.5 months and 15.5 months, respectively. PFS (7.2 vs 6.2 months, p = 0.038) and OS (19.0 vs 14.0 months, p = 0.014) were longer after sequence treatments than those after concurrent treatment. The central nervous system (CNS) ORR of sequence treatment was superior to that of concurrent treatment (80.4% vs 58.6%, p < 0.05). Vomiting (17.2%) and diarrhea (10.3%) were the most common adverse reactions ⩾ grade 3. WBRT combined with pyrotinib is safe and effective for the treatments of active BM in HER2-positive BC. WBRT combined with sequence pyrotinib + capecitabine is more effective and less toxic than concurrent treatment. Therefore, sequence treatment is potentially a preferred regimen for patients with active BM in HER2-positive BC. The size and number of BM lesions, presence or absence of hepatic metastasis, and combination mode of radiotherapy and targeted therapy are independent risk factors for active BM prognosis.

Functional identification of PGM1 in the regulating development and depositing of inosine monophosphate specific for myoblasts.

Background: Inosine monophosphate (IMP) is naturally present in poultry muscle and plays a key role in improving meat flavour. However, IMP deposition is regulated by numerous genes and complex molecular networks. In order to excavate key candidate genes that may regulate IMP synthesis, we performed proteome and metabolome analyses on the leg muscle, compared to the breast muscle control of 180-day-old Jingyuan chickens (hens), which had different IMP content. The key candidate genes identified by a differential analysis were verified to be associated with regulation of IMP-specific deposition. Results: The results showed that the differentially expressed (DE) proteins and metabolites jointly involve 14 metabolic pathways, among which the purine metabolic pathway closely related to IMP synthesis and metabolism is enriched with four DE proteins downregulated (with higher expression in breast muscles than in leg muscles), including adenylate kinase 1 (AK1), adenosine monophosphate deaminase 1 (AMPD1), pyruvate kinase muscle isoenzyme 2 (PKM2) and phosphoglucomutase 1 (PGM1), six DE metabolites, Hypoxanthine, Guanosine, L-Glutamine, AICAR, AMP and Adenylsuccinic acid. Analysis of PGM1 gene showed that the high expression of PGM1 promoted the proliferation and differentiation of myoblasts and inhibited the apoptosis of myoblasts. ELISA tests have shown that PGM1 reduced adenosine triphosphate (ATP) and IMP and uric acid (UA), while enhancing the biosynthesis of hypoxanthine (HX). In addition, up-regulation of PGM1 inhibited the expression of purine metabolism pathway related genes, and promoted the IMP de novo and salvage synthesis pathways. Conclusion: This study preliminarily explored the mechanism of action of PGM1 in regulating the growth and development of myoblasts and specific IMP deposition in Jingyuan chickens, which provided certain theoretical basis for the development and utilization of excellent traits in Jingyuan chickens.

Pyrotinib for Elderly Patients with Advanced HER2-Positive Breast Cancer.

Introduction: According to the latest global cancer data released by WHO in 2020, the incidence of breast cancer (BC) has been the most prevalent, and the mortality rate of female malignant tumor ranks the first. Methods: To evaluate toxicity and efficacy regarding oral Pyrotinib for elderly patients with advanced HER2-positive breast cancer (BC) in Xinjiang, 45 elderly patients having advanced HER2-positive BC with age ≥65 years and receiving Pyrotinib-based combined therapy from January 2019 to May 2021 in Xinjiang were enrolled in this study. PFS, CBR, ORR and drug-related adverse events (AE) of oral Pyrotinib in the patients were retrospectively analyzed. All 45 patients completed the efficacy evaluation. Results: Total ORR and CBR of the whole group was 37.8% and 77.8%, respectively. There were 14 patients with brain metastases (31.1%), with a median PFS of 6.8 months (95% CI: 5.4~9.8). In terms of the number of treatment lines, mPFS for line 1-2 was 8.3 months (95% CI: 6.3~11.4), and mPFS for line ≥3 was 3.3 months (95% CI: 2.7~5.1). At the final maintenance dose, mPFS at standard doses of 400mg, 320mg and 240mg were 9.1 months (95% CI: 4.1~9.5), 8.3 months (95% CI: 4.3~12.2) and 4.8 months (95% CI: 2.1~7.5), respectively. Discussion: Applying Pyrotinib in elderly patients, the main adverse reaction was diarrhea, accounting for 88.9% (40/45). Pyrotinib is safe and effective for elderly patients with advanced HER2 positive BC.

Pyrotinib-based treatments in HER2-positive breast cancer patients with brain metastases.

OBJECTIVES: Extensive application of anti-HER2 targeted therapy improves significantly the HER2-positive advanced breast cancer (BC) prognosis, however, it is still difficult to treat brain metastasis. In current study, we explored effective approaches via combining pyrotinib to treat brain metastasis in patients with HER2-positive advanced BC based upon clinical data. MATERIALS AND METHODS: Current study included 61 HER2-positive BC patients with brain metastases (BM) who were treated by pyrotinib-based regimens. The systemic regimens included pyrotinib combined with capecitabine, pyrotinib combined with nab-paclitaxel, and pyrotinib combined with vinorelbine. Patients' progression-free survival (PFS), overall survival (OS), clinical benefit rate (CBR) and objective response rate (ORR), as well as drug-related adverse events (AEs) in regard of each combination regimen were analyzed. RESULTS: Pyrotinib-based systemic therapy resulted in 8.6 months median PFS (mPFS) and 18.0 months median OS (mOS) among the BM patients. Regarding different regimens, the combination of pyrotinib with nab-paclitaxel was superior to the combination with capecitabine and vinorelbine with respect to PFS and OS. The central nervous system (CNS) ORR did not showcase significant difference among 3 regimens, however, nab-paclitaxel combined regimen obtained the best peripheral ORR (84.6%) (p ≤ .05). CONCLUSIONS: Pyrotinib-based combination therapy is safe for HER2-positive brain metastasis treatment. Compared with vinorelbine or capecitabine, pyrotinib combined with nab-paclitaxel is more effective with less toxicity, which is the preferable regimen for HER2-positive brain metastasis.KEY MESSAGESPresent investigation investigated effective methods through combining pyrotinib to treat brain metastasis with HER2-positive advanced brain cancer. The outcomes verified that pyrotinib-based combination therapy was safe and efficient to treat HER2-positive brain metastasis. Therefore, it is effective to treat brain metastasis applying anti-HER2 targeted therapies although pyrotinib showcases efficiency regarding its treatments for the metastasis.

Intra-Cardiac Injection of Human Prostate Cancer Cells to Create a Bone Metastasis Xenograft Mouse Model.

As the most common male malignancy, prostate cancer (PC) ranks second in mortality, primarily due to a 65%-75% bone metastasis rate. Therefore, it is essential to understand the process and related mechanisms of prostate cancer bone metastasis for developing new therapeutics. For this, an animal model of bone metastasis is an essential tool. Here, we report detailed procedures to generate a bone metastasis mouse model via intra-cardiac injection of prostate cancer cells. A bioluminescence imaging system can determine whether prostate cancer cells have been accurately injected into the heart and monitor cancer cell metastasis since it has great advantages in monitoring metastatic lesion development. This model replicates the natural development of disseminated cancer cells to form micro-metastases in the bone and imitates the pathological process of prostate cancer bone metastasis. It provides an effective tool for further exploration of the molecular mechanisms and the in vivo therapeutic effects of this disease.

Microsporum gypseum Isolated from Ailuropoda melanoleuca Provokes Inflammation and Triggers Th17 Adaptive Immunity Response.

Microsporum gypseum causes dermatomycoses in giant pandas (Ailuropoda melanoleuca). This study aimed to investigate the immune response of M. gypseum following deep infection. The degree of damage to the heart, liver, spleen, lungs, and kidneys was evaluated using tissue fungal load, organ index, and histopathological methods. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) detected the mRNA expression of receptors and cytokines in the lung, and immunofluorescence staining and flow cytometry, were used to assess immune cells in the lung. The results indicated that conidia mainly colonized the lungs and caused serious injury with M. gypseum infection. Furthermore, dectin-1, TLR-2, and TLR-4 played a role in recognizing M. gypseum cells. Numerous inflammatory cells, mainly macrophages, dendritic cells, polymorphonuclear neutrophils, and inflammatory cytokines (TGF-ß, TNF-α, IL-1ß, IL-6, IL-10, IL-12, and IL-23), were activated in the early stages of infection. With the high expression of IL-22, IL-17A, and IL-17F, the Th17 pathway exerted an adaptive immune response to M. gypseum infection. These results can potentially aid in the diagnosis and treatment of diseases caused by M. gypseum in giant pandas.

Significance of HOXD transcription factors family in progression, migration and angiogenesis of cancer.

The transcription factors (TFs) of the HOX family play significant roles during early embryonic development and cellular processes. They also play a key role in tumorigenesis as tumor oncogenes or suppressors. Furthermore, TFs of the HOXD geFIne cluster affect proliferation, migration, and invasion of tumors. Consequently, dysregulated activity of HOXD TFs has been linked to clinicopathological characteristics of cancer. HOXD TFs are regulated by non-coding RNAs and methylation of DNA on promoter and enhancer regions. In addition, HOXD genes modulate the biological function of cancer cells via the MEK and AKT signaling pathways, thus, making HOXD TFs, a suitable molecular marker for cancer prognosis and therapy. In this review, we summarized the roles of HOXD TFs in different cancers and highlighted its potential as a diagnostic and therapeutic target.

The combination of high glucose and LPS induces autophagy in bovine kidney epithelial cells via the Notch3/mTOR signaling pathway.

BACKGROUND: Aside respiratory diseases, beef cattle may also suffer from serious kidney diseases after transportation. Hyperglycemia and gram-negative bacterial infection may be the main reasons why bovine is prone to severe kidney disease during transportation stress, however, the precise mechanism is still unclear. The purpose of the current study is to explore whether the combined treatment of high glucose (HG) and lipopolysaccharide (LPS) could induce madin-darby bovine kidney (MDBK) cells injury and autophagy, as well as investigate the potential molecular mechanisms involved. RESULTS: As we discovered, the combined effect of HG and LPS decreased MDBK cells viability. And, HG and LPS combination also induced autophagy in MDBK cells, which was characterized by increasing the expression of LC3-II/I and Beclin1 and decreasing p62 expression. LC3 fluorescence signal formation was also significantly increased by HG and LPS combination treatment. Furthermore, we measured whether the mammalian target of rapamycin (mTOR) and the Notch3 signaling pathways were involved in HG and LPS-induced autophagy. The results showed that the combination of HG and LPS significantly increased the protein expression of Notch3 and decreased protein expression of p-mTOR, indicating that Notch3 and mTOR signaling pathways were activated. However, co-treatment with the Notch3 inhibitor (DAPT) could reverse the induction of autophagy, and increased the protein expression of p-mTOR. CONCLUSIONS: This study demonstrated that the combination effect of HG and LPS could induce autophagy in MDBK cells, and the Notch3/mTOR signaling pathway was involved in HG and LPS-induced autophagy.

Oncogenetic Function and Prognostic Value of DNA Topoisomerase II Alpha in Human Malignances: A Pan-Cancer Analysis.

Increasing studies have revealed significant associations between TOP2A with oncogenesis and prognosis of human cancers; however, pan-cancer analysis has not been reported. Here, we explored the potential carcinogenic function and the association with clinical outcomes of TOP2A in 33 different human cancers. The results showed that TOP2A was amplified in 31 investigated cancers; TOP2A expression was significantly associated with metastasis of six different cancers and significantly associated with the survival of patients in ten different cancers; TOP2A-encoded protein was obviously upregulated in five available cancers; phosphorylated TOP2A protein at S1106 was significantly upregulated in all six available cancers. Moreover, TOP2A expression was found to be associated with the cancer-associated immune cell infiltration, including fibroblasts, Tregs, and macrophages. In addition, the Kyoto encyclopedia of genes and genomes (KEGG) pathway and Gene Ontology (GO) enrichment analyses revealed a most significant association between TOP2A with the Wnt signaling pathway and DNA conformation change. This work provides a comprehensive knowledge of TOP2A in different cancers, including carcinogenic function, prognostic values for metastasis, and clinical outcomes.