Design, synthesis and biological evaluation of indazole derivatives as VEGFR-2 kinase inhibitors with anti-angiogenic properties.

The strategy of inhibiting angiogenesis, specifically by targeting vascular endothelial growth factor receptor 2 (VEGFR-2), has been proven effective in tumor treatment. In this study, we designed several VEGFR-2 kinase inhibitors based on an indazole scaffold. Among them, the most potent compound, 30, inhibits VEGFR-2 (IC50 = 1.24 nM) with subtle selectivity over other kinases. It demonstrates significant inhibitory activity against HUVEC angiogenesis and inhibits cell migration in a dose-dependent manner. Additionally, it exhibits low acute toxicity in mice. In vivo studies, compound 30 demonstrates favorable pharmacokinetic profiles. It suppresses tumor angiogenesis in the zebrafish subintestinal vessel model, indicating that it may be a potential angiogenesis inhibitor for further development.

A scientometric study of oral cancer research in South and Southeast Asia with emphasis on risk factors control.

Background/purpose: South Asia and Southeast Asia are the regions with relatively high and increased disease burden of oral cancer. The purpose of this study was to analyze the scientometric characteristics of oral cancer research in these regions. Materials and methods: There are 8 countries from South Asia and 11 countries from Southeast Asia. All the articles on oral cancer from these countries were retrieved in the Scopus database. Results: A total of 5660 articles originated from South Asia (n = 4718) and Southeast Asia (n = 942). India (n = 4302; 91.2%) was the country publishing most articles on oral cancer in South Asia, and Malaysia (n = 355; 37.7%) was first in Southeast Asia. Tobacco smoking, alcohol consumption, and areca nut as risk factors were common keywords, attention should be paid to them while developing polices for oral cancer control. In India, the most topic including distinctive keywords was diagnostics (sensitivity/specificity, saliva, and predictive value), followed by molecular biology (antioxidants, lipid peroxidation, and glutathione), experimental in vivo (hamster and cheek pouch), and risk factor (smokeless tobacco). In Malaysia, the most topic containing keywords was molecular biology followed by epidemiology and drug research. Conclusion: This study for the first time reported the scientometric characteristics of oral cancer research in South Asia (India) and Southeast Asia (Malaysia). It is essential to improve the public awareness of risk factors control to reduce the oral cancer burden, especially in low-and middle-income countries.

Piezo1 regulates TGF-ß1 induced epithelial-mesenchymal transition in chronic rhinosinusitis with nasal polyps.

BACKGROUND: Epithelial-mesenchymal transition (EMT) is involved in local tissue remodeling in chronic rhinosinusitis with nasal polyps (CRSwNP). However, the function of Piezo1 in EMT process remains unclear. This study aimed to characterize potential roles of Piezo1 in EMT process in CRSwNP. METHODS: Overall, 22 nasal polyp (NP) tissues from patients with CRSwNP and 20 middle turbinate from healthy individuals were obtained during surgery. The expression of Piezo1, E-cadherin, vimentin, and α-smooth muscle actin (α-SMA) was measured by using western blot (Wb) in NP tissues and primary human nasal epithelial cells (pHNECs) and the location and level were assessed by immunofluorescence staining. BEAS-2B cells were stimulated with transforming growth factor (TGF)-ß1 to induce EMT in vitro model and examined using qRT-PCR. BEAS-2B cells were treated with Yoda1 and RuR to calculate protein level by Wb analysis. Yoda1 and RuR treated NP murine model was evaluated by H&E (hematoxylin-eosin) staining and immunohistochemistry. RESULTS: Compared with the control group, E-cadherin was decreased while the level of Piezo1, vimentin, and α-SMA was increased in NP group. Piezo1, vimentin, and α-SMA were upregulated in TGF-ß1-induced BEAS-2B cells. Yoda1 inhibited E-cadherin expression and promoted Piezo1 and the aforementioned mesenchymal markers, whereas RuR showed contrary results. The results from the murine model treated with Yoda1 and RuR were consistent with those results in the EMT model in vitro. CONCLUSION: Piezo1 is linked with EMT process in CRSwNP and the activation of Piezo1 exacerbates EMT process of nasal polyps.

All-Optical Photoacoustic Spectroscopy-Based Dual-Component Greenhouse Gas Analyzer.

To achieve high sensitivity detection of dual-component greenhouse gases carbon dioxide and methane simultaneously, a multimechanism synergistic enhanced all-optical photoacoustic spectroscopy gas analyzer is presented. The acoustic resonance of the photoacoustic cell and the mechanical resonance of a fiber-optic cantilever acoustic sensor are used to enhance the photoacoustic signals of the dual-component gas. The optimized multipass beam reflection structure enhances the effective excitation power of the dual-component gas. The highly sensitive detection of carbon dioxide and methane at dual-frequency operating points is realized by dual-channel laser modulation combined with dual-input digital lock-in amplification technology. The Allan-Werle deviation analysis results show that with a 100 s average time, the minimum detection limits of carbon dioxide and methane are 76.5 and 1.9 ppb, respectively. The corresponding normalized noise equivalent absorption (NNEA) coefficients are 3.1 × 10-10 and 2.9 × 10-10 cm-1 W/Hz1/2, respectively.

Ultra small gold nanoclusters supported on two-dimensional bismuth selenium nanosheets for synergistic photothermal and photodynamic tumor therapy.

Two-dimensional (2D) bismuth selenium (Bi2Se3) nanosheets have exceptional surface area and superior surface modification capabilities, facilitating the effective loading of nanoprobes, metal particles, and other substances. Additionally, thiolated ultrasmall gold nanoclusters (Au NCs), distinguished by their high photoluminescent activity and modulatable surface charges, enable efficient loading onto the 2D Bi2Se3 surfaces. In this study, we successfully prepared Bi2Se3 nanosheets by sonication-assisted liquid phase exfoliation and loaded Au clusters on their surface through an amide bond reaction. The loading of Au NCs significantly augments the photothermal and photocatalytic capabilities of Bi2Se3 nanosheets and exhibits obvious anti-cancer therapeutic effects through in vitro and in vivo experiments. In summary, the as-prepared AuNC@Bi2Se3 nanocomposites showed combined near-infrared light-initiated photothermal/photodynamic therapy (PTT/PDT) against tumors, demonstrating their potential as novel theranostic agents for biomedical applications.

The tissue virome of black-spotted frogs reveals a diversity of uncharacterized viruses.

Amphibians are an essential class in the maintenance of global ecosystem equilibrium, but they face serious extinction risks driven by climate change and infectious diseases. Unfortunately, the virus diversity harbored by these creatures has been rarely investigated. By profiling the virus flora residing in different tissues of 100 farmed black-spotted frogs (Rana nigromaculata) using a combination of DNA and RNA viromic methods, we captured 28 high-quality viral sequences covering at least 11 viral families. Most of these sequences were remarkably divergent, adding at least 10 new species and 4 new genera within the families Orthomyxoviridae, Adenoviridae, Nodaviridae, Phenuiviridae, and Picornaviridae. We recovered five orthomyxovirus segments, with three distantly neighboring two Chinese fish-related viruses. The recombination event of frog virus 3 occurred among the frog and turtle strains. The relative abundance and molecular detection revealed different tissue tropisms of these viruses, with the orthomyxovirus and adenoviruses being enteric and probably also neurotropic, but the new astrovirus and picornavirus being hepatophilic. These results expand the spectrum of viruses harbored by anurans, highlighting the necessity to continuously monitor these viruses and to investigate the virus diversity in a broader area with more diverse amphibian species.

Deliberation concerning the role of M1-type macrophage subset in oral carcinogenesis.

Over the last decade, accumulating evidence has suggested that tumor-associated macrophages (TAMs) play a significant role in the tumor development. This commentary wishes to highlight the findings by You, et al. that M1-like TAMs could cascade a mesenchymal/stem-like phenotype of oral squamous cell carcinoma (OSCC) via the IL6/Stat3/THBS1 feedback loop. These unprecedented findings identified M1-like TAMs-regulated processes as potentially tumor-promotion in the context of OSCC immunomicroenvironment.

Cadmium causes cerebral mitochondrial dysfunction through regulating mitochondrial HSF1.

Mitochondria, as the powerhouse of the cell, play a vital role in maintaining cellular energy homeostasis and are known to be a primary target of cadmium (Cd) toxicity. The improper targeting of proteins to mitochondria can compromise the normal functions of the mitochondria. However, the precise mechanism by which protein localization contributes to the development of mitochondrial dysfunction induced by Cd is still not fully understood. For this research, Hy-Line white variety chicks (1-day-old) were used and equally distributed into 4 groups: the Control group (fed with a basic diet), the Cd35 group (basic diet with 35 mg/kg CdCl2), the Cd70 group (basic diet with 70 mg/kg CdCl2) and the Cd140 group (basic diet with 140 mg/kg CdCl2), respectively for 90 days. It was found that Cd caused the accumulation of heat shock factor 1 (HSF1) in the mitochondria, and the overexpression of HSF1 in the mitochondria led to mitochondrial dysfunction and neuronal damage. This process is due to the mitochondrial HSF1 (mtHSF1), causing mitochondrial fission through the upregulation of dynamin-related protein 1 (Drp1) content, while inhibiting oligomer formation of single-stranded DNA-binding protein 1 (SSBP1), resulting in the mitochondrial DNA (mtDNA) deletion. The findings unveil an unforeseen role of HSF1 in triggering mitochondrial dysfunction.

Foxq1 activates CB2R with oleamide to alleviate POCD.

Postoperative cognitive dysfunction (POCD) is a major concern, particularly among older adults. This study used social isolation (ISO) and multiomics analyses in aged mice to investigate potential mechanisms underlying POCD development. Aged mice were divided into two groups: ISO and paired housing (PH). Oleamide and the cannabinoid receptor type 2 (CB2R) antagonist AM630 were administered intraperitoneally, while Foxq1 adeno-associated viral (AAV) vector was injected directly into the hippocampus. Intramedullary tibial surgeries were subsequently performed to establish the POCD models. Behavioral tests comprising the Y-maze, open field test, and novel object recognition were conducted 2 days after surgery. Hippocampal and serum inflammatory cytokines were assessed. Following surgery, ISO mice demonstrated intensified cognitive impairments and escalated inflammatory markers. Integrative transcriptomic and metabolomic analysis revealed elevated oleamide concentrations in the hippocampus and serum of PH mice, with associative investigations indicating a close relationship between the Foxq1 gene and oleamide levels. While oleamide administration and Foxq1 gene overexpression substantially ameliorated postoperative cognitive performance and systemic inflammation in mice, CB2R antagonist AM630 impeded these enhancements. The Foxq1 gene and oleamide may be crucial in alleviating POCD. While potentially acting through CB2R-mediated pathways, these factors may modulate neuroinflammation and attenuate proinflammatory cytokine levels within the hippocampus, substantially improving cognitive performance postsurgery. This study lays the groundwork for future research into therapeutic approaches targeting the Foxq1-oleamide-CB2R axis, with the ultimate goal of preventing or mitigating POCD.

Tocilizumab effectively reduces flares of hyperimmunoglobulin D syndrome in children: Three cases in China.

Hyperimmunoglobulin D syndrome (HIDS) is a rare but severe autoinflammatory disease with a poor prognosis if not diagnosed and treated early. Here, we report three cases of HIDS in children with typical clinical manifestations and a clear genetic diagnosis. Patient 1 experienced recurrent fever flares with a maculo-papular skin rash. Patient 2 presented with periodic fever, cholestasis, lymphadenopathy, aphthous stomatitis, arthralgia, and abdominal pain and underwent surgery for intestinal obstruction. Patient 3, a sibling of patient 2, presented with periodic fever and underwent a surgical procedure for intussusception. All three patients were administered interleukin (IL)-6 receptor antagonist (tocilizumab). The results showed that tocilizumab effectively reduced inflammatory flares. Early diagnosis and tocilizumab treatment are effective at improving the prognosis of HIDS patients.

LINC00908 attenuates LUAD tumorigenesis through DEAD-box helicase 54.

Lung adenocarcinoma (LUAD) is one of the leading causes of cancer-related death worldwide. We identified a specific long non-coding RNA (LncRNA), LINC00908, which was downregulated in LUAD tissues and associated with good outcome. LINC00908 inhibited glycolysis by regulating the expression of the DEAD-box helicase 54 (DDX54), which was screened by a nine-gene risk signature, where DDX54 showed a positive correlation with several glycolysis-related genes. Experimental verification confirmed that DDX54 regulated nine key glycolytic enzymes, thereby affecting the level of glycolysis in LUAD. Further, the expression of LINC00908 in LUAD tumorigenesis was modulated by a transcription factor, regulatory factor X2 (RFX2). The RFX2/LINC00908/DDX54 axis regulated LUAD tumor growth, migration, invasion, cell apoptosis and glycolysis both in vitro and in vivo. These results demonstrate that this axis may serve as a novel mediator in LUAD progress and offer a novel therapeutic target for more precise diagnosis and treatment of LUAD.

MRI-Measured Pancreatic Fat Correlates with Increased Arterial Stiffness in Patients Who are Overweight and Obese.

Purpose: Arterial stiffness is often increased in overweight or obese individuals before the development of hypertension (HT). This study aimed to determine the connection between pancreatic fat and atherosclerosis in overweight and obese people without HT. Patients and methods: We included 128 patients who were non-hypertensive and overweight or obese in a study between December 2019 and November 2022. Medical history was collected, and all participants underwent a physical examination and blood tests. Pancreatic fat content was measured by magnetic resonance imaging (MRI) and was grouped into quartiles based on pancreatic fat fraction (PFF). The upper three quartiles (PFF≥10.33%) were defined as non-alcoholic fatty pancreas disease (NAFPD) and the first quartile (PFF<10.33%) as non-NAFPD. High baPWV (H-baPWV) and low baPWV (L-baPWV) were classified according to the median baPWV (1159 cm/s). The effect of NAFPD on baPWV was examined using binary logistic regression. The study population consisted of 96 NAFPD and 32 non-NAFPD cases. Results: Participants with NAFPD had significantly higher levels of baPWV than people without. The rates of NAFPD and the PFF values varied significantly in the L-baPWV and H-baPWV groups. Logistic regression analysis suggested that the presence of NAFPD was independently correlated with increased baPWV after adjusting for age, smoking, body mass index, blood pressure, lipid profiles, and glycemic index. Conclusion: NAFPD is an independent risk factor for increased baPWV in individuals with overweight and obesity but no HT, suggesting that the presence of NAFPD may be a warning signal of early atherosclerosis.

Chondromyxoid fibroma of the temporomandibular joint - a rare case.

BACKGROUND: Chondromyxoid fibroma (CMF) is a rare cartilaginous tumor, accounting for < 1% of benign bone tumors. We report a case of temporomandibular joint (TMJ)-CMF, involving the pterygopalatine space and skull base and discuss its epidemiology, clinical characteristics, and management. CASE PRESENTATION: A 56-year-old woman presented with facial asymmetry and progressive mouth opening restriction due to a mass expanding upwardly to the auriculotemporal region. Using digital techniques to determine the lesion's boundary and reconstruct the normal glenoid fossa, the temporalis myofascial flap was transplanted between the titanium mesh and condyle to reconstruct the disc after tumor resection. CONCLUSION: This case highlights the importance of identifying patients with TMJ-CMF.

Tepidibacillus marianensis sp. nov., a novel heterotrophic iron-reducing bacterium isolated from Mariana Trench sediment.

A novel chemoheterotrophic iron-reducing micro-organism, designated as strain LSZ-M11000T, was isolated from sediment of the Marianas Trench. Phylogenetic analysis based on the 16S rRNA gene revealed that strain LSZ-M11000T belonged to genus Tepidibacillus, with 97 % identity to that of Tepidibacillus fermentans STGHT, a mesophilic bacterium isolated from the Severo-Stavropolskoye underground gas storage facility in Russia. The polar lipid profile of strain LSZ-M11000T consisted of diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, as well as other unidentified phospholipids and lipids. The major fatty acids were C16 : 0 (28.4 %), C18 : 0 (15.8 %), iso-C15 : 0 (12.9 %), and anteiso-C15 : 0 (12.0 %). Strain LSZ-M11000T had no menaquinone. Genome sequencing revealed that the genome size of strain LSZ-M11000T was 2.97 Mb and the DNA G+C content was 37.9 mol%. The average nucleotide identity values between strain LSZ-M11000T and its close phylogenetic relatives, Tepidibacillus fermentans STGHT and Tepidibacillus decaturensis Z9T, were 76.4 and 72.6 %, respectively. The corresponding DNA-DNA hybridization estimates were 20.9 and 23.4 %, respectively. Cells of strain LSZ-M11000T were rod-shaped (1.0-1.5×0.3-0.5 µm). Using pyruvate as an electron donor, it was capable of reducing KMnO4, MnO2, As(V), NaNO3, NaNO2, Na2SO4, Na2S2O3, and K2Cr2O7. Based on phenotypic, genotypic, and phylogenetic evidence, strain LSZ-M11000T is proposed to be a novel strain of the genus Tepidibacillus, for which the name Tepdibacillus marianensis is proposed. The type strain is LSZ-M11000T (=CCAM 1008T=JCM 39431T).

Clinical significance of lncRNA XIST expression in cholangiocarcinoma and its effect on cell migration and invasion.

BACKGROUND: Cholangiocarcinoma is a malignant tumor that occurs in the bile duct system, and the prognosis of patients is poor. Currently, research suggests that long non-coding RNAs (lncRNAs) in the treatment and prevention of cholangiocarcinoma. This study primarily focuses on the regulation and potential mechanism of the lncRNA XIST (XIST) in cholangiocarcinoma. METHODS: The levels of XIST and miR-126-3p in cholangiocarcinoma tissues and cells were detected using real-time quantitative polymerase chain reaction (RT-qPCR). Cell transfection status, including migration and invasion, was examined via the Transwell method. The relationship between XIST and miR-126-3p was observed by dual-luciferase gene reporter assay and verified by rescue assays. Additionally, the prognostic significance of XIST in cholangiocarcinoma was determined using Kaplan-Meier and multivariate Cox regression analyses. RESULTS: XIST expression was increased in cholangiocarcinoma, while miR-126-3p was decreased, in both tissues and cells. The successful construction of silencing XIST was found to inhibit the count of cell migration and invasion. XIST directly targeted miR-126-3p to regulate the progression of cholangiocarcinoma. CONCLUSION: XIST sponging miR-126-3p inhibited the progression of cholangiocarcinoma and improved the prognosis for patients. This finding provides new insights and opportunities for future studies on cholangiocarcinoma prognostic biomarkers.

Fiber-Optic Photoacoustic Gas Microsensor Dual Enhanced by Helmholtz Resonator and Interferometric Cantilever.

A high-sensitivity fiber-optic photoacoustic (PA) gas microsensor is demonstrated with dual enhancement based on acoustics and detection. Due to the characteristic of small size, a Helmholtz resonator is integrated into a miniature PA sensor. The acoustically amplified PA signal is detected by a high-sensitivity fiber Fabry-Perot (F-P) interferometric cantilever. The first-order resonant frequencies of the interferometric cantilever and Helmholtz resonator are matched by subtle adjustments. The weak PA signal is significantly enhanced in a volume of only 0.35 mL, which breaks the volume limitation of the resonance modes in traditional PA sensing systems. To improve the resolution of the microsensor, a white light interferometry (WLI)-based spectral demodulation algorithm is utilized. The experimental results indicate that the minimum detection limit of acetylene (C2H2) drops to about 15 ppb with an averaging time of 100 s, corresponding to the normalized noise equivalent absorption (NNEA) coefficient of 2.7 × 10-9 W·cm-1·Hz-1/2. The dual resonance enhanced fiber-optic PA gas microsensor has the merits of high sensitivity, intrinsic safety, and compact structure.

Nano­selenium alleviates cadmium-induced blood-brain barrier destruction by restoring the Wnt7A/ß-catenin pathway.

Selenium (Se), a highly beneficial animal feed additive, exhibits remarkable antioxidant and anti-inflammatory properties. Nano­selenium (Nano-Se) is an advanced formulation of Se featuring a specialized drug delivery vehicle, with good bioavailability, higher efficacy, and lower toxicity compared to the traditional form of Se. With the advancement of industry, cadmium (Cd) contamination occurs in different countries and regions and thereby contaminating different food crops, and the degree of pollution is degree increasing year by year. The present investigation entailed the oral administration of CdCl2 and/or Nano-Se to male chickens of the Hy-Line Variety White breed, which are one day old, subsequent to a 7-day adaptive feeding period, for a duration of 90 days. The study aimed to elucidate the potential protective impact of Nano-Se on Cd exposure. The study found that Nano-Se demonstrates potential in mitigating the blood-brain barrier (BBB) dysfunction characterized by impairment of adherens junctions (AJS) and tight junctions (TJS) by inhibiting reactive oxygen species (ROS) overproduction. In addition, the data uncovered that Nano-Se demonstrates a proficient ability in alleviating BBB impairment and inflammatory reactions caused by Cd through the modulation of the Wnt7A/ß-catenin pathway, highlights its potential to maintain brain homeostasis. Hence, this research anticipates that the utilization of Nano-Se effectively mitigate the detrimental impacts associated with Cd exposure on the BBB.

Epigenetic silencing of LDHB promotes hepatocellular carcinoma by remodeling the tumor microenvironment.

Lactate dehydrogenase B (LDHB) reversibly catalyzes the conversion of pyruvate to lactate or lactate to pyruvate and expressed in various malignancies. However, the role of LDHB in modulating immune responses against hepatocellular carcinoma (HCC) remains largely unknown. Here, we found that down-regulation of lactate dehydrogenase B (LDHB) was coupled with the promoter hypermethylation and knocking down the DNA methyltransferase 3A (DNMT 3A) restored LDHB expression levels in HCC cell lines. Bioinformatics analysis of the HCC cohort from The Cancer Genome Atlas revealed a significant positive correlation between LDHB expression and immune regulatory signaling pathways and immune cell infiltrations. Moreover, immune checkpoint inhibitors (ICIs) have shown considerable promise for HCC treatment and patients with higher LDHB expression responded better to ICIs. Finally, we found that overexpression of LDHB suppressed HCC growth in immunocompetent but not in immunodeficient mice, suggesting that the host immune system was involved in the LDHB-medicated tumor suppression. Our findings indicate that DNMT3A-mediated epigenetic silencing of LDHB may contribute to HCC progression through remodeling the tumor immune microenvironment, and LDHB may become a potential prognostic biomarker and therapeutic target for HCC immunotherapy.

NIR-II Light-Driven Genetically Engineered Exosome Nanocatalysts for Efficient Phototherapy against Glioblastoma.

Glioblastoma (GBM) poses a significant therapeutic challenge due to its invasive nature and limited drug penetration through the blood-brain barrier (BBB). In response, here we present an innovative biomimetic approach involving the development of genetically engineered exosome nanocatalysts (Mn@Bi2Se3@RGE-Exos) for efficient GBM therapy via improving the BBB penetration and enzyme-like catalytic activities. Interestingly, a photothermally activatable multiple enzyme-like reactivity is observed in such a nanosystem. Upon NIR-II light irradiation, Mn@Bi2Se3@RGE-Exos are capable of converting hydrogen peroxide into hydroxyl radicals, oxygen, and superoxide radicals, providing a peroxidase (POD), oxidase (OXD), and catalase (CAT)-like nanocatalytic cascade. This consequently leads to strong oxidative stresses to damage GBM cells. In vitro, in vivo, and proteomic analysis further reveal the potential of Mn@Bi2Se3@RGE-Exos for the disruption of cellular homeostasis, enhancement of immunological response, and the induction of cancer cell ferroptosis, showcasing a great promise in anticancer efficacy against GBM with a favorable biosafety profile. Overall, the success of this study provides a feasible strategy for future design and clinical study of stimuli-responsive nanocatalytic medicine, especially in the context of challenging brain cancers like GBM.