Cu(II) complex that synergistically potentiates cytotoxicity and an antitumor immune response by targeting cellular redox homeostasis.

Developing anticancer drugs with low side effects is an ongoing challenge. Immunogenic cell death (ICD) has received extensive attention as a potential synergistic modality for cancer immunotherapy. However, only a limited set of drugs or treatment modalities can trigger an ICD response and none of them have cytotoxic selectivity. This provides an incentive to explore strategies that might provide more effective ICD inducers free of adverse side effects. Here, we report a metal-based complex (Cu-1) that disrupts cellular redox homeostasis and effectively stimulates an antitumor immune response with high cytotoxic specificity. Upon entering tumor cells, this Cu(II) complex enhances the production of intracellular radical oxidative species while concurrently depleting glutathione (GSH). As the result of heightening cellular oxidative stress, Cu-1 gives rise to a relatively high cytotoxicity to cancer cells, whereas normal cells with low levels of GSH are relatively unaffected. The present Cu(II) complex initiates a potent ferroptosis-dependent ICD response and effectively inhibits in vivo tumor growth in an animal model (c57BL/6 mice challenged with colorectal cancer). This study presents a strategy to develop metal-based drugs that could synergistically potentiate cytotoxic selectivity and promote apoptosis-independent ICD responses through perturbations in redox homeostasis.

A DNA-based hydrogel for exosome separation and biomedical applications.

Exosomes (EXOs) have been proven as biomarkers for disease diagnosis and agents for therapeutics. Great challenge remains in the separation of EXOs with high-purity and low-damage from complex biological media, which is critical for the downstream applications. Herein, we report a DNA-based hydrogel to realize the specific and nondestructive separation of EXOs from complex biological media. The separated EXOs were directly utilized in the detection of human breast cancer in clinical samples, as well as applied in the therapeutics of myocardial infarction in rat models. The materials chemistry basis of this strategy involved the synthesis of ultralong DNA chains via an enzymatic amplification, and the formation of DNA hydrogels through complementary base-pairing. These ultralong DNA chains that contained polyvalent aptamers were able to recognize and bind with the receptors on EXOs, and the specific and efficient binding ensured the selective separation of EXOs from media into the further formed networked DNA hydrogel. Based on this DNA hydrogel, rationally designed optical modules were introduced for the detection of exosomal pathogenic microRNA, which achieved the classification of breast cancer patients versus healthy donors with 100% precision. Furthermore, the DNA hydrogel that contained mesenchymal stem cell-derived EXOs was proved with significant therapeutic efficacy in repairing infarcted myocardium of rat models. We envision that this DNA hydrogel-based bioseparation system is promising as a powerful biotechnology, which will promote the development of extracellular vesicles in nanobiomedicine.

Systemic inflammation and risk of Parkinson's disease: A prospective cohort study and genetic analysis.

BACKGROUND: Multiple evidence has suggested the complex interplay between Parkinson's disease (PD) and systemic inflammation marked by C-reactive protein (CRP) and interleukin 6 (IL-6). Nevertheless, the findings across studies have shown inconsistency, and the direction of the effect remains controversial. Here, we aimed to explore the link between CRP and IL-6 and the risk of PD. METHODS: Based on data from the UK Biobank, we investigated the association between baseline CRP and IL-6 and the risk of incident PD with Cox proportional hazards regression analysis. We further performed extensive genetic analyses including genetic correlation, polygenic risk score (PRS), and pleiotropic enrichment based on summary statistics from previous genome-wide association studies. RESULTS: A higher level of CRP at baseline was associated with a lower risk of PD (HR = 0.85, 95 % CI: 0.79-0.90, P = 4.23E-07). The results remained consistent in the subgroup analyses stratified by sex, age and body mass index. From the genetic perspective, a significant negative genetic correlation was identified between CRP and PD risk (correlation: -0.14, P = 6.31E-05). Higher PRS of CRP was associated with a lower risk of PD (P = 0.015, beta = -0.04, SE = 0.017). Moreover, we observed significant pleiotropic enrichment for PD conditional on CRP, and identified 13 risk loci for PD, some of which are implicated in immune functionality and have been linked to PD, including CTSB, HNF4A, PPM1G, ACMSD, and NCOR1. In contrast, no significant association was identified between IL-6 and PD. CONCLUSIONS: Systemic inflammation at baseline measured by CRP level is associated with decreased future risk of PD. These discoveries contribute to a deeper comprehension of the role of inflammation in the risk of PD, and hold implications for the design of therapeutic interventions in clinical trials.

First report of citrus leaf blotch virus infecting Forsythia viridissima in China.

Green-stem forsythia (Forsythia viridissima), also known as golden bell, is cultivated widely in China as an early spring flowering shrub. In July 2020, yellow or white vein clearing symptoms on leaves were observed in approximate 15% golden bell plants along a landscape river in Ningbo city, Zhejiang province, China. Symptomatic leaves from six different plants were collected and pooled. Total RNA was extracted from about 200 mg pooled sample using TRIzol Reagent (Invitrogen, Carlsbad, USA) and used for high-throughput sequencing (HTS). The cDNA library was constructed using a TruSeq RNA Sample Preparation Kit (Illumina) and an Illumina NovaSeq 6000 platform was utilized to yield 150 nt paired-end reads. CLC Genomic Workbench 11 (QIAGEN) with default parameters were used for data analysis. A total of 41,604,174 paired-end reads were obtained, and 156,853 contigs (16 - 26,665 nt) were generated de novo and compared with sequences in the NCBI nt and nr database using BLASTn and BLASTx, respectively. A total of 197,277 reads were mapped to the citrus leaf blotch virus (CLBV; genus Citrivirus, family Betaflexiviridae) genome with an average coverage of 3191×. A contig of 8783 nt (excluding the poly(A) tail) was aligned to CLBV isolate Vib (accession No. OP751940) by BLASTn with the highest nt sequence identity of 99.7% and 99% query coverage, suggesting that the samples were infected with CLBV (Myung-Hwi Kim et al. 2023). No other virus was detected by this analysis. Subsequently, leaves of the six plants collected above, three plants with mild chlorotic symptoms and three plants without obvious symptoms were tested separately by RT-PCR and all were positive for CLBV. Sap from multiple symptomatic F. viridissima leaves was mechanically inoculated to Nicotiana benthamiana, N. tabacum and Datura stramonium in sextuplicate, but after two months, none of the inoculated plants had obvious symptoms and all of them tested negative for CLBV using RT-PCR. To determine the genome sequence of CLBV present in F. viridissima, a single sample from one plant was selected for genome validtion. The contig sequence was confirmed by Sanger sequencing of RT-PCR products amplified using CLBV-specific primers, and the 5' terminal sequence of the virus was determined using a commercial SUPERSWITCH RACE cDNA Synthesis Kit (Tiosbio, Beijing, China). The complete genomic sequence of CLBV isolated from F. viridissima was 8787 nts long, excluding the poly(A) tail, has the expected three predicted ORFs and was deposited in the GenBank database (accession no. OR766026). Phylogenetic analysis of different CLBV genome sequences from fruit trees and other hosts in GenBank using MEGA11 showed that the golden bell isolate was most closely related to isolate Vib (OP751940) from Viburnum lentago in South Korea, with which it was almost identical (99.7% complete nt sequence identity and >99% aa sequence identity in each of the three ORFs). Ten viruses have been previously reported from Forsythia spp. (Kaminska, M. 1985; Lee et al. 1997), but this is the first report of CLBV in this host. CLBV mainly infects citrus, kiwifruit and apple causing mosaic, chlorosis or yellow vein clearing symptoms, however, bud union disorder was observed in 'Nagami' kumquat infected by CLBV, which caused serious production losses (Cao et al. 2017; Li et al. 2018; Liu et al. 2019; Galipienso et al. 2001). Therefore, further investigation is needed to assess if F. viridissima can be an intermediate host to transfer CLBV to other crops.

Deep-Learning Aided Atomic-Scale Phase Segmentation toward Diagnosing Complex Oxide Cathodes for Lithium-Ion Batteries.

Phase transformation─a universal phenomenon in materials─plays a key role in determining their properties. Resolving complex phase domains in materials is critical to fostering a new fundamental understanding that facilitates new material development. So far, although conventional classification strategies such as order-parameter methods have been developed to distinguish remarkably disparate phases, highly accurate and efficient phase segmentation for material systems composed of multiphases remains unavailable. Here, by coupling hard-attention-enhanced U-Net network and geometry simulation with atomic-resolution transmission electron microscopy, we successfully developed a deep-learning tool enabling automated atom-by-atom phase segmentation of intertwined phase domains in technologically important cathode materials for lithium-ion batteries. The new strategy outperforms traditional methods and quantitatively elucidates the correlation between the multiple phases formed during battery operation. Our work demonstrates how deep learning can be employed to foster an in-depth understanding of phase transformation-related key issues in complex materials.

The metabolic reprogramming of γ-aminobutyrate in oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) is the most common head and neck malignancy. The oncometabolites have been studied in OSCC, but the mechanism of metabolic reprogramming remains unclear. To identify the potential metabolic markers to distinguish malignant oral squamous cell carcinoma (OSCC) tissue from adjacent healthy tissue and study the mechanism of metabolic reprogramming in OSCC. We compared the metabolites between cancerous and paracancerous tissues of OSCC patients by 1HNMR analysis. We established OSCC derived cell lines and analyzed their difference of RNA expression by RNA sequencing. We investigated the metabolism of γ-aminobutyrate in OSCC derived cells by real time PCR and western blotting. Our data revealed that much more γ-aminobutyrate was produced in cancerous tissues of OSCC patients. The investigation based on OSCC derived cells showed that the increase of γ-aminobutyrate was promoted by the synthesis of glutamate beyond the mitochondria. In OSCC cancerous tissue derived cells, the glutamate was catalyzed to glutamine by glutamine synthetase (GLUL), and then the generated glutamine was metabolized to glutamate by glutaminase (GLS). Finally, the glutamate produced by glutamate-glutamine-glutamate cycle was converted to γ-aminobutyrate by glutamate decarboxylase 2 (GAD2). Our study is not only benefit for understanding the pathological mechanisms of OSCC, but also has application prospects for the diagnosis of OSCC.

Hematologic traits and primary biliary cholangitis: a Mendelian randomization study.

Hematologic abnormalities was observationally associated with the susceptibility of primary biliary cholangitis (PBC). However, the conclusion is still controversial and whether there exists a causal association remains elusive. Here we aimed to explore the causative role of hematological traits in the risk of PBC. We conducted two-sample and multivariable Mendelian randomization analyses based on summary statistics from previous large genome-wide association studies. Totally twelve red blood cell and six white blood cell traits were analyzed. Genetically determined higher hemoglobin level was significantly associated with a reduced risk of PBC (OR: 0.62, 95% CI: 0.47-0.81, P: 5.59E-04). Meanwhile, higher hematocrit level was nominally associated with reduced risk of PBC (OR: 0.73, 95% CI: 0.57-0.93, P: 0.01). These results could help better understand the role of hematological traits in the risk of PBC, and provide potential targets for the disease prevention and treatment.

Novel rare mutation in a conserved site of PTPRB causes human hypoplastic left heart syndrome.

Hypoplastic left heart syndrome (HLHS) is a rare but fatal birth defect in which the left side of the heart is underdeveloped. HLHS accounts for 2% to 4% of congenital heart anomalies. Whole genome sequencing (WGS) was conducted for a family trio consisting of a proband and his parents. A homozygous rare variant was detected in the PTPRB (Protein Tyrosine Phosphatase Receptor Type B) gene of the proband by functional annotation and co-segregation analysis. Sanger sequencing was used to confirm genotypes of the variant. The in silico prediction tools, including Mutation Taster, SpliceAI, and CADD, were used to predict the impact of the mutation. The allele frequencies across populations were compared based on multiple databases, including "1000 genomes" and "gnomAD". We used two vectors (pcMINI and pcDNA3.1) to generate a minigene construct to validate the mutational effect at the transcriptional level. Family-based WGS analyses showed that only a homozygous splice acceptor variant (NC_000012.12: g.70636068T>G, NM_001109754.4: c.56-2A>C, NG_029940.2: g.6373A>C) at the exon-intron border of PTPRB gene associates with HLHS. This variant is also within the region with the enhancer activity based on UCSC genome annotation. Genotyping and Sanger sequencing revealed that the proband's parents are heterozygous for this variant. Evolutionary conservation analysis revealed that the site (NC_000012.12: g.70636068) is extremely conserved across species, supporting the evolutionary functional constraints of the ancestral wild type (T). In silico tools universally predicted a deleterious or disease-causing impact of the mutation from T to G. The mutation was not found in the 1000 genomes and gnomAD databases, which indicates that this mutation is very rare in most human populations. A splicing assay indicated that the mutated minigene caused aberrant splicing of mRNA, in which a 3 bp missing in the second exon resulted in the deletion of one amino acid (NP_001103224.1:p.Glu19del) compared to the normal protein of PRPTB (also the VE-PTP). Structure prediction revealed that the deletion occurred within the C-region of the signal peptide of VE-PTP, suggesting signal peptide-related defects as a potential mechanism for the HLHS cellular pathogeny. We report a rare homozygous variant with splicing error in PTPRB associated with HLHS. Previous model species studies revealed conserved functions of PTPRB in cardiovascular and heart development in mice and zebrafish. Our study is the first report to show the association between PTPRB and HLHS in humans.

Exploring the molecular characteristics of the malignant potential of gastric adenocarcinoma with enteroblastic differentiation.

AIMS: Gastric adenocarcinoma with enteroblastic differentiation (GAED) is a rare subset of alpha-fetoprotein (AFP)-producing carcinomas with poor prognosis. However, the molecular features associated with the malignant potential of GEAD remain partially elucidated. METHODS AND RESULTS: In this study, the relationship between clinicopathological parameters and aggressive biological behaviour was analysed in 37 patients with GAED. The results showed that GAED tended to infiltrate the deep layer of the gastric wall and possessed more frequent vascular invasion than conventional gastric adenocarcinoma (CGA) (P < 0.001). All distant metastases were observed in the GAED group, not the CGA group (P < 0.001). High HER2 expression was found in nearly 24.32% of the informative cases, and none showed EBV-encoded RNA positivity or deficient mismatch repair. The most frequently mutated gene in GAED was p53. Programmed cell death-ligand 1 (PD-L1) immunostaining revealed 13 patients with a combined positive score (CPS) ≥ 5 (65%, 13 of 20). Thus, based on these molecular markers (immunostaining, in situ hybridisation and mutation analysis), GAED may be classified as a unique subgroup of the chromosomal instability subtype with HER2+ /EBV- /MSS/TP53+ /PD-L1+ . Next-generation sequencing analyses showed that mutations in the TOPI, ELOA and NOTCH3 genes were found only in GAED, and abnormally expressed genes in GAED were significantly enriched in hepatocellular carcinoma-, gland development-, and gastric cancer-related pathways. CONCLUSION: The HER2+ /EBV- /MSS/TP53+ /PD-L1+ profile and hepatocellular carcinoma-related pathways may be significant in the malignant potential of GAED. In addition to anti-HER2 therapy, immune check-point inhibitors may be an effective treatment option for patients with GAED.

Complete genome sequence of a novel mitovirus detected in Colocasia esculenta.

A novel mitovirus was detected in taro (Colocasia esculenta) growing in Ningbo, China. The complete genome sequence of Colocasia esculenta associated mitovirus 1 (CeaMV1) was determined by next-generation sequencing combined with RT-PCR and RACE. The genome is 2921 nucleotides long and contains a single ORF encoding a putative RNA-dependent RNA polymerase. Homology searches and phylogenetic analysis suggested that CeaMV1 is a member of a new species in the genus Duamitovirus. This is the first report of a member of the family Mitoviridae associated with taro.

Complete nucleotide sequence of hackberry virus A, a tentative member of the genus Waikavirus.

The complete genomic sequence of a waikavirus from Chinese hackberry in Zhejiang province, China, named "hackberry virus A" (HVA), was determined using high-throughput sequencing (HTS) combined with reverse transcription polymerase chain reaction (RT-PCR) and rapid amplification of cDNA ends (RACE) PCR. The bicistronic genomic RNA of HVA was found to consist of 12,691 nucleotides (nt), excluding the 3'-terminal poly(A) tail, and to encode a large polyprotein of 3783 amino acids (aa) and an additional 10.3-kDa protein. The aa sequences of the Pro-Pol and the CP regions of this virus share 39.8-44.2% and 25.5-36.4% identity, respectively, with currently known waikaviruses. These values are significantly below the current species demarcation threshold (< 75% and < 80% aa identity for the CP and Pro-Pol region, respectively) for the family Secoviridae, indicating that HVA represents a new species in the genus Waikavirus. This is the first report of a virus infecting Chinese hackberry.

Target Profiling of an Iridium(III)-Based Immunogenic Cell Death Inducer Unveils the Engagement of Unfolded Protein Response Regulator BiP.

Clinical chemotherapeutic drugs have occasionally been observed to induce antitumor immune responses beyond the direct cytotoxicity. Such effects are coined as immunogenic cell death (ICD), representing a "second hit" from the host immune system to tumor cells. Although chemo-immunotherapy is highly promising, ICD inducers remain sparse with vague drug-target mechanisms. Here, we report an endoplasmic reticulum stress-inducing cyclometalated Ir(III)-bisNHC complex (1a) as a new ICD inducer, and based on this compound, a clickable photoaffinity probe was designed for target identification, which unveiled the engagement of the master regulator protein BiP (binding immunoglobulin protein)/GRP78 of the unfolded protein response pathway. This has been confirmed by a series of cellular and biochemical studies including fluorescence microscopy, cellular thermal shift assay, enzymatic assays, and so forth, showing the capability of 1a for BiP destabilization. Notably, besides 1a, the previously reported ICD inducers including KP1339, mitoxantrone, and oxaliplatin were also found to engage BiP interaction, suggesting the important role of BiP in eliciting anticancer immunity. We believe that the ICD-related target information in this work will help to understand the mode of action of ICD that is beneficial to designing new ICD agents with high specificity and improved efficacy.

Sensitivity of Sniffer Dogs for a Diagnosis of Parkinson's Disease: A Diagnostic Accuracy Study.

BACKGROUND: The diagnostic criteria for Parkinson's disease (PD) remain complex, which is especially problematic for nonmovement disorder experts. A test is required to establish a diagnosis of PD with improved accuracy and reproducibility. OBJECTIVE: The study aimed to investigate the sensitivity and specificity of tests using sniffer dogs to diagnose PD. METHODS: A prospective, diagnostic case-control study was conducted in four tertiary medical centers in China to evaluate the accuracy of sniffer dogs to distinguish between 109 clinically established medicated patients with PD, 654 subjects without PD, 37 drug-naïve patients with PD, and 185 non-PD controls. The primary outcomes were sensitivity and specificity of sniffer dog's identification. RESULTS: In the study with patients who were medicated, when two or all three sniffer dogs yielded positive detection results in a sample tested, the index test sensitivity, specificity, and positive and negative likelihood ratios were 91% (95% CI: 84%-96%), 95% (95% CI: 93%-97%), and 19.16 (95% CI: 13.52-27.16) and 0.10 (95% CI: 0.05-0.17), respectively. The corresponding sensitivity, specificity, and positive and negative likelihood ratios in patients who were drug-naïve were 89% (95% CI: 75%-96%), 86% (95% CI: 81%-91%), and 6.6 (95% CI: 4.51-9.66) and 0.13 (95% CI: 0.05-0.32), respectively. CONCLUSIONS: Tests using sniffer dogs may be a useful, noninvasive, fast, and cost-effective method to identify patients with PD in community screening and health prevention checkups as well as in neurological practice. © 2022 International Parkinson and Movement Disorder Society.

Primary nature of brown carbon absorption in a frigid atmosphere with strong haze chemistry.

Severe haze hovered over Harbin during the heating season of 2019-2020, making it one of the ten most polluted Chinese cities in January of 2020. Here we focused on the optical properties and sources of brown carbon (BrC) during the extreme atmospheric pollution periods. Enhanced formation of secondary BrC (BrCsec) was evident as relative humidity (RH) became higher, accompanied with a decrease of ozone but concurrent increases of aerosol water content and secondary inorganic aerosols. These features were generally similar to the characteristics of haze chemistry observed during winter haze events in the North China Plain, and indicated that heterogeneous reactions involving aerosol water might be at play in the formation of BrCsec, despite the low temperatures in Harbin. Although BrCsec accounted for a substantial fraction of brown carbon mass, its contribution to BrC absorption was much smaller (6 vs. 28%), pointing to a lower mass absorption efficiency (MAE) of BrCsec compared to primary BrC. In addition, emissions of biomass burning BrC (BrCBB) were inferred to increase with increasing RH, coinciding with a large drop of temperature. Since both the less absorbing BrCsec and the more absorbing BrCBB increased as RH became higher, the MAE of total BrC were largely unchanged throughout the measurement period. This study unfolded the contrast in the source apportionment results of BrC mass and absorption, and could have implications for the simulation of radiative forcing by brown carbon.

Transformation of Highly Stable Pt Single Sites on Defect Engineered Ceria into Robust Pt Clusters for Vehicle Emission Control.

Engineering surface defects on metal oxide supports could help promote the dispersion of active sites and catalytic performance of supported catalysts. Herein, a strategy of ZrO2 doping was proposed to create rich surface defects on CeO2 (CZO) and, with these defects, to improve Pt dispersion and enhance its affinity as single sites to the CZO support (Pt/CZO). The strongly anchored Pt single sites on CZO support were initially not efficient for catalytic oxidation of CO/C3H6. However, after a simple activation by H2 reduction, the catalytic oxidation performance over Pt/CZO catalyst was significantly boosted and better than Pt/CeO2. Pt/CZO catalyst also exhibited much higher thermal stability. The structural evolution of Pt active sites by H2 treatment was systematically investigated on aged Pt/CZO and Pt/CeO2 catalysts. With H2 reduction, ionic Pt single sites were transformed into active Pt clusters. Much smaller Pt clusters were created on CZO (ca. 1.2 nm) than on CeO2 (ca. 1.8 nm) due to stronger Pt-CeO2 interaction on aged Pt/CZO. Consequently, more exposed active Pt sites were obtained on the smaller clusters surrounded by more oxygen defects and Ce3+ species, which directly translated to the higher catalytic oxidation performance of activated Pt/CZO catalyst in vehicle emission control applications.

Current status of lymph node dissection in gastric cancer.

Gastrectomy with lymph node (LN) dissection has been regarded as the standard surgery for gastric cancer (GC), however, the rational extent of lymphadenectomy remains controversial. Though gastrectomy with extended lymphadenectomy beyond D2 is classified as a non-standard gastrectomy, its clinical significance has been evaluated in many studies. Although hard evidence is lacking, D2 plus superior mesenteric vein (No. 14v) LN dissection is recommended when harbor metastasis to No. 6 nodes is suspected in the lower stomach, and dissection of splenic hilar (No. 10) LN can be performed for advanced GC invading the greater curvature of the upper stomach, and D2 plus posterior surface of the pancreatic head (No. 13) LN dissection may be an option in a potentially curative gastrectomy for cancer invading the duodenum. Prophylactic D2+ para-aortic nodal dissection (PAND) was not routinely recommended for advanced GC patients, but therapeutic D2 plus PAND may offer a chance of cure in selected patients, preoperative chemotherapy was considered as the standard treatment for GC with para-aortic node metastasis. There has been no consensus on the extent of lymphadenectomy for the adenocarcinoma of the esophagogastric junction (AEG) so far. The length of esophageal invasion can be used as a reference point for mediastinal LN metastases, and the distance from the esophagogastric junction to the distal end of the tumor is essential for determining the optimal extent of resection. The quality of lymphadenectomy may influence prognosis in GC patients. Both hospital volume and surgeon volume were important factors for the quality of radical gastrectomy. Centralization of GC surgery may be needed to improve prognosis.

Deficiency of microglial Hv1 channel is associated with activation of autophagic pathway and ROS production in LPC-induced demyelination mouse model.

BACKGROUND: Multiple sclerosis (MS) is an immune-mediated demyelinated disease of the central nervous system. Activation of microglia is involved in the pathogenesis of myelin loss. OBJECTIVE: This study is focused on the role of Hv1 in regulating demyelination and microglial activation through reactive oxygen species (ROS) production after lysophosphatidylcholine (LPC)-mediated demyelination. We also explored autophagy in this process. METHODS: A model of demyelination using two-point LPC injection into the corpus callosum was established. LFB staining, immunofluorescence, Western blot, and electron microscopy were used to study the severity of demyelination. Microglial phenotype and autophagy were detected by immunofluorescence and Western blot. Morris water maze was used to test spatial learning and memory ability. RESULTS: We have identified that LPC-mediated myelin damage was reduced by Hv1 deficiency. Furthermore, we found that ROS and autophagy of microglia increased in the demyelination region, which was also inhibited by Hv1 knockout. CONCLUSION: These results suggested that microglial Hv1 deficiency ameliorates demyelination through inhibition of ROS-mediated autophagy and microglial phenotypic transformation.

Mibefradil Alleviates High-Glucose-induced Cardiac Hypertrophy by Inhibiting PI3K/Akt/mTOR-mediated Autophagy.

Cardiac hypertrophy causes heart failure and is associated with hyperglycemia in patients with diabetes mellitus. Mibefradil, which acts as a T-type calcium channel blocker, exerts beneficial effects in patients with heart failure. In this study, we explored the effects and mechanism of mibefradil on high-glucose-induced cardiac hypertrophy in H9c2 cells. H9c2 cells were incubated in a high-glucose medium and then treated with different concentrations of mibefradil in the presence or absence of the Akt inhibitor MK2206 or mTOR inhibitor rapamycin. Cell size was evaluated through immunofluorescence, and mRNA expression of cardiac hypertrophy markers (atrial natriuretic peptide, brain natriuretic peptide, and ß-myosin heavy chain) was assessed by using quantitative real-time polymerase chain reaction. Changes in the expression of p-PI3K, p-Akt, and p-mTOR were evaluated using Western blotting, and autophagosome formation was detected using transmission electron microscopy. Our results indicate that mibefradil reduced the size of H9c2 cells, decreased mRNA expression of atrial natriuretic peptide, brain natriuretic peptide, and ß-myosin heavy chain, and decreased the level of autophagic flux. However, MK2206 and rapamycin induced autophagy and reversed the effects of mibefradil on high-glucose-induced H9c2 cells. In conclusion, mibefradil ameliorated high-glucose-induced cardiac hypertrophy by activating the PI3K/Akt/mTOR pathway and inhibiting excessive autophagy. Our study shows that mibefradil can be used therapeutically to ameliorate cardiac hypertrophy in patients with diabetes mellitus.

Hydrogen Sulfide Inhibits Homocysteine-Induced Neuronal Senescence by Up-Regulation of SIRT1.

Homocysteine (Hcy) accelerates neuronal senescence and induces age-related neurodegenerative diseases. Silence signal regulating factor 1 (SIRT1) prolongs lifespan and takes neuroprotective effects. We have previously demonstrated that hydrogen sulfide (H2S) prevents Hcy-induced apoptosis of neuronal cells and has neuroprotective effect. In the present work, we aimed to investigate whether H2S protects HT22 cells against Hcy-induced neuronal senescence and whether SIRT1 mediates this role of H2S. We found that Hcy induced cellular senescence in HT22 cells, as determined by ß-galactosidase staining, expressions of P16INK4a, P21CIPL, and trypan blue Staining, which are the markers of cellular senescence. However, sodium hydrosulfide (NaHS, the donor of H2S) significantly reversed Hcy-induced cellular senescence. Interestingly, NaHS not only up-regulated the expression of SIRT1 in HT22 cells but also reversed Hcy-downregulated the expression of SIRT1 in HT22 cells. Furthermore, we found that pretreatment with Sirtinol (an inhibitor of SIRT1) markedly reversed the protection of NaHS against Hcy-induced HT22 cells senescence and apoptosis. Our findings illustrated that H2S protects HT22 cells against Hcy-induced senescence by up-regulating SIRT1.

Outcomes of enteral metallic stent in patients with pancreatic carcinoma and gastric outlet obstruction: A single center experience.

BACKGROUND: Duodenal obstruction is uncommon in patients with pancreatic cancer. However, the obstruction rate is increasing as a result of advancements in chemotherapy and target therapy. This study aimed to investigate the effect of self-expandable metal stent placement on outcomes of patients with duodenal obstruction secondary to pancreatic carcinoma. METHODS: Twenty-nine consecutive inoperable patients with pancreatic cancer and gastric outlet obstruction who received metallic stent placement in our hospital between September 2009 and October 2017 were enrolled for analysis. RESULTS: Fifteen male patients and 14 female patients receiving stent placement with a median age of 68 years (range, 50-85 years) were included. The technical and clinical success rates of the procedure were 100% and 89.7%, respectively. The Gastric Outlet Obstruction Scoring System scores were significantly improved at day 1 (1.14 ± 0.51) and days 7 (2.21 ± 0.9) after the implantation compared to those prior to the procedure (0.38 ± 0.49) (p < 0.001). Aspiration pneumonia and bleeding developed in 1 patient (3.4%) after the procedure. Stent dysfunction developed in 6 of 29 patients (20.6%). The median stent patency time was 109 days (range, 10-314 days). The median survival time was 114 days (range, 15-323 days). Post-stent chemotherapy predicted better survival (hazard ratio: 0.2, 95% confidence interval: 0.08-0.51, p = 0.001). CONCLUSION: Metallic stent placement is an effective treatment for patients with inoperable pancreatic cancer leading to gastric outlet obstruction. Chemotherapy may be considered following stent placement.