Unveiling the role of proton concentration in dinuclear metal complexes for boosting photocatalytic CO2 reduction.

The reaction kinetics of photocatalytic CO2 reduction is highly dependent on the transfer rate of electrons and protons to the CO2 molecules adsorbed on catalytic centers. Studies on uncovering the proton effect in catalysts on photocatalytic activity of CO2 reduction are significant but rarely reported. In this paper, we, from the molecular level, revealed that the photocatalytic activity of CO2 reduction is closely related to the proton availability in catalysts. Specifically, four dinuclear Co(II) complexes based on Robson-type ligands with different number of carboxylic groups (-nCOOH; n = 0, 2, 4, 6) were designed and synthesized. All these complexes show photocatalytic activity for CO2 reduction to CO in a water-containing system upon visible-light illumination. Interestingly, the CO yields increase positively with the increase of the carboxylic-group number in dinuclear Co(II) complexes. The one containing -6COOH shows the best photocatalytic activity for CO2 reduction to CO, with the TON value reaching as high as 10,294. The value is 1.8, 3.4, and 7.8 times higher than those containing -4COOH, -2COOH, and -0COOH, respectively. The high TON value also makes the dinuclear Co(II) complex with -6COOH outstanding among reported homogeneous molecular catalysts for photocatalytic CO2 reduction. Control experiments and density functional theory calculation indicated that more carboxylic groups in the catalyst endow the catalyst with more proton relays, thus accelerating the proton transfer and boosting the photocatalytic CO2 reduction. This study, at a molecular level, elucidates that more carboxylic groups in catalysts are beneficial for boosting the reaction kinetics of photocatalytic CO2 reduction.

Dual Regulation of Nicotine on NLRP3 Inflammasome in Macrophages with the Involvement of Lysosomal Destabilization, ROS and α7nAChR.

Nicotine, the primary alkaloid in tobacco products, has been shown to have immunoregulatory function in at least 20 diseases. The biological mechanism of action of nicotine immunoregulation is complex, resulting in an improvement of some disease states and exacerbation of others. Given the central role of the NLRP3 inflammasome in macrophages among multiple inflammatory diseases, this study examined how nicotine alters NLRP3 inflammasome activation in macrophages. NLRP3 inflammasome activation was examined mechanistically in the context of different nicotine dosages. We show NLRP3 inflammasome activation, apoptosis-associated speck-like protein (ASC) expression, caspase-1 activity and subsequent IL-1ß secretion were positively correlated with nicotine in a dose-dependent relationship, and destabilization of lysosomes and ROS production were also involved. At high concentrations of nicotine surpassing 0.25 mM, NLRP3 inflammasome activity declined, along with increased expression of the anti-inflammatory Alpha7 nicotinic acetylcholine receptor (α7nAChR) and the inhibition of TLR4/NF-κB signaling. Consequently, high doses of nicotine also reduced ASC expression, caspase-1 activity and IL-1ß secretion in macrophages. Collectively, these results suggest a dual regulatory function of nicotine on NLRP3 inflammasome activation in macrophages, that is involved with the pro-inflammatory effects of lysosomal destabilization and ROS production. We also show nicotine mediates anti-inflammatory effects by activating α7nAChR at high doses.

Identification of active compounds in Vernonia anthelmintica (L.) willd by targeted metabolome MRM and kaempferol promotes HaCaT cell proliferation and reduces oxidative stress.

Introduction: Vernonia anthelmintica (L.) Willd. is a traditional treatment for vitiligo in Xinjiang. However, its therapeutic mechanism remains unclear owing to its complex composition and limited research on its chemical profile. Methods: We employed a targeted metabolome approach, combining selective reaction monitoring/multiple response monitoring (SRM/MRM) with high-performance liquid chromatography and MRM mass spectrometry to quantitatively analyze the flavonoid constituents of Vernonia anthelmintica. We also used network pharmacology and molecular docking to identify potential vitiligo-linked compounds and targets of V. anthelmintica seeds. Additionally, we assessed HaCaT cell proliferation by AAPH-induced, alongside changes in SOD activity and MDA content, following treatment with V. anthelmintica components. Finally, flow cytometry was used to detect apoptosis and ROS levels. Results and Discussion: We identified 36 flavonoid compounds in V. anthelmintica seeds, with 14 compounds exhibiting druggability. AKT1, VEGFA, ESR1, PTGS2, and IL2 have been identified as key therapeutic target genes, with PI3K/AKT signaling being an important pathway. Notably, kaempferol, one of the identified compounds, exhibited high expression in network pharmacology analysis. Kaempferol exhibited a strong binding affinity to important targets. Further, kaempferol enhanced HaCaT cell viability, inhibited apoptosis, reduced MDA levels, suppressed ROS activity, and upregulated SOD activity, increase the expression of cellular antioxidant genes, including HO-1, GCLC, GCLM, Nrf2, NQO1 and Keap1, providing significant protection against oxidative stress damage in vitro. Here, we present the first comprehensive study integrating SRM/MRM approaches and network analysis to identify active flavonoid compounds within V. anthelmintica (L.) Willd. Moreover, we revealed that its active ingredient, kaempferol, offers protection against AAPH-induced damage in keratinocytes, highlighting its potential as a clinical resource.

Efficacy of radiofrequency ablation combined with sorafenib for treating liver cancer complicated with portal hypertension and prognostic factors.

BACKGROUND: Patients with liver cancer complicated by portal hypertension present complex challenges in treatment. AIM: To evaluate the efficacy of radiofrequency ablation in combination with sorafenib for improving liver function and its impact on the prognosis of patients with this condition. METHODS: Data from 100 patients with liver cancer complicated with portal hypertension from May 2014 to March 2019 were analyzed and divided into a study group (n = 50) and a control group (n = 50) according to the treatment regimen. The research group received radiofrequency ablation (RFA) in combination with sorafenib, and the control group only received RFA. The short-term efficacy of both the research and control groups was observed. Liver function and portal hypertension were compared before and after treatment. Alpha-fetoprotein (AFP), glypican-3 (GPC-3), and AFP-L3 levels were compared between the two groups prior to and after treatment. The occurrence of adverse reactions in both groups was observed. The 3-year survival rate was compared between the two groups. Basic data were compared between the survival and non-surviving groups. To identify the independent risk factors for poor prognosis in patients with liver cancer complicated by portal hypertension, multivariate logistic regression analysis was employed. RESULTS: When comparing the two groups, the research group's total effective rate (82.00%) was significantly greater than that of the control group (56.00%; P < 0.05). Following treatment, alanine aminotransferase and aspartate aminotransferase levels increased, and portal vein pressure decreased in both groups. The degree of improvement for every index was substantially greater in the research group than in the control group (P < 0.05). Following treatment, the AFP, GPC-3, and AFP-L3 levels in both groups decreased, with the research group having significantly lower levels than the control group (P < 0.05). The incidence of diarrhea, rash, nausea and vomiting, and fatigue in the research group was significantly greater than that in the control group (P < 0.05). The 1-, 2-, and 3-year survival rates of the research group (94.00%, 84.00%, and 72.00%, respectively) were significantly greater than those of the control group (80.00%, 64.00%, and 40.00%, respectively; P < 0.05). Significant differences were observed between the survival group and the non-surviving group in terms of Child-Pugh grade, history of hepatitis, number of tumors, tumor size, use of sorafenib, stage of liver cancer, histological differentiation, history of splenectomy and other basic data (P < 0.05). Logistic regression analysis demonstrated that high Child-Pugh grade, tumor size (6-10 cm), history of hepatitis, no use of sorafenib, liver cancer stage IIIC, and previous splenectomy were independent risk factors for poor prognosis in patients with liver cancer complicated with portal hypertension (P < 0.05). CONCLUSION: Patients suffering from liver cancer complicated by portal hypertension benefit from the combination of RFA and sorafenib therapy because it effectively restores liver function and increases survival rates. The prognosis of patients suffering from liver cancer complicated by portal hypertension is strongly associated with factors such as high Child-Pugh grade, tumor size (6-10 cm), history of hepatitis, lack of sorafenib use, liver cancer at stage IIIC, and prior splenectomy.

Formation of Disordered High-Entropy-Alloy Nanoparticles for Highly Efficient Hydrogen Electrocatalysis.

Nanoparticles composed of high-entropy alloys (HEA NPs) exhibit remarkable performance in electrocatalytic processes such as hydrogen evolution and oxidations. In this study, two types of quinary HEA NPs of PtRhPdIrRu, are synthesized, featuring disordered and crystallized nanostructures, both with and without a boiling mixture. The disordered HEA NPs (d-HEA NPs) with a size of 3.5 nm is synthesized under intense boiling conditions, attributed to improved heat and mass transfer during reduction of precursors and particle growth. The disordered HEA NPs displayed an exceptionally high turnover frequency of 33.1 s-1 at an overpotential of 50 mV, surpassing commercial Pt NPs in acidic electrolytes by 5.4 times. Additionally, d-HEA NPs exhibited superior stability at a constant electrolyzing current of 50 mA cm-2 compared to commercial Pt NPs. When employed as the anodic catalyst in an H2-O2 fuel cell, d-HEA NPs demonstrated a remarkable high current power density of 15.3 kW per gram of noble metal. Consequently, these findings highlight the potential of d-HEA NPs in electrochemical applications involving hydrogen.

Identification and validation of RNA-binding protein SLC3A2 regulates melanocyte ferroptosis in vitiligo by integrated analysis of single-cell and bulk RNA-sequencing.

BACKGROUND: The pathogenesis of vitiligo remains unclear. The genes encoding vitiligo-related RNA-binding proteins (RBPs) and their underlying pathogenic mechanism have not been determined. RESULTS: Single-cell transcriptome sequencing (scRNA-seq) data from the CNCB database was obtained to identify distinct cell types and subpopulations and the relative proportion changes in vitiligo and healthy samples. We identified 14 different cell types and 28 cell subpopulations. The proportion of each cell subpopulation significantly differed between the patients with vitiligo and healthy groups. Using RBP genes for unsupervised clustering, we obtained the specific RBP genes of different cell types in vitiligo and healthy groups. The RBP gene expression was highly heterogeneous; there were significant differences in some cell types, such as keratinocytes, Langerhans, and melanocytes, while there were no significant differences in other cells, such as T cells and fibroblasts, in the two groups. The melanocyte-specific RBP genes were enriched in the apoptosis and immune-related pathways in the patients with vitiligo. Combined with the bulk RNA-seq data of melanocytes, key RBP genes related to melanocytes were identified, including eight upregulated RBP genes (CDKN2A, HLA-A, RPL12, RPL29, RPL31, RPS19, RPS21, and RPS28) and one downregulated RBP gene (SLC3A2). Cell experiments were conducted to explore the role of the key RBP gene SLC3A2 in vitiligo. Cell experiments confirmed that melanocyte proliferation decreased, whereas apoptosis increased, after SLC3A2 knockdown. SLC3A2 knockdown in melanocytes also decreased the SOD activity and melanin content; increased the Fe2+, ROS, and MDA content; significantly increased the expression levels of TYR and COX2; and decreased the expression levels of glutathione and GPX4. CONCLUSION: We identified the RBP genes of different cell subsets in patients with vitiligo and confirmed that downregulating SLC3A2 can promote ferroptosis in melanocytes. These findings provide new insights into the pathogenesis of vitiligo.

The Role of Nicotine Metabolic Rate on Nicotine Dependence and Rewarding: Nicotine Metabolism in Chinese Male Smokers and Male Mice.

The exact relationship between nicotine metabolism and dependence is not fully understood but is known to be influenced at a molecular level by genetic factors. A sample comprising 274 Chinese adult male smokers was categorized into groups based on their metabolic rates, namely fast, intermediate, and slow metabolizers. We then measured their smoking topography, evaluated their nicotine dependence, and assessed the rewarding effects. Based on these findings, we proposed the hypothesis that the rate of nicotine metabolism could influence the level of dopamine release which in turn had repercussions on the pleasurable and rewarding effects. To test this hypothesis, male mice were selected with different nicotine metabolic rates that closely resembled in the smoker group. We evaluated their nicotine dependence and rewarding effects through conditioned place preference and withdrawal symptom tests, supplemented with dopamine release measurements. In both animal and human, the slow metabolism group (SMG) required less nicotine to maintain a comparable level of dependence than the fast metabolism group (FMG). The SMG could achieve similar rewarding effects to FMG despite consuming less nicotine. Comparable dopamine levels released were therefore critical in setting the nicotine acquisition behavior in this animal model and also for the smokers tested. Our findings suggested that even within the same ethnicity of established smokers (Chinese Han), differences in nicotine metabolism were an important parameter to modulate the degree of nicotine dependence.

The Effectiveness of Cognitive Behavioral Therapy-Based Intervention on Improving Sleep-Related Outcomes for People with Diabetes: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Background: Sleep-related outcomes in people with diabetes are poor, which is closely linked to reducing the development of diabetes. Cognitive behavioral therapy (CBT) based intervention presents innovative solutions that can help improve sleep-related outcomes. Aim: This synthesis aims to assess the effectiveness of CBT-based intervention compared to controls in Randomized Controlled Trials (RCTs) for sleep-related outcomes among people with diabetes. Methods: Eight electronic databases were systematically searched: PubMed, EMBASE, Cochrane library, Web of Science, PsycINFO, CINAHL, China National Knowledge Infrastructure (CNKI), and Wan Fang database. We examined CBT-based intervention's effectiveness on sleep-related outcomes in people with diabetes in RCTs identified in these databases from their inception to 1st November 2023, and updated on 15 January 2024. The risk of bias was assessed using the Cochrane Risk of Bias tool by two reviewers. The meta-analysis of included studies was conducted by RevMan 5.3 software. Results: Seven studies in total (n = 2633 participants) were included in this systematic review based on our inclusion criteria. The systematic review found CBT-based intervention significantly improved sleep quality (Pittsburgh Sleep Quality Index, PSQI scores) at immediate post-intervention [95% CI=(-1.31 to -0.32), p = 0.001], six months [95% CI=(-0.75 to -0.22), p = 0.0003], and 12 months [95% CI=(-0.72 to -0.24), <0.0001], compared to control groups. Furthermore, our findings demonstrated that six sessions [95% CI= (-0.38 to -0.13), p < 0.0001] or more than six sessions [95% CI=(-1.76 to -0.02), p = 0.05] of CBT-based intervention could improve sleep quality compared to controls (I2=0%). Interestingly, CBT-based intervention improves total sleep time at post-intervention in people with diabetes compared to the control group [95% CI= (-0.57 to -0.12), p = 0.003]. However, there was no significant that CBT-based intervention is beneficial to time to fall asleep [95% CI (-1.89 to 0.43), p = 0.22] and sleep efficiency [95% CI (-1.27 to 0.27), p = 0.20] after intervention, compared to control group. Conclusion: CBT-based intervention appears to have a beneficial effect on improving sleep quality and total sleep time among people with diabetes. CBT-based intervention could be considered a strategy among healthcare providers to enhance sleep quality and total sleep time for people with diabetes. More RCTs with rigorous designs and long-term follow-up are warranted to provide conclusive evidence of the CBT-based intervention on sleep-related outcomes and to explore the mechanisms by which the CBT-based interventions improve sleep-related outcomes.

Cited2 inhibited hypoxia-induced proliferation and migration of PASMCs via the TGF-ß1/Cited2/PPARγ pathway.

Objectives: Proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) contribute to hypoxia-induced pulmonary hypertension (HPH). The transcription factor Cbp/p300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 2 (Cited2) has been implicated in the control of tumor cells and mesenchymal stem cell (MSC) and cardiomyocyte growth or migration. Whether Cited2 is involved in the proliferation and migration of PASMCs and the underlying mechanisms deserve to be explored. Materials and Methods: Cited2 expression was detected in rat PASMCs under hypoxia conditions and HPH rat models. The effect of Cited2 on the proliferation and migration of PASMC was detected by overexpression or knockdown of the Cited2 gene. After PAMSCs were treated with recombinant TGF-ß1 and the lentivirus vector overexpressing Cited2, expression of peroxisome proliferator-activated receptor gamma (PPARγ) was examined by western blotting. Results: We revealed that hypoxia down-regulated the expression of Cited2 in PASMCs and rat pulmonary arteries. Cited2 overexpression inhibited the proliferation and migration of PASMCs under hypoxia, while Cited2 knockdown induced the proliferation and migration of PASMCs. Cited2 inhibits the negative regulation of the TGF-ß1 pathway on PPARγ to inhibit the proliferation and migration of PASMCs. Conclusion: These findings suggest that increased Cited2 expression contributes to the inhibition of PASMCs proliferation and migration by regulating TGF-ß1-mediated target gene expression in HPH and provides a new target for molecular therapy of HPH.

A comprehensive metabolomics analysis of volatile and non-volatile compounds in matcha processed from different tea varieties.

Tea varieties play a crucial role on the quality formation of matcha. This research aimed to examine the impact of four specific tea plant varieties (Okumidori, Longjing 43, Zhongcha108, and E'Cha 1) on various aspects of matcha, including sensory evaluation, major components, color quality, volatile and non-volatile metabolomic profiles. The findings revealed that the levels of tea polyphenols, ester catechins, nonester catechins, and amino acids varied among these four varieties. Notably, 177 significant different metabolites, such as phenolic acids, flavonoids, tannins, alkaloids were identified among 1383 non-volatile compounds. In addition, 97 key aroma-active compounds were identified based on their odor activity value exceeding 1. Aldehydes, heterocyclic compounds, and ketones were closely associated with the formation of volatile metabolites. Overall, this study enhances our understanding of how different tea plant varieties impact the quality of matcha, and can provide valuable guidance for improving matcha varieties in a favorable direction.

Comprehensive bioinformation analysis of homeodomain-leucine zipper gene family and expression pattern of HD-Zip I under abiotic stress in Salix suchowensis.

BACKGROUND: Homeodomain-leucine zipper (HD-Zip) transcription factors are plant-specific and play important roles in plant defense against environmental stresses. Identification and functional studies have been carried out in model plants such as rice, Arabidopsis thaliana, and poplar, but comprehensive analysis on the HD-Zip family of Salix suchowensis have not been reported. RESULTS: A total of 55 HD-Zip genes were identified in the willow genome, unevenly distributed on 18 chromosomes except for chromosome 19. And segmental duplication events containing SsHD-Zip were detected on all chromosomes except chromosomes 13 and 19. The SsHD-Zip were classified into 4 subfamilies subfamilies (I-IV) according to the evolutionary analysis, and members of each subfamily shared similar domain structure and gene structure. The combination of GO annotation and promoter analysis showed that SsHD-Zip genes responded to multiple abiotic stresses. Furthermore, the results of qPCR analysis showed that the SsHD-Zip I gene exhibited different degrees of expression under salt stress, PEG treatment and heat treatment. Moreover, there was a synergistic effect between SsHD-Zip I genes under stress conditions based on coregulatory networks analysis. CONCLUSIONS: In this study, HD-Zip transcription factors were systematically identified and analyzed at the whole genome level. These results preliminarily clarified the structural characteristics and related functions of willow HD-Zip family members, and it was found that SsHox34, SsHox36 and SsHox51 genes were significantly involved in the response to various stresses. Together, these findings laid the foundation for further research on the resistance functions of willow HD-Zip genes.

Cell death induced by nicotine in human neuroblastoma SH-SY5Y cells is mainly attributed to cytoplasmic vacuolation originating from the trans-Golgi network.

Humans are usually exposed to nicotine through the use of tobacco products. Although it is generally believed that nicotine is relatively harmless in tobacco consumption, it is, in fact, a toxic substance that warrants careful consideration of its potential toxicity. However, the current understanding of the neurotoxicity of nicotine is still very limited. In this study, we aim to reveal the toxic risk of nicotine to key target neuronal cells and its potential toxic mechanisms. The results showed that nicotine induced cell death, ROS increase, mitochondrial membrane potential decrease, and DNA damage in SH-SY5Y human neuroblastoma cells at millimolar concentrations, but did not cause toxic effects at the physiological concentration. These toxic effects were accompanied by cytoplasmic vacuolation. The inhibition of cytoplasmic vacuolation by bafilomycin A1 greatly reduced nicotine-induced cell death, indicating that cytoplasmic vacuolation is the key driving factor of cell death. These cytoplasmic vacuoles originated from the trans-Golgi network (TGN) and expressed microtubule-associated protein 1 light chain 3-II (LC3-II) and lysosomal associated membrane protein 1(LAMP1). The presence of LC3-II and LAMP1 within these vacuoles serves as evidence of compromised TGN structure and function. These findings provide valuable new insights into the potential neurotoxic risk and mechanisms of nicotine.

Phylogenetic and Taxonomic Analyses Reveal Three New Wood-Inhabiting Fungi (Polyporales, Basidiomycota) in China.

Three new wood-inhabiting fungal species, Cerioporus yunnanensis, Perenniporiopsis sinensis, and Sarcoporia yunnanensis, are proposed based on a combination of the morphological features and molecular evidence. Cerioporus yunnanensis is characterized by the pileate basidiomata having a fawn brown to black pileal surface, a dimitic hyphal system with clamped generative hyphae, and the presence of the fusoid cystidioles and cylindrical basidiospores (9-12.5 × 3.5-5 µm). Perenniporiopsis sinensis is distinct from the osseous pileus with verrucose, an orange-yellow to dark reddish-brown pileal surface with a cream margin, a trimitic hyphal system with clamped generative hyphae, and the presence of the fusiform cystidioles and ellipsoid basidiospores (9-11 × 5.5-6.5 µm). Sarcoporia yunnanensis is typical of the pileate basidiomata with a salmon to reddish-brown pileal surface, a monomitic hyphal system with clamped generative hyphae, and the presence of the ellipsoid basidiospores (4-5.5 × 2.5-4 µm). Sequences of ITS + nLSU + mt-SSU + TEF1 + RPB1 + RPB2 genes were used for the phylogenetic analyses using maximum likelihood, maximum parsimony, and Bayesian inference methods. The multiple genes with six loci analysis showed that the three new species nested within the order Polyporales, in which C. yunnanensis and P. sinensis nested into the family Polyporaceae, and S. yunnanensis grouped into the family Sarcoporiaceae.

Liver toxicity in rats after subchronic exposure to HTP aerosol and cigarette smoke.

Background: Heated tobacco product (HTP) considered to be a novel tobacco product which was reported safer than traditional cigarettes evidenced by lower potential harmful components released. Liver is an important detoxification organ of the body, the chemical components in aerosols are metabolized in the liver after absorbed, so it is necessary to explore the effect of HTP on the liver. Materials and Methods: The potential effect of HTP and cigarette smoke (CS) on SD rats was explored according to OECD 413 subchronic inhalation. The rats were randomly divided into Sham (air), different dosage of HTP groups (HTP_10, 23 and 50 µg nicotine/L aerosol) and Cig_23 (23 µg nicotine/L aerosol) group. After exposure, the clinical pathology, inflammation and oxidative stress were measured. Results: The clinical pathology results showed that both HTP_50 and Cig_23 led to abnormality of ALT for male rats. CS and HTP exposure reduced the expression of IL-1ß, IL-6 and TNF-α and mitochondrial medicated oxidative stress. In addition, the ATP production was reduced in Cig_23 group. Although inflammation and oxidative stress were displayed, no apoptosis were observed by TUNEL assay and these existed obvious pathological changes only in HTP_50 group, while in CS group with equivalent nicotine, hepatocytes swelling were observed in liver. Conclusion: CS exposure induced liver damage through mitochondrial mediated oxidative stress and inflammation, which was also observed in high concentration of HTP exposure group. For the same equivalent nicotine, HTP may show lower toxic effect on liver than CS.

Evaluation of toxicity of heated tobacco products aerosol and cigarette smoke to BEAS-2B cells based on 3D biomimetic chip model.

It is still a controversial topic about evaluating whether heated tobacco products (HTP) really reduce harm, which involves the choice of an experimental model. Here, a three-dimensional (3D) biomimetic chip model was used to evaluate the toxicity of aerosols came from HTP and smoke produced by cigarettes (Cig). Based on cell-related experiments, we found that the toxicity of Cig smoke extract diluted four times was also much higher than that of undiluted HTP, showing higher oxidative stress response and cause mitochondrial dysfunction. Meanwhile, both tobacco products all affect the tricarboxylic acid cycle (TCA), which is manifested by a significant decrease in the mRNA expression of TCA key rate-limiting enzymes. Summarily, 3D Biomimetic chip technology can be used as an ideal model to evaluate HTP. It can provide important data for tobacco risk assessment when 3D chip model was used. Our experimental results showed that HTP may be less harmful than tobacco cigarettes, but it does show significant cytotoxicity with the increase of dose. Therefore, the potential clinical effects of HTP on targeted organs such as lung should be further studied.

Gliclazide Reduces Colitis-Associated Colorectal Cancer Formation by Deceasing Colonic Inflammation and Regulating AMPK-NF-κB Signaling Pathway.

BACKGROUND: Gliclazide is a potential anti-cancer drug candidate for preventing carcinogenesis. However, the effect of gliclazide on colitis-associated colorectal cancer remains unknown. AIMS: We aimed to evaluate whether gliclazide plays a protective role in colitis-associated colorectal cancer and the underlying molecular mechanism. METHODS: The administration of azoxymethane (AOM) followed by dextran sulfate sodium (DSS) aimed to induce colitis-associated colorectal cancer in mice. C57BL mice were gavaged with gliclazide (6 mg/kg by gavage 5 days a week) for 12 weeks immediately following AOM administration. After sacrificing the mice, colon tissues were measured for tumor number and tumor burden. The proliferation- and inflammation-related molecular mechanisms were explored. RESULTS: The administration of gliclazide significantly reduced the tumor number and tumor burden in mice. Cell proliferation decreased in the gliclazide group compared with the control group, as indicated by reduced Ki-67 expression. Furthermore, gliclazide alleviated colonic inflammation, significantly decreased pro-inflammatory factor TNF-α levels and increased anti-inflammatory factor IL-10 levels in vivo. In vivo and vitro, it was shown that gliclazide increased the level of phospho-AMPK (p-AMPK) and inhibited NF-κB activity. Further studies demonstrated that the inhibition of NF-κB activity induced by gliclazide was mediated by p-AMPK in vitro. CONCLUSIONS: Gliclazide effectively alleviated colonic inflammation and prevented colonic carcinogenesis in an AOM-DSS mouse model by modulating the AMPK-NF-κB signaling pathway. Thus, gliclazide holds potential as a chemopreventive agent for colitis-associated colorectal cancer.

Testicular tissue response following a 90-day subchronic exposure to HTP aerosols and cigarette smoke in rats.

Background: Researches have shown that chronic inhalation of cigarette smoke (CS) disrupts male reproductive system, but it is unclear about the mechanisms behind reproductive damages by tobacco toxicants in male rats. This study was designed to explore the effects of heated tobacco products (HTP) aerosols and CS exposure on the testicular health of rats. Materials and Methods: Experiments were performed on male SD rats exposed to filtered air, HTP aerosols at 10 µg/L, 23 µg/L, and 50 µg/L nicotine-equivalent contents, and also CS at 23 µg/L nicotine-equivalent content for 90 days in five exposure groups (coded as sham, HTP_10, HTP_23, HTP_50 and Cig_23). The expression of serum testosterone, testicular tissue inflammatory cytokines (IL-1ß, IL-6, IL-10, TNF-α), reactive oxygen species (ROS), superoxide dismutase (SOD) and malondialdehyde (MDA), NLRP3 inflammasome-related mRNAs and proteins (NLRP3, ASC, and Caspase-1), the degree of pyroptosis and histopathology were investigated. Results: The results demonstrated that HTP_50 and Cig_23 caused varying degrees of oxidative damage to rat testis, resulting in a decrease of sperm quantity and serum testosterone contents, an increase in the deformity rate, expression levels of proinflammatory cytokines, and NLRP3 inflammasome-related mRNA, and an increase in the NLRP3, ASC, and Caspase-1-immunopositive cells, pyroptosis cell indices, and histopathological damage in the testes of rats. Responses from the HTP_10 and HTP_23 groups were less than those found in the above two exposure groups. Conclusion: These findings indicate that HTP_50 and Cig_23 induced oxidative stress in rat testes, induced inflammation and pyroptosis through the ROS/NLRP3/Caspase-1 pathway, and destroyed the integrity of thetesticular tissue structure.

The Effect of Transplantation of Cultured Autologous Melanocytes on CXCL9, CXCL10 and CXCL11 Expressions in Vitiligo.

Background: Vitiligo is an acquired chronic autoimmune skin disorder with an estimated prevalence of 1% worldwide. The CD8+ T-cell-mediated chemokines such as CXCR3, CXCL9 and CXCL10 are the non-specific action immunomodulators that are responsible for the depigmentation and progression in vitiligo. Aim: This study aimed to explore the expression levels of serum CXCL9-11 in vitiligo patients who received the transplantation of cultured autologous melanocytes (TCAMs) before and after the operation and correlate their expressions with clinical stage, subtype and course of the vitiligo disease. Materials and Methods: The expression levels of serum CXCL9-11 were measured in the peripheral blood of 26 progressive vitiligo patients, 24 stable vitiligo, 13 TCAM patients and 30 healthy control (HC) cases using enzyme-linked immunosorbent assay (ELISA). The potential correlations between their expressions and disease features such as stage, type and surgical treatment were evaluated using Student's t-test. Results: The expression levels of serum CXCL9-11 increased by ~1.4, ~1.6 and ~2.3-fold in vitiligo patients compared with HCs (P < 0.01). The expression levels of all chemokines were significantly higher in progressive vitiligo patients than in stable vitiligo (P < 0.01). The increasing expression levels of serum CXCL9, CXCL10 and CXCL11 were significantly related to the different types of vitiligo patients (P < 0.05). Preoperative expression levels of serum CXCL9-11 were significantly higher than the post-operative expression levels (P < 0.01). Conclusion: Our results demonstrate that increasing expression levels of the CXC family play a key role in the immunopathogenesis of vitiligo. The abnormal expression of the CXC family may be considered an effective and therapeutic target for TCAM treatment.

SIRT3 Regulates the ROS-FPR1/HIF-1α Axis under Hypoxic Conditions to Influence Lung Cancer Progression.

Hypoxia-inducible factor (HIF-1α) is a therapeutic target in lung cancer, and the deacetylase sirtuin 3 (SIRT3) is closely associated with tumorigenesis. Formyl peptide receptor 1 (FPR1) is involved in a wide range of physiopathological processes in various tumor cells. We explored whether SIRT3 affects the development of lung cancer by regulating the reactive oxygen species (ROS)-FPR1/HIF-1α axis under hypoxic conditions. The effects of SIRT3 overexpression on the levels of FPR1, HIF-1α, ROS, inflammatory factors, and cell proliferation and migration in A549 cells under hypoxic conditions were assessed in combination with the FPR1 inhibitor. BALB/c nude mice were subcutaneously injected with cancer cells transfected/untransfected with SIRT3 overexpressing lentiviral vectors. Immunohistochemistry and enzyme-linked immunosorbent assay were performed to detect SIRT3 expression and the expression levels of IL-1ß, TNF-α, and IL-6, respectively, in tumor tissues. Cell proliferation, invasion, migration, and IL-1ß, TNF-α, IL-6, and ROS levels were significantly higher in the Hypoxia group than in the Control group. Moreover, the mRNA and protein expression levels of SIRT3 were significantly down-regulated, whereas they were significantly up-regulated for FPR1 and HIF-1α. In contrast, SIRT3 overexpression in a hypoxic environment inhibited cell proliferation, invasion, and migration, decreased IL-1ß, TNF-α, IL-6, and ROS levels, up-regulated the mRNA and protein expression levels of SIRT3, and down-regulated the mRNA and protein expression levels of FPR1 and HIF-1α. In addition, we found the same results in tumorigenic experiments in nude mice. SIRT3 in hypoxic environments may affect tumor cell proliferation, invasion, migration, and inflammation levels via the ROS-FPR1/HIF-1α axis, thereby inhibiting tumor cell development.

Generation of an iPSC line (TSHSUi001-A) from a patient with Peutz-Jeghers syndrome due to STK11 mutation.

We established an iPSC line (TSHSUi001-A) from a patient with Peutz-Jeghers syndrome, carrying heterozygous c.290 + 1G > A mutation in STK11 gene. Peripheral blood mononuclear cells were reprogrammed using non-integrating delivery of OCT4, SOX2, KFL4, BCL-XL and c-MYC. The iPSC line expressed pluripotency markers, could differentiate into cells of three germ layers in vitro, and displayed a normal karyotype.