Downregulation of miR-337-3p in hypoxia/reoxygenation neuroblastoma cells increases KCTD11 expression.

Neurodegeneration is linked to the progressive loss of neural function and is associated with several diseases. Hypoxia is a hallmark in many of these diseases, and several therapies have been developed to treat this disease, including gene expression therapies that should be tightly controlled to avoid side effects. Cells experiencing hypoxia undergo a series of physiological responses that are induced by the activation of various transcription factors. Modulation of microRNA (miRNA) expression to alter transcriptional regulation has been demonstrated to be beneficial in treating multiple diseases, and in this study, we therefore explored potential miRNA candidates that could influence hypoxia-induced nerve cell death. Our data suggest that in mouse neuroblasts Neuro-2a cells with hypoxia/reoxygenation (H/R), miR-337-3p is downregulated to increase the expression of Potassium channel tetramerization domain containing 11 (KCTD11) and subsequently promote apoptosis. Here, we demonstrate for the first time that KCTD11 plays a role in the cellular response to hypoxia, and we also provide a possible regulatory mechanism by identifying the axis of miR-337-3p/KCTD11 as a promising candidate modulator of nerve cell survival after H/R exposure.

Effect of intravenous lidocaine on outcomes in patients receiving propofol for gastrointestinal endoscopic procedures: an updated systematic review and meta-analysis.

BACKGROUND: Gastrointestinal endoscopic procedures (GEPs) are frequently employed for the diagnosis and treatment of various gastrointestinal ailments. While propofol sedation is widely used during these procedures, there is a concern regarding its potential negative effects. Intravenous (IV) lidocaine has been suggested as an add-on to propofol sedation for GEPs, but current evidence on its efficiency and safety is limited. This systematic review and meta-analysis aimed to assess the impact of IV lidocaine on outcomes in patients receiving propofol during GEPs. METHODS: Electronic databases were screened for randomized controlled trials (RCTs), published up to 31 March 2023, investigating the effectiveness of intravenous lidocaine addition to propofol sedation during GEPs. RESULTS: A total of 12 RCTs involving 712 patients that received IV lidocaine and propofol for GEF and 719 patients that received propofol were analyzed. Adding IV lidocaine to propofol sedation led to significant reduction in pain after the procedure (standardized mean difference (SMD) = - 0.91, 95% confidence interval [CI]; - 1.51 to - 0.32), decreased propofol usage (SMD = - 0.89; 95% CI, - 1.31 to - 0.48), lower recovery time (SMD = - 0.95 min; 95% CI, - 1.48 to - 0.43), and decreased pain score (SMD = - 0.91; 95% CI, - 1.51 to - 0.32). The overall rate of adverse events was markedly less in the lidocaine group than in the control group (RR = 0.74; 95% CI, 0.56 to 0.99). CONCLUSION: Our results show that IV lidocaine improves patient outcomes by reducing post-procedural pain, decreasing propofol usage, shortening recovery time, and lowering pain scores. This study provides compelling evidence supporting the use of intravenous lidocaine as an adjunct to propofol sedation for gastrointestinal endoscopic procedures. However, further research is necessary to optimize the use of lidocaine and fully understand its long-term effects.

Hsa_circ_0001278 Facilitates Colorectal Cancer Progression via Sponging miR-338-5p and Regulating AMOTL1 Expression.

BACKGROUND: Colorectal cancer (CRC) ranks as the third most common cancer and is second in terms of mortality worldwide. Circular RNAs are involved in the occurrence and development of malignant tumors by functioning either as oncogenes or tumor suppressors. METHOD: This study investigated the functions of hsa_circ_0001278 in CRC. We analyzed the expression of hsa_circ_0001278 in CRC tissues and adjacent normal tissues. In order to understand the roles of hsa_circ_0001278 in CRC in terms of cellular biological behavior, in vitro experiments were conducted. A mechanistic study was designed to investigate the regulatory effect of hsa_circ_0001278 on CRC. RESULTS: Hsa_circ_0001278 was found to be significantly upregulated in CRC specimens. The functional analysis indicated that hsa_circ_0001278 promotes aggressive phenotypes of CRC cells. Further mechanistic studies revealed that hsa_circ_0001278 sponges miR-338-5p to regulate angiomotin-like 1 (AMOTL1), thereby facilitating CRC progression. CONCLUSION: Our results demonstrate that hsa_circ_0001278 promotes malignant behaviors in CRC cells by sponging miR-338-5p to regulate AMOTL1 expression. This suggests that hsa_circ_0001278 may serve as a novel target for CRC treatment.

Copper-Catalyzed Enantioconvergent Radical C(sp3)-N Cross-Coupling of Activated Racemic Alkyl Halides with (Hetero)aromatic Amines under Ambient Conditions.

The enantioconvergent C(sp3)-N cross-coupling of racemic alkyl halides with (hetero)aromatic amines represents an ideal means to afford enantioenriched N-alkyl (hetero)aromatic amines yet has remained unexplored due to the catalyst poisoning specifically for strong-coordinating heteroaromatic amines. Here, we demonstrate a copper-catalyzed enantioconvergent radical C(sp3)-N cross-coupling of activated racemic alkyl halides with (hetero)aromatic amines under ambient conditions. The key to success is the judicious selection of appropriate multidentate anionic ligands through readily fine-tuning both electronic and steric properties for the formation of a stable and rigid chelating Cu complex. Thus, this kind of ligand could not only enhance the reducing capability of a copper catalyst to provide an enantioconvergent radical pathway but also avoid the coordination with other coordinating heteroatoms, thereby overcoming catalyst poisoning and/or chiral ligand displacement. This protocol covers a wide range of coupling partners (89 examples for activated racemic secondary/tertiary alkyl bromides/chlorides and (hetero)aromatic amines) with high functional group compatibility. When allied with follow-up transformations, it provides a highly flexible platform to access synthetically useful enantioenriched amine building blocks.

Variant rs8400 enhances ALKBH5 expression through disrupting miR-186 binding and promotes neuroblastoma progression.

Objective: AlkB homolog 5 (ALKBH5) has been proven to be closely related to tumors. However, the role and molecular mechanism of ALKBH5 in neuroblastomas have rarely been reported. Methods: The potential functional single-nucleotide polymorphisms (SNPs) in ALKBH5 were identified by National Center for Biotechnology Information (NCBI) dbSNP screening and SNPinfo software. TaqMan probes were used for genotyping. A multiple logistic regression model was used to evaluate the effects of different SNP loci on the risk of neuroblastoma. The expression of ALKBH5 in neuroblastoma was evaluated by Western blotting and immunohistochemistry (IHC). Cell counting kit-8 (CCK-8), plate colony formation and 5-ethynyl-2'-deoxyuridine (EdU) incorporation assays were used to evaluate cell proliferation. Wound healing and Transwell assays were used to compare cell migration and invasion. Thermodynamic modelling was performed to predict the ability of miRNAs to bind to ALKBH5 with the rs8400 G/A polymorphism. RNA sequencing, N6-methyladenosine (m6A) sequencing, m6A methylated RNA immunoprecipitation (MeRIP) and a luciferase assay were used to identify the targeting effect of ALKBH5 on SPP1. Results: ALKBH5 was highly expressed in neuroblastoma. Knocking down ALKBH5 inhibited the proliferation, migration and invasion of cancer cells. miR-186-3p negatively regulates the expression of ALKBH5, and this ability is affected by the rs8400 polymorphism. When the G nucleotide was mutated to A, the ability of miR-186-3p to bind to the 3'-UTR of ALKBH5 decreased, resulting in upregulation of ALKBH5. SPP1 is the downstream target gene of the ALKBH5 oncogene. Knocking down SPP1 partially restored the inhibitory effect of ALKBH5 downregulation on neuroblastoma. Downregulation of ALKBH5 can improve the therapeutic efficacy of carboplatin and etoposide in neuroblastoma. Conclusions: We first found that the rs8400 G>A polymorphism in the m6A demethylase-encoding gene ALKBH5 increases neuroblastoma susceptibility and determines the related mechanisms. The aberrant regulation of ALKBH5 by miR-186-3p caused by this genetic variation in ALKBH5 promotes the occurrence and development of neuroblastoma through the ALKBH5-SPP1 axis.

Cu(I)-Catalyzed Chemo- and Enantioselective Desymmetrizing C-O Bond Coupling of Acyl Radicals.

Transition-metal-catalyzed enantioselective functionalization of acyl radicals has so far not been realized, probably due to their relatively high reactivity, which renders the chemo- and stereocontrol challenging. Herein, we describe Cu(I)-catalyzed enantioselective desymmetrizing C-O bond coupling of acyl radicals. This reaction is compatible with (hetero)aryl and alkyl aldehydes and, more importantly, displays a very broad scope of challenging alcohol substrates, such as 2,2-disubstituted 1,3-diols, 2-substituted-2-chloro-1,3-diols, 2-substituted 1,2,3-triols, 2-substituted serinols, and meso primary 1,4-diols, providing enantioenriched esters characterized by challenging acyclic tetrasubstituted carbon stereocenters. Partnered by one- or two-step follow-up transformations, this reaction provides a convenient and practical strategy for the rapid preparation of chiral C3 building blocks from readily available alcohols, particularly the industrially relevant glycerol. Mechanistic studies supported the proposed C-O bond coupling of acyl radicals.

Enantioconvergent Cu-catalysed N-alkylation of aliphatic amines.

Chiral amines are commonly used in the pharmaceutical and agrochemical industries1. The strong demand for unnatural chiral amines has driven the development of catalytic asymmetric methods1,2. Although the N-alkylation of aliphatic amines with alkyl halides has been widely adopted for over 100 years, catalyst poisoning and unfettered reactivity have been preventing the development of a catalyst-controlled enantioselective version3-5. Here we report the use of chiral tridentate anionic ligands to enable the copper-catalysed chemoselective and enantioconvergent N-alkylation of aliphatic amines with α-carbonyl alkyl chlorides. This method can directly convert feedstock chemicals, including ammonia and pharmaceutically relevant amines, into unnatural chiral α-amino amides under mild and robust conditions. Excellent enantioselectivity and functional-group tolerance were observed. The power of the method is demonstrated in a number of complex settings, including late-stage functionalization and in the expedited synthesis of diverse amine drug molecules. The current method indicates that multidentate anionic ligands are a general solution for overcoming transition-metal-catalyst poisoning.

Altered transcriptomic and metabolomic profiles of testicular interstitial fluid during aging in mice.

The testicular interstitial fluid (TIF) that bathes seminiferous tubules and testicular interstitial cells is the main microenvironment of the testis and involved in crosstalk between testicular cells. TIF also provides a new mean to investigate dysfunctional states of testis such as spermatogenic disorder and aging. In this study, we performed integrative omics analysis on the exosomal transcriptomics and liquid chromatography-tandem mass spectrometry (LC-MS/MS) based non-targeted metabolomics in TIF by comparison between 21-month-old and 3-month-old male mice. A total of 1627 genes were identified as aging-related differently expressed genes (DEGs) in mouse TIF exosomes, with 1139 downregulated and 488 upregulated. Functional and pathway analysis revealed that the DEGs were associated with oxidative stress, carbon metabolism, and systemic lupus erythematosus. By comparing the DEGs with the Aging Atlas Database, we screened out key aging-related genes functioning as oxidative stress regulators, and their expression pattern in human testis with age was confirmed by immunohistochemistry results in the Human Protein Atlas database. In addition, the metabolomic analysis identified mild differences between young and old groups with 28 downregulated differently expressed metabolites (DEMs) and 6 upregulated DEMs, in the negative ion mode, including decreased level of several antioxidant metabolites. The KEGG analysis demonstrated that 10 pathways were upregulated, while the pyrimidine metabolism pathway was downregulated in the aged mice TIF. Taken together, this study highlighted the prominent role of oxidative stress that contributed to the aging microenvironment in the TIF, and brought comprehensive transcriptomic and metabolomic perspectives for understanding the mechanism underlying the testicular aging.

Cu-catalysed enantioselective radical heteroatomic S-O cross-coupling.

The transition-metal-catalysed cross-coupling reaction has established itself as one of the most reliable and practical synthetic tools for the efficient construction of carbon-carbon/heteroatom (p-block elements other than carbon) bonds in both racemic and enantioselective manners. In contrast, development of the corresponding heteroatom-heteroatom cross-couplings has so far remained elusive, probably due to the under-investigated and often challenging heteroatom-heteroatom reductive elimination. Here we demonstrate the use of single-electron reductive elimination as a strategy for developing enantioselective S-O coupling under Cu catalysis, based on both experimental and theoretical results. The reaction manifests its synthetic potential by the ready preparation of challenging chiral alcohols featuring congested stereocentres, the expedient valorization of the biomass-derived feedstock glycerol, and the remarkable catalytic 4,6-desymmetrization of inositol. These results demonstrate the potential of enantioselective radical heteroatomic cross-coupling as a general chiral heteroatom-heteroatom formation strategy.

Altered small non-coding RNA expression profiles of extracellular vesicles in the prostatic fluid of patients with chronic pelvic pain syndrome.

Chronic pelvic pain syndrome (CPPS) and chronic prostatitis (CP) is difficult to distinguish from each other, herein termed CP/CPPS. The present study aimed at gaining further insight into the change in extracellular vesicles (EVs) in the prostatic fluid of males with CPPS. From December 2019 to November 2020, after clinical screening, 24 patients with CPPS without obvious urinary symptoms and 13 healthy male participants were included. EVs were isolated from expressed prostatic secretion (EPS) of all subjects. The small non-coding ribonucleic acid (sncRNA) expression of EVs was sequenced, analyzed, and validated by quantitative real-time polymerase chain reaction (qPCR) assays. The results showed that numerous sncRNAs were differentially expressed between the patients and healthy participants. Further qPCR assays validated that several chronic pain-related miRNAs, including miR-204-5p, let-7d-3p, let-7b-3p, let-7c-3p, miR-146a-5p, and miR-320a-5p, were differentially expressed. Series sncRNAs including several chronic pain-related miRNAs were altered in EVs in prostatic fluid of patients with CPPS, which may serve as diagnostic markers for CPPS.

Copper-Catalyzed anti-Selective Radical 1,2-Alkylarylation of Terminal Alkynes.

A copper-catalyzed highly anti-selective radical 1,2-alkylarylation of terminal alkynes with aryl boronic acids and alkyl bromides has been established. The reaction exhibits high compatibility with a wide range of terminal alkynes and diverse aryl boronic acids, thus providing facile access to various stereodefined trisubstituted alkenes in high yield under mild reaction conditions. Preliminary mechanistic investigations support the formation of alkyl radicals and their subsequent addition to alkynes in the reaction.

Risk Scores Based on Six Survival-Related RNAs in a Competing Endogenous Network Composed of Differentially Expressed RNAs Between Clear Cell Renal Cell Carcinoma Patients Carrying Wild-Type or Mutant Von Hippel-Lindau Serve Well to Predict Malignancy and Prognosis.

Clear cell renal cell carcinoma (ccRCC) carrying wild-type Von Hippel-Lindau (VHL) tumor suppressor are more invasive and of high morbidity. Concurrently, competing endogenous RNA (ceRNA) network has been suggested to play an important role in ccRCC malignancy. In order to understand why the patients carrying wild-type VHL gene have high degrees of invasion and morbidity, we applied bioinformatics approaches to identify 861 differentially expressed RNAs (DE-RNAs) between patients carrying wild-type and patients carrying mutant VHL from The Cancer Genome Atlas (TCGA) database, established a ceRNA network including 122 RNAs, and elected six survival-related DE-RNAs including Linc00942, Linc00858, RP13_392I16.1, hsa-miR-182-5p, hsa-miR-183-5p, and PAX3. Examining clinical samples from our hospital revealed that patients carrying wild-type VHL had significantly higher levels of all six RNAs than those carrying mutant VHL. Patients carrying wild-type VHL had significantly higher risk scores, which were calculated based on expression levels of all six RNAs, than those carrying mutant VHL. Patients with higher risk scores had significantly shorter survival times than those with lower risk scores. Therefore, the risk scores serve well to predict malignancy and prognosis.

Research Progress on the Antiosteoarthritic Mechanism of Action of Natural Products.

BACKGROUND: Osteoarthritis (OA) is a clinical joint degenerative disease, the pathogenic factors of which include age, obesity, and mechanical injury. Its main pathological features include cartilage loss, narrowing of joint space, and osteophyte formation. At present, there are a variety of treatment methods for OA. Natural products, which are gradually being applied in the treatment of OA, are advantageous as they present with low toxicity and low costs and act on multiple targets. METHODS: The terms "natural products," "osteoarthritis," and "chondrocytes" were searched in PubMed to screen the related literature in the recent 10 years. RESULTS: We comprehensively introduced 62 published papers on 48 natural products involving 6, 3, 5, 12, 4, and 5 kinds of terpenoids, polysaccharides, polyphenols, flavonoids, alkaloids, and saponins, respectively (and others). CONCLUSION: The mechanisms of their anti-OA action mainly involve reducing the production of inflammatory factors, reducing oxidative stress, regulating the metabolism of chondrocytes, promoting the proliferation of chondrocytes, or inhibiting chondrocyte apoptosis. This article summarizes the anti-OA activity of natural products in the last 10 years and provides candidate monomers for further study for use in OA treatment.

Double-stranded RNA-specific adenosine deaminase-knockdown inhibits the proliferation and induces apoptosis of DU145 and PC3 cells by promoting the phosphorylation of H2A.X variant histone.

Double-stranded RNA-specific adenosine deaminase (ADAR1) is a member of the adenosine deaminases acting on RNA family that catalyze the adenosine-to-inosine editing of double-stranded RNA substrates. Several studies have reported that ADAR1 is closely associated with numerous malignancies. However, the functional roles of ADAR1 in prostate cancer (PCa) have not been fully elucidated. Thus, the present study aimed to investigate the effects of ADAR1 on PCa. The results demonstrated that ADAR1 was highly expressed in PCa tissues compared with normal tissues. Furthermore, the protein expression level of ADAR1 was significantly increased in castration-resistant PCa (CRPCa) tissues and CRPCa cell lines. Thus, these findings indicated that ADAR1 may act as a tumor promoter for PCa development. Next, the potential effects of ADAR1-knockdown on the proliferation of DU145 and PC3 cells were investigated. ADAR1 was knocked down via small interfering RNA transfection, which was found to exert antitumor effects on DU145 and PC3 cells at 24 and 48 h post transfection. Furthermore, a significant positive association was observed between ADAR1-knockdown and the apoptosis of DU145 and PC3 cells, which increased the phosphorylation of H2A.X variant histone. The results of the present study indicated a positive association between ADAR1 expression and PCa, which may promote the development of CRPCa. Moreover, ADAR1-knockdown may serve as a tumor suppressor and represent a potential target for the treatment of PCa.

Impact of YTHDF1 gene polymorphisms on Wilms tumor susceptibility: A five-center case-control study.

BACKGROUND: Wilms tumor is the most frequent renal malignancy in children. YTHDF1 is associated with the development of several kinds of cancers, yet whether common variants of the YTHDF1 gene influence Wilms tumor risk is unknown. We present, here, a hospital-based case-control study specifically designed to investigate the role of YTHDF1 genetic variants on Wilms tumor. METHODS: We successfully genotyped samples of 408 Wilms tumor cases and 1198 controls which were collected from five hospitals across China. The unconditional logistic regression was adopted to analyze the contributions of YTHDF1 gene single nucleotide polymorphisms (SNPs) to the risk of Wilms tumor. The odds ratio (OR) and 95% confidence interval (CI) were generated to evaluate the conferring risk of YTHDF1 gene SNPs (rs6011668 C>T, rs6090311 A>G). RESULTS: Neither of the two SNPs could contribute to the risk of Wilms tumor. A negative association was also detected in the combined effects of protective genotypes on Wilms tumor risk. The stratification analysis revealed that compared with those with CC genotype, rs6011668 CT/TT genotype was associated with increased Wilms tumor risk in those ≤18 months (OR = 1.54, 95% CI = 1.02-2.30, p = 0.038), and with decreased Wilms tumor risk in those >18 months (OR = 0.70, 95% CI = 0.50-0.97, p = 0.034). CONCLUSION: Our present work sheds some light on the potential role of YTHDF1 gene polymorphisms on Wilms tumor risk.

Electrophysiological Correlates of Processing Warning Signs With Different Background Colors: An Event-Related Potentials Investigation.

Warning signs, as a type of safety signs, are widely applied in our daily lives to informing people about potential hazards and prompting safe behavior. Although previous studies have paid attention to the color of warning signs, they are mostly based on surveys and behavioral experiments. The neural substrates underlying the perception of warning signs with different background colors remain not clearly characterized. Therefore, this research is intended to address this gap with event-related potentials (ERPs) technique. Warning signs with three different background colors (i.e., white, yellow, and blue) were used in the experiment. The results showed that the perceptual differences between different warning signs were present in the form of differential ERPs components (P1, N1, P2, N2, and P3) though subjects were not required to explicitly attend to the warning signs.

Risk-adapted treatment reduced chemotherapy exposure for clinical stage I pediatric testicular cancer.

BACKGROUND: Different from adult clinical stage I (CS1) testicular cancer, surveillance has been recommended for CS1 pediatric testicular cancer. However, among high-risk children, more than 50% suffer a relapse and progression during surveillance, and adjuvant chemotherapy needs to be administered. Risk-adapted treatment might reduce chemotherapy exposure among these children. METHODS: A decision model was designed and calculated using TreeAge Pro 2011 software. Clinical utilities such as the relapse rates of different groups during surveillance or after chemotherapy were collected from the literature. A survey of urologists was conducted to evaluate the toxicity of first-line and second-line chemotherapy. Using the decision analysis model, chemotherapy exposure of the risk-adapted treatment and surveillance strategies were compared based on this series of clinical utilities. One-way and two-way tests were applied to check the feasibility. RESULTS: In the base case decision analysis of CS1 pediatric testicular cancer, risk-adapted treatment resulted in a lower exposure to chemotherapy than surveillance (average: 0.7965 cycles verse 1.3419 cycles). The sensitivity analysis demonstrated that when the relapse rate after primary chemotherapy was ≤ 0.10 and the relapse rate of the high-risk group was ≥ 0.40, risk-adapted treatment would result in a lower exposure to chemotherapy, without any association with the proportion of low-risk patients, the relapse rate of the low-risk group, the relapse rate after salvage chemotherapy or the toxicity utility of second-line chemotherapy compared to first-line chemotherapy. CONCLUSIONS: Based on the decision analysis, risk-adapted treatment might decrease chemotherapy exposure for these high-risk patients, and an evaluation after orchiectomy was critical to this process. Additional clinical studies are needed to validate this statement.