Integrated analysis to identify the AC005154.6/hsa-miR-29c-3p/CCNL2 axis as a novel prognostic biomarker associated with immune infiltration in prostate cancer.

BACKGROUND: Prostate cancer (PCa) is currently the major malignancy in men. It is becoming increasingly clear that competitive endogenous RNA (ceRNA) regulation networks are important in a wide variety of cancers. Nevertheless, there is still much to learn about the biological functions of the ceRNA network in prostate cancer. METHODS: The ceRNA network was constructed using the "GDCRNATools" package. Based on survival analysis, we obtained AC005154.6/hsa-miR-29c-3p/CCNL2 for further analysis. The prognostic model based on this ceRNA network was constructed by univariate and multivariate Cox regression methods. Furthermore, functional enrichment analysis, mutation landscape analysis, immune infiltration analysis, drug sensitivity analysis, methylation analysis, pan-cancer analysis, and molecular experiments of CCNL2 were carried out to investigate the role of CCNL2 in tumorigenesis. RESULTS: We identified the AC005154.6/CCNL2 axis as a risk factor that can promote the progression of prostate cancer by bioinformatics analysis and molecular experiments. Immune infiltration analysis suggested that CCNL2 may act as a novel biomarker for treatment decisions. The methylation level of CCNL2 was significantly decreased in tumor samples, possibly contributing to the upregulation of CCNL2 in prostate cancer. Moreover, CCNL2 is differentially expressed in multiple cancers and is tightly correlated with immune infiltration. CONCLUSION: The current study constructed a ceRNA network, AC005154.6/hsa-miR-29c-3p/CCNL2. Potentially, this biomarker can be used for early diagnosis and decision-making about prostate cancer treatment.

A Study of Type II ɛ-PL Degrading Enzyme (pldII) in Streptomyces albulus through the CRISPRi System.

ε-Poly-L-lysine (ε-PL) is a widely used antibacterial peptide polymerized of 25-35 L-lysine residues. The antibacterial effect of ε-PL is closely related to the polymerization degree. However, the mechanism of ε-PL degradation in S. albulus remains unclear. This study utilized the integrative plasmid pSET152-based CRISPRi system to transcriptionally repress the ε-PL degrading enzyme (pldII). The expression of pldII is regulated by changing the recognition site of dCas9. Through the ε-PL bacteriostatic experiments of repression strains, it was found that the repression of pldII improves the antibacterial effect of the ε-PL product. The consecutive MALDI-TOF-MS results confirmed that the molecular weight distribution of the ε-PL was changed after repression. The repression strain S1 showed a particular peak with a polymerization degree of 44, and other repression strains also generated ε-PL with a polymerization degree of over 40. Furthermore, the homology modeling and substrate docking of pldII, a typical endo-type metallopeptidase, were performed to resolve the degradation mechanism of ε-PL in S. albulus. The hydrolysis of ε-PL within pldII, initiated from the N-terminus by two amino acid-binding residues, Thr194 and Glu281, led to varying levels of polymerization of ε-PL.

Bioinformatics analysis identified shared differentially expressed genes as potential biomarkers for Hashimoto's thyroiditis-related papillary thyroid cancer.

Background: Although the etiology of Hashimoto's thyroiditis (HT), a common autoimmune endocrine disease, is unknown, studies suggest a potential association with genetic factors and environmental conditions inducing excessive iodine intake. Additionally, HT patients have a high risk of papillary thyroid cancer (PTC), which is probably related to the chronic inflammation and autoimmune pathologic process occurring in HT, as it is thought to be associated with neoplastic transformation. Methods: Bioinformatics approaches can identify differentially expressed genes (DEGs) and analyze DEG functions in diseases. R software was used in this study to identify DEGs in HT and PTC using data in Gene Expression Omnibus (GEO). The online tools DAVID, Reactome, and AmiGO were employed for annotation, visualization, and integration of DEGs related to HT and PTC, and the STRING database and Cytoscape software were applied to predict and visualize protein-protein networks (PPIs) for DEG-encoded proteins. Coexpressed DEGs in HT and PTC were validated by reverse transcription PCR (RT-PCR). Results: In total, 326, 231, and 210 DEGs in HT specimens and samples of central PTC and PTC invasive areas, respectively, were detected. According to the PPI network, PTPN6, HLA-A, C3AR1, LCK and ITGB2 are hub genes among HT-DEGs, whereas FN1, CDH2, SERPINA1, and CYR61 are PTC-DEG hub genes. The shared DEGs LTF and CCL21 were validated by RT-PCR. Both bioinformatics and RT-PCR analyses showed LTF and CCL21 to be upregulated in HT tissues and downregulated in PTC tissues. Conclusions: We identified that expression of LTF and CCL21 are significantly different in HT and PTC, suggesting an underlying association between HT and PTC.

Modeling sulfide production in full flow concrete sewers based on the HRT variation of sewerage.

The corrosion and odor in concrete sewers are mainly related to the sulfide production, which is, under certain circumstances, directly proportional to the hydraulic retention time (HRT) of the sewer. To reduce the corrosion and control the odor in concrete sewers, it is necessary to model the production of sulfide in the concrete sewers with different HRTs. However, previous researches were mostly carried out in simulated Perspex-made sewers, and the obtained theoretical formulas based on the Monod equation were impractical because of the complexity. An actual concrete pipe with domestic sewage was employed in this study to obtain a simple but practical model, which can be applied to quantitively describe the sulfide production according to the HRT of the sewer and the chemical oxygen demand (COD) of the sewage. The empirical equation obtained was rs = (0.045 × lnHRT + 0.071) × ([COD] - b)0.6, the coefficient is a logarithmic function of the HRT, and the sulfide production rate and COD have a power relationship. Based on the data of COD and HRT obtained in the realistic sewer, the production of sulfide in the sewer can be predicted for better maintaining sewers through sulfide control.

[A preliminary pharmacophylogenetic study of Solanaceae medicinal plants containing tropane alkaloids].

The Solanaceae plants distributed in China belong to 105 species and 35 varietas of 24 genera. Some medicinal plants of Solanaceae are rich in tropane alkaloids(TAs), which have significant pharmacological activities. In this paper, the geographical distribution, chemical components, traditional therapeutic effect, pharmacological activities, and biosynthetic pathways of TAs in Solanaceous plants were summarized. Besides, the phylogeny of medicinal plants belonging to Solanaceae was visualized by network diagram. Fourteen genera of Solanaceae plants in China contain TAs and have medical records. TAs mainly exist in Datura, Anisodus, Atropa, Physochlaina, and Hyoscyamus. The TAs-containing species were mainly concentrated in Southwest China, and the content of TAs was closely related to plant distribution area and altitude. The Solanaceae plants containing TAs mainly have antispasmodic, analgesic, antiasthmatic, and antitussive effects. Modern pharmacological studies have proved the central sedative, pupil dilating, glandular secretion-inhibiting, and anti-asthma activities of TAs. These pharmacological activities provide a reasonable explanation for the traditional therapeutic efficacy of tropane drugs. In this paper, the geographical distribution, chemical components, traditional therapeutic effect, and modern pharmacological activities of TAs-containing species in Solanaceae were analyzed for the first time. Based on these data, the genetic relationship of TAs-containing Solanaceae species was preliminarily discussed, which provided a scientific basis for the basic research on TAs-containing solanaceous species and was of great significance for the development of natural medicinal plant resources containing TAs.

The interactions between gut microbiota and bioactive ingredients of traditional Chinese medicines: A review.

In recent years, the interaction between the bioactive ingredients of traditional Chinese medicine (TCM) and gut microbiota has been a focus of many studies. When TCM enters the digestive tract, some bioactive ingredients are not absorbed into the gut well thus leading to low bioavailability. Ingredients of TCM are metabolised, or biotransformed by gut microbiota, thereby producing new bioactive molecules, and promote medicine absorption into the circulation. At the same time, the ingredients of TCM effect the composition and structure of gut microbiota, thereby influencing the remote function of diseased organs / tissues through the systemic action of the gut microbiota. In this review, we summarise the gut microbiota-mediated metabolism of flavonoids, alkaloids, terpenoids, saponins, polysaccharides, phenylpropanoids, and organic acids, along with a discussion on the metabolites formed and the biotransformation pathways involving various enzymes. We also highlight the importance of bioactive ingredients of TCM in regulating gut microbiota.

Metal-Free Trifluoroalkylation of Quinoxalin-2(1H)-ones with Unactivated Alkenes and Langlois' Reagent.

A K2S2O8-mediated three-component protocol has been developed for the construction of 3-trifluoroalkylated quinoxalin-2(1H)-ones under metal-free conditions. The present reaction could be accomplished through the trifluoroalkylation of quinoxalin-2(1H)-ones with unactivated alkenes and Langlois' reagent (CF3SO2Na), which provided a highly attractive approach to access a series of biologically important 3-trifluoroalkylated quinoxalin-2(1H)-ones.

Bi3+-Doped BaYF5:Yb,Er Upconversion Nanoparticles with Enhanced Luminescence and Application Case for X-ray Computed Tomography Imaging.

In this work, BaYF5:20%Yb3+/2%Er3+/x%Bi3+ (abbreviated as BaYF5:Yb,Er,Bix, where x = 0-3.0) upconversion nanoparticles (UCNPs) with various doping concentrations of Bi3+ were synthesized through a simple hydrothermal method. The influence of the doping amount of Bi3+ on the microstructures and upconversion luminescence (UCL) properties of the BaYF5:Yb,Er,Bix UCNPs was studied in detail. The doping concentration of Bi3+ has little influence on the microstructures of the UCNPs but significantly impacts their UCL intensities. Under excitation of a 980 nm near-IR laser, the observed UCL intensities for the BaYF5:Yb,Er,Bix UCNPs display first an increasing trend and then a decreasing trend with an increase in the ratio x, giving a maximum at x = 2.5. A possible energy-transfer process and simplified energy levels of the BaYF5:Yb,Er,Bix UCNPs were proposed. The potential of the BaYF5:Yb,Er,Bix UCNPs as contrast agents for computerized tomography (CT) imaging was successfully demonstrated. An obvious accumulation of BaYF5:Yb,Er,Bix in tumor sites was achieved because of high passive targeting by the enhanced permeability and retention effect and relatively low uptake by a reticuloendothelial system such as liver and spleen. This work paves a new route for the design of luminescence-enhanced UNCPs as promising bioimaging agents for cancer theranostics.

[Analysis on formula of Mongolian medicine for prevention of COVID-19].

The epidemic situation of coronavirus disease 2019(COVID-19) is developing rapidly in the world, and the influence is serious. In this study, the prescription of Mongolian medicine to prevent new type of COVID-19 was investigated. Based on the second edition and the third edition of COVID-19 Mongolian Medicine Prevention and Treatment Guidance Program issued by the Inner Mongolia Autonomous Region Health Commission, using Excel 2007, SPSS Modeler 18, SPSS Statistics 25, Cytoscape 3.7.1 statistical software as a tool, the association rules analysis and cluster analysis of Mongolian medicine included in the standard were carried out. Among the 45 prophylactic prescriptions included in the standard, a total of 34 high-frequency drugs using frequency ≥5 were used, of which Carthami Flos(21 times, 4.46%), Chebulae Fructus(20 times, 4.26%), Moschus(13 times, 2.77%), Myristicae Semen(12 times, 2.55%), Santali Albi Lignum(12 times, 2.55%), and Bovis Calculus(12 times, 2.55%) were the most common. The main drugs for the prevention of COVID-19 were Liang(13 times, 38.23%), Wen(9 times, 26.47%), the flavor was Ku(20 times, 34.48%), Xin(13 times, 22.41%), Gan(11 times, 18.97%), the most used drugs treating hot evil(99 times, 32.46%), treatment of "Heyi" drugs(51 times, 16.72%), treatment of "Badagan" drugs(40 times, 13.11%), treatment of "sticky" drugs(37 times, 12.13%), and a cough, eliminating phlegm and antiasthmatic(31 times, 10.16%), the association rule analysis found that the highest association intensity of the drug pair combination of 11. Clustering analysis using the cluster analysis of inter-group join method found a total of 8 categories. In this study, 45 prescriptions of Mongolian medicine for the prevention of COVID-19 were collec-ted and further analyzed, hoping to provide new ideas for clinical diagnosis and treatment.

Radiofrequency ablation versus surgical resection for intrahepatic hepatocellular carcinoma recurrence: a meta-analysis.

BACKGROUND: To compare the clinical efficacy and safety of radiofrequency ablation (RFA) versus surgical resection (SR) for intrahepatic hepatocellular carcinoma (HCC) recurrence by meta-analytical techniques. METHODS: Literature documenting a comparison of RFA and SR for intrahepatic HCC recurrence was identified by searching PubMed, Embase, Cochrane Library, and Web of Science databases, for those from inception to July 2014 with no limits. The heterogeneity was tested by the Cochrane Q statistic; the pooled estimates were measured using either fixed or random effect model. Furthermore, subgroup and sensitivity analyses were conducted to explore heterogeneity between studies and to assess the efficacy of different studies. RESULTS: Seven studies were included with a total of 718 patients (359 treated with RFA and 359 treated with SR). Our meta-analysis showed that the 1-, 3-, and 5-y overall survival rate and procedure-related mortality rate were similar in patients treated with RFA or SR. Meanwhile, SR was associated with significantly higher 1-, 3-, and 5-y re-recurrence-free survival rate and procedure-related morbidity rate compared with RFA. In the subgroup analysis of patients in China, the results concerning overall and re-recurrence-free survival were similar to the outcomes of the meta-analysis without regional restriction. In the subgroup analysis of intrahepatic recurrent HCC ≤3 cm, the 1-, 3-, and 5-y overall survival rate did not differ significantly in the comparison of RFA and SR. CONCLUSIONS: Although RFA was associated with lower re-recurrence-free survival, it seems to be as effective as SR for the treatment of intrahepatic HCC recurrence owing to comparable overall survival benefits. The advantages of being less invasive, highly target-selective, and repeatable may render RFA a preferred treatment option for selected patients.

Localized primary gastrointestinal diffuse large B cell lymphoma received a surgical approach: an analysis of prognostic factors and comparison of staging systems in 101 patients from a single institution.

BACKGROUND: Diffuse large B cell lymphoma (DLBCL) represents the most common histological subtype of primary gastrointestinal lymphoma and is a heterogeneous group of disease. Prognostic characterization of individual patients is an essential prerequisite for a proper risk-based therapeutic choice. METHODS: Clinical and pathological prognostic factors were identified, and predictive value of four previously described prognostic systems were assessed in 101 primary gastrointestinal DLBCL (PG-DLBCL) patients with localized disease, including Ann Arbor staging with Musshoff modification, International Prognostic Index (IPI), Lugano classification, and Paris staging system. RESULTS: Univariate factors correlated with inferior survival time were clinical parameters [age>60 years old, multiple extranodal/gastrointestinal involvement, elevated serum lactate dehydrogenase and ß2-microglobulin, and decreased serum albumin], as well as pathological parameters (invasion depth beyond serosa, involvement of regional lymph node or adjacent tissue, Ki-67 index, and Bcl-2 expression). Major independent variables of adverse outcome indicated by multivariate analysis were multiple gastrointestinal involvement. In patients unfit for Rituximab but received surgery, radical surgery significantly prolonged the survival time, comparing with alleviative surgery. Addition of Rituximab could overcome the negative prognostic effect of alleviative surgery. Among the four prognostic systems, IPI and Lugano classification clearly separated patients into different risk groups. IPI was able to further stratify the early-stage patients of Lugano classification into groups with distinct prognosis. CONCLUSIONS: Radical surgery might be proposed for the patients unfit for Rituximab treatment, and a combination of clinical and pathological staging systems was more helpful to predict the disease outcome of PG-DLBCL patients.

Self-Healing Dynamic Hydrogel Microparticles with Structural Color for Wound Management.

Chronic diabetic wounds confront a significant medical challenge because of increasing prevalence and difficult-healing circumstances. It is vital to develop multifunctional hydrogel dressings, with well-designed morphology and structure to enhance flexibility and effectiveness in wound management. To achieve these, we propose a self-healing hydrogel dressing based on structural color microspheres for wound management. The microsphere comprised a photothermal-responsive inverse opal framework, which was constructed by hyaluronic acid methacryloyl, silk fibroin methacryloyl and black phosphorus quantum dots (BPQDs), and was further re-filled with a dynamic hydrogel. The dynamic hydrogel filler was formed by Knoevenagel condensation reaction between cyanoacetate and benzaldehyde-functionalized dextran (DEX-CA and DEX-BA). Notably, the composite microspheres can be applied arbitrarily, and they can adhere together upon near-infrared irradiation by leveraging the BPQDs-mediated photothermal effect and the thermoreversible stiffness change of dynamic hydrogel. Additionally, eumenitin and vascular endothelial growth factor were co-loaded in the microspheres and their release behavior can be regulated by the same mechanism. Moreover, effective monitoring of the drug release process can be achieved through visual color variations. The microsphere system has demonstrated desired capabilities of controllable drug release and efficient wound management. These characteristics suggest broad prospects for the proposed composite microspheres in clinical applications.

Approaches to Improving the Selectivity of Nanozymes.

Nanozymes mimic enzymes and that includes their selectivity. To achieve selectivity, significant inspiration for nanoparticle design can come from the geometric and molecular features that make enzymes selective catalysts. The two central features enzymes use are control over the arrangement of atoms in the active site and the placing of the active site down a nanoconfined substrate channel. The implementation of enzyme-inspired features has already been shown to both improve activity and selectivity of nanoparticles for a variety of catalytic and sensing applications. The tuning and control of active sites on metal nanoparticle surfaces ranges from simply changing the composition of the surface metal to sophisticated approaches such as the immobilization of single atoms on a metal substrate. Molecular frameworks provide a powerful platform for the implementation of isolated and discrete active sites while unique diffusional environments further improve selectivity. The implementation of nanoconfined substrate channels around these highly controlled active sites offers further ability to control selectivity through altering the solution environment and transport of reactants and products. Implementing these strategies together offers a unique opportunity to improve nanozyme selectivity in both sensing and catalysis.

STX4 as a potential biomarker for predicting prognosis and guiding clinical treatment decisions in clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) represents a frequent subtype of kidney cancer, with the prognosis remaining poor for individuals with metastatic disease. Given its resistance to both radiation and chemotherapy, targeted therapies and immunotherapies have emerged as critical for effective ccRCC treatment. Within this context, the SNARE protein STX4, which is associated with malignant cancer cell migration, provides a promising focus. The underlying mechanism, however, requires further illumination. Furthermore, the influence of STX4 on the ccRCC tumor microenvironment remains to be determined. In our research, we utilized multiple databases and immunohistochemical staining to confirm differential STX4 expression and its prognostic implications. We evaluated the potential tumor-promoting function of STX4 in ccRCC cell lines through molecular studies. Additionally, we conducted functional enrichment analysis to delve deeper into the underlying mechanisms and performed immune infiltration and drug sensitivity analyses to assess the potential of STX4 as a prognostic biomarker and therapeutic target. Our study reveals that STX4 contributes to cancer progression by enhancing AKT expression and stimulating the activation of VEGF signaling pathways. Additionally, STX4 further fosters CD8+ T-cell infiltration and diminishes the percentage of CAFs and M2-TAMs. Our findings suggest that patients presenting higher STX4 levels may exhibit enhanced responsiveness to immunotherapy and higher sensitivity to the medications axitinib and everolimus. Finally, we propose STX4 expression assessment as a novel approach to predict patient response to respective immunotherapies and targeted treatments, hence potentially improving patient outcomes.

A detrimental role of endothelial S1PR2 in cardiac ischemia-reperfusion injury via modulating mitochondrial dysfunction, NLRP3 inflammasome activation, and pyroptosis.

Sphingosine 1-phosphate (S1P), a bioactive lipid molecule, exerts multifaceted effects on cardiovascular functions via S1P receptors, but its effects on cardiac I/R injury are not fully understood. Plasma lipidomics analysis by mass spectrometry revealed that sphingosine lipids, including sphingosine 1-phosphate (S1P), were significantly down-regulated following cardiac I/R injury in mice. The reduced S1P levels were also observed in the plasma of coronary heart disease (CHD) patients after percutaneous coronary intervention (PCI) compared with those without PCI. We found that S1P exerted a cardioprotective effect via endothelial cell (EC)-S1PR1, whereas EC-S1PR2 displayed a detrimental effect on cardiac I/R. Our data showed that EC-specific S1pr2 loss-of-function significantly lessened inflammatory responses and diminished cardiac I/R injury, while EC-specific S1pr2 gain-of-function aggravated cardiac I/R injury. Mechanistically, EC-S1PR2 initiated excessive mitochondrial fission and elevated ROS production via RHO/ROCK1/DRP1 pathway, leading to NLRP3 inflammasome activation and subsequent cell pyroptosis, thereby exacerbating inflammation and I/R injuries. Furthermore, RGD-peptide magnetic nanoparticles packaging S1pr2-siRNA to specifically knockdown S1PR2 in endothelial cells significantly ameliorated cardiac I/R injury. Taken together, our investigations demonstrate that EC-S1PR2 induces excessive mitochondrial fission, which results in NLRP3 inflammasome activation and subsequently triggers cell pyroptosis, ultimately exacerbating inflammatory responses and aggravating heart injuries following I/R.

MiRNA-100 ameliorates diabetes mellitus-induced erectile dysfunction by modulating autophagy, anti-inflammatory, and antifibrotic effects.

BACKGROUND: Diabetes mellitus-induced erectile dysfunction (DMED) has become a common disease in adult men that can seriously reduce the quality of life of patients, and new therapies are urgently needed. miRNA-100 has many targets and can induce autophagy and reduce fibrosis by inhibiting the mTOR pathway and the TGF-ß pathway. However, no research has been conducted with miR-100 in the field of DMED, and the specific mechanism of action is still unclear. OBJECTIVES: To ascertain the effects of miR-100 on corpus cavernosum tissue of DMED rats and vascular endothelial cells in a high glucose environment and to elucidate the relevant mechanisms in autophagy, fibrosis and inflammation to find a new approach for the DMED therapy. METHODS: Thirty rats were divided into three groups: the control group, the DMED group, and the DMED + miR-100 group. Using intraperitoneal injections of streptozotocin, all rats except the control group were modeled with diabetes mellitus, which was verified using the apomorphine (APO) test. For rats in the DMED + miR-100 group, rno-miR-100-5p agomir (50 nmol/kg, every 2 days, 6 times in total) was injected via the tail vein. After 13 weeks, the erectile function of each rat was assessed using cavernous manometry, and the corpus cavernosum tissue was harvested for subsequent experiments. For cellular experiments, human coronary microartery endothelial cells (HCMEC) were divided into four groups: the control group, the high-glucose (HG, 40 mM) group, the HG + mimic group, and the HG + inhibitor group. The cells were cultured for 6 days and collected for subsequent experiments 2 days after transfection. RESULTS: Diabetic modeling impaired the erectile function in rats, and miR-100 reversed this effect. By measuring autophagy-related proteins such as mTOR/Raptor/Beclin1/p62/LC3B, we found that miR-100 could suppress the expression of mTOR and induce autophagy. The analysis of the eNOS/NO/cGMP axis function indicated that impaired endothelial function was improved by miR-100. By evaluating the TGF-ß1/CTGF/Smad2/3 and NF-κB/TNF-α pathways, we found that miR-100 could lower the level of inflammation and fibrosis, which contributed to the improvement of the erectile function. Cellular experiments can be used as supporting evidence for these findings. CONCLUSION: MiR-100 can improve the erectile function by inhibiting mTOR and thus inducing autophagy, improving the endothelial function through the eNOS/NO/cGMP axis, and exerting antifibrotic and anti-inflammatory effects, which may provide new ideas and directions for the treatment of DMED.

Ablation of vacuole protein sorting 18 (Vps18) gene leads to neurodegeneration and impaired neuronal migration by disrupting multiple vesicle transport pathways to lysosomes.

Intracellular vesicle transport pathways are critical for neuronal survival and central nervous system development. The Vps-C complex regulates multiple vesicle transport pathways to the lysosome in lower organisms. However, little is known regarding its physiological function in mammals. We deleted Vps18, a central member of Vps-C core complex, in neural cells by generating Vps18(F/F); Nestin-Cre mice (Vps18 conditional knock-out mice). These mice displayed severe neurodegeneration and neuronal migration defects. Mechanistic studies revealed that Vps18 deficiency caused neurodegeneration by blocking multiple vesicle transport pathways to the lysosome, including autophagy, endocytosis, and biosynthetic pathways. Our study also showed that ablation of Vps18 resulted in up-regulation of ß1 integrin in mouse brain probably due to lysosome dysfunction but had no effects on the reelin pathway, expression of N-cadherin, or activation of JNK, which are implicated in the regulation of neuronal migration. Finally, we demonstrated that knocking down ß1 integrin partially rescued the migration defects, suggesting that Vps18 deficiency-mediated up-regulation of ß1 integrin may contribute to the defect of neuronal migration in the Vps18-deficient brain. Our results demonstrate important roles of Vps18 in neuron survival and migration, which are disrupted in multiple neural disorders.

The role of calcium channels in prostate cancer progression and potential as a druggable target for prostate cancer treatment.

Prostate cancer (PCa) is the most diagnosed cancer among men. Discovering novel prognostic biomarkers and potential therapeutic targets are critical. Calcium signaling has been implicated in PCa progression and development of treatment resistance. Altered modification of Ca2+ flows leads to serious pathophysiological processes, such as malignant transformation, tumor proliferation, epithelial to mesenchymal transition, evasion of apoptosis, and treatment resistance. Calcium channels control and contribute to these processes. PCa has shown defective Ca2+ channels, which subsequently promotes tumor metastasis and growth. Store-operated Ca2+ entry channels such as Orai and STIM channels and transient receptor potential channels play a significant role in PCa pathogenesis. Pharmacological modulation of these calcium channels or pumps has been suggested as a practical approach. In this review, we discuss the role of calcium channels in PCa development and progression, and we identify current novel discoveries of drugs that target specific calcium channels for the treatment of PCa.

CPT2-mediated fatty acid oxidation inhibits tumorigenesis and enhances sorafenib sensitivity via the ROS/PPARγ/NF-κB pathway in clear cell renal cell carcinoma.

Kidney cancer is a common kind of tumor with approximately 400,000 new diagnoses each year. Clear cell renal cell carcinoma (ccRCC) accounts for 70-80% of all renal cell carcinomas. Lipid metabolism disorder is a hallmark of ccRCC. With a better knowledge of the importance of fatty acid oxidation (FAO) in cancer, carnitine palmitoyltransferase 2 (CPT2) has gained prominence as a major mediator in the cancer metabolic pathway. However, the biological functions and mechanism of CPT2 in the progression of ccRCC are still unclear. Herein, we performed assays in vitro and in vivo to explore CPT2 functions in ccRCC. Moreover, we discovered that CPT2 induced FAO, which inhibited the generation of reactive oxygen species (ROS) by increasing nicotinamide adenine dinucleotide phosphate (NADPH) production. Additionally, we demonstrated that CPT2 suppresses tumor proliferation, invasion, and migration by inhibiting the ROS/ PPARγ /NF-κB pathway. Gene set enrichment analysis (GSEA) and drug sensitivity analysis showed that high expression of CPT2 in ccRCC was associated with higher sorafenib sensitivity, which was also validated in vitro and in vivo. In summary, our results suggest that CPT2 acts as a tumor suppressor in the development of ccRCC through the ROS/PPARγ/NF-κB pathway. Moreover, CPT2 is a potential therapeutic target for increasing sorafenib sensitivity in ccRCC.

Organoid-on-a-chip: Current challenges, trends, and future scope toward medicine.

In vitro organoid models, typically defined as 3D multicellular aggregates, have been extensively used as a promising tool in drug screening, disease progression research, and precision medicine. Combined with advanced microfluidics technique, organoid-on-a-chip can flexibly replicate in vivo organs within the biomimetic physiological microenvironment by accurately regulating different parameters, such as fluid conditions and concentration gradients of biochemical factors. Since engineered organ reconstruction has opened a new paradigm in biomedicine, innovative approaches are increasingly required in micro-nano fabrication, tissue construction, and development of pharmaceutical products. In this Perspective review, the advantages and characteristics of organoid-on-a-chip are first introduced. Challenges in current organoid culture, extracellular matrix building, and device manufacturing techniques are subsequently demonstrated, followed by potential alternative approaches, respectively. The future directions and emerging application scenarios of organoid-on-a-chip are finally prospected to further satisfy the clinical demands.