Development and validation of a preoperative radiomics-based nomogram to identify patients who can benefit from splenic hilar lymphadenectomy: a pooled analysis of three prospective trials.

BACKGROUND: We aimed to use preoperative computed tomography images to develop a radiomic nomogram to select patients who would benefit from spleen-preserving splenic hilar (No.10) lymphadenectomy (SPSHL). METHODS: A pooled analysis of three distinct prospective studies was performed. The splenic hilar lymph node (SHLN) ratio (sLNR) was established as the quotient of the number of metastatic SHLN to the total number of SHLN. Radiomic features reflecting the phenotypes of the primary tumor (RS1) and SHLN region (RS2) were extracted and used as predictive factors for sLNR. RESULTS: This study included 733 patients: 301 in the D2 group and 432 in the D2+No.10 group. The optimal sLNR cutoff value was set at 0.4, and the D2+No.10 group was divided into three groups: sLNR=0, sLNR≤0.4, and sLNR>0.4. Patients in the D2+No. 10 group were randomly divided into the training (n=302) and validation (n=130) cohorts. The AUCs value of the nomogram, including RS1 and RS2, were 0.952 in the training cohort and 0.888 in the validation cohort. The entire cohort was divided into three groups based on the nomogram scores: low, moderate and high SHLN metastasis burden groups (LMB, MMB and HMB, respectively). A similar 5-year OS rate was found between the D2 and D2+No. 10 groups in the LMB and HMB groups. In the MMB group, the 5-year OS of the D2+No. 10 group (73.4%) was significantly higher than that of the D2 group (37.6%) (P<0.001). CONCLUSIONS: The nomogram showed good predictive ability for distinguishing patients with various SHLN metastasis burdens. It can accurately identify patients who would benefit from SPSHL.

Transplant of fecal microbiota from healthy young mice relieves cognitive defects in late-stage diabetic mice by reducing metabolic disorders and neuroinflammation.

Fecal microbiota transplant (FMT) is becoming as a promising area of interest for treating refractory diseases. In this study, we investigated the effects of FMT on diabetes-associated cognitive defects in mice as well as the underlying mechanisms. Fecal microbiota was prepared from 8-week-aged healthy mice. Late-stage type 1 diabetics (T1D) mice with a 30-week history of streptozotocin-induced diabetics were treated with antibiotics for 7 days, and then were transplanted with bacterial suspension (100 µL, i.g.) once a day for 14 days. We found that FMT from healthy young mice significantly alleviated cognitive defects of late-stage T1D mice assessed in Morris water maze test. We revealed that FMT significantly reduced the relative abundance of Gram-negative bacteria in the gut microbiota and enhanced intestinal barrier integrity, mitigating LPS translocation into the bloodstream and NLRP3 inflammasome activation in the hippocampus, thereby reducing T1D-induced neuronal loss and astrocytic proliferation. FMT also reshaped the metabolic phenotypes in the hippocampus of T1D mice especially for alanine, aspartate and glutamate metabolism. Moreover, we showed that application of aspartate (0.1 mM) significantly inhibited NLRP3 inflammasome activation and IL-1ß production in BV2 cells under a HG/LPS condition. We conclude that FMT can effectively relieve T1D-associated cognitive decline via reducing the gut-brain metabolic disorders and neuroinflammation, providing a potential therapeutic approach for diabetes-related brain disorders in clinic.

Branched-Chain Amino Acids Deficiency Promotes Diabetic Neuropathic Pain Through Upregulating LAT1 and Inhibiting Kv1.2 Channel.

Diabetic neuropathic pain (DNP), one of the most common complications of diabetes, is characterized by bilateral symmetrical distal limb pain and substantial morbidity. To compare the differences  is aimed at serum metabolite levels between 81 DNP and 73 T2DM patients without neuropathy and found that the levels of branched-chain amino acids (BCAA) are significantly lower in DNP patients than in T2DM patients. In high-fat diet/low-dose streptozotocin (HFD/STZ)-induced T2DM and leptin receptor-deficient diabetic (db/db) mouse models, it is verified that BCAA deficiency aggravated, whereas BCAA supplementation alleviated DNP symptoms. Mechanistically, using a combination of RNA sequencing of mouse dorsal root ganglion (DRG) tissues and label-free quantitative proteomic analysis of cultured cells, it is found that BCAA deficiency activated the expression of L-type amino acid transporter 1 (LAT1) through ATF4, which is reversed by BCAA supplementation. Abnormally upregulated LAT1 reduced Kv1.2 localization to the cell membrane, and inhibited Kv1.2 channels, thereby increasing neuronal excitability and causing neuropathy. Furthermore, intraperitoneal injection of the LAT1 inhibitor, BCH, alleviated DNP symptoms in mice, confirming that BCAA-deficiency-induced LAT1 activation contributes to the onset of DNP. These findings provide fresh insights into the metabolic differences between DNP and T2DM, and the development of approaches for the management of DNP.

Effects of regulator of G protein signaling 2 (RGS2) overexpression in the paraventricular nucleus on blood pressure in rats with angiotensin II-induced hypertension.

The hypothalamic paraventricular nucleus (PVN) regulates sympathetic activity and blood pressure. The regulator of G protein signaling 2 (RGS2) is a negative G protein regulator, which selectively regulates G⍺q signaling, a potential cause of hypertension. This study aimed to examine angiotensin II (ANG II)-G protein-RGS2 signaling on the central mechanisms of blood pressure control, sympathetic activation, and kidney function. The Sprague Dawley rats were infused with ANG II (200 ng/kg/min) via osmotic mini pump to induce hypertension. Adenovirus (AV) vectors encoding RGS2 was transfected into the PVN in vivo. By radio telemetry measurements, we found AV-RGS2 transfection to the PVN significantly attenuated the increase of mean arterial pressure in ANG II infusion rats from days 2-7 of the 2-week experiment (Day 7: ANG II + AV-RGS2 141.3 ± 10.0 mmHg vs. ANG II 166.9 ± 9.3 mmHg, p < 0.05). AV-RGS2 transfection significantly reduced the serum norepinephrine level and acute volume reflex and increased daily urine volume and sodium excretion in ANG II-infused hypertensive rats. AV-RGS2 transfection significantly reduced G⍺q and PKC protein expressions within the PVN in ANG II infusion rats. In cultured mouse hypothalamic cells, real-time PCR study showed ANG II treatment increased mRNA expression of G⍺q, G⍺s, and RGS2, and AV-RGS2 treatment decreased ANG II-induced mRNA expression of G⍺q and G⍺s. Using confocal imagery, we found that AV-RGS2 attenuated the increase of calcium influx in ANG II-treated cells. Our results suggest that central overexpression of RGS2 in the PVN attenuated the increase of blood pressure and sympathetic outflow, and improves kidney excretory function in hypertensive rats. This may be via the alteration of ANG II-G-protein-RGS2 signaling in the central nervous system.

Nicotinamide riboside restores nicotinamide adenine dinucleotide levels and alleviates brain injury by inhibiting oxidative stress and neuroinflammation in a mouse model of intracerebral hemorrhage.

Hemorrhagic stroke is a global health problem owing to its high morbidity and mortality rates. Nicotinamide riboside is an important precursor of nicotinamide adenine dinucleotide characterized by a high bioavailability, safety profile, and robust effects on many cellular signaling processes. This study aimed to investigate the protective effects of nicotinamide riboside against collagenase-induced hemorrhagic stroke and its underlying mechanisms of action. An intracerebral hemorrhage model was constructed by stereotactically injecting collagenase into the right striatum of adult male Institute for Cancer Research mice. After 30 minutes, nicotinamide riboside was administered via the tail vein. The mice were sacrificed at different time points for assessments. Nicotinamide riboside reduced collagenase-induced hemorrhagic area, significantly reduced cerebral water content and histopathological damage, promoted neurological function recovery, and suppressed reactive oxygen species production and neuroinflammation. Nicotinamide riboside exerts neuroprotective effects against collagenase-induced intracerebral hemorrhage by inhibiting neuroinflammation and oxidative stress.

T. gondii excretory proteins promote the osteogenic differentiation of human bone mesenchymal stem cells via the BMP/Smad signaling pathway.

BACKGROUND: Bone defects, resulting from substantial bone loss that exceeds the natural self-healing capacity, pose significant challenges to current therapeutic approaches due to various limitations. In the quest for alternative therapeutic strategies, bone tissue engineering has emerged as a promising avenue. Notably, excretory proteins from Toxoplasma gondii (TgEP), recognized for their immunogenicity and broad spectrum of biological activities secreted or excreted during the parasite's lifecycle, have been identified as potential facilitators of osteogenic differentiation in human bone marrow mesenchymal stem cells (hBMSCs). Building on our previous findings that TgEP can enhance osteogenic differentiation, this study investigated the molecular mechanisms underlying this effect and assessed its therapeutic potential in vivo. METHODS: We determined the optimum concentration of TgEP through cell cytotoxicity and cell proliferation assays. Subsequently, hBMSCs were treated with the appropriate concentration of TgEP. We assessed osteogenic protein markers, including alkaline phosphatase (ALP), Runx2, and Osx, as well as components of the BMP/Smad signaling pathway using quantitative real-time PCR (qRT-PCR), siRNA interference of hBMSCs, Western blot analysis, and other methods. Furthermore, we created a bone defect model in Sprague-Dawley (SD) male rats and filled the defect areas with the GelMa hydrogel, with or without TgEP. Microcomputed tomography (micro-CT) was employed to analyze the bone parameters of defect sites. H&E, Masson and immunohistochemical staining were used to assess the repair conditions of the defect area. RESULTS: Our results indicate that TgEP promotes the expression of key osteogenic markers, including ALP, Runx2, and Osx, as well as the activation of Smad1, BMP2, and phosphorylated Smad1/5-crucial elements of the BMP/Smad signaling pathway. Furthermore, in vivo experiments using a bone defect model in rats demonstrated that TgEP markedly promoted bone defect repair. CONCLUSION: Our results provide compelling evidence that TgEP facilitates hBMSC osteogenic differentiation through the BMP/Smad signaling pathway, highlighting its potential as a therapeutic approach for bone tissue engineering for bone defect healing.

Silk-based intelligent fibers and textiles: structures, properties, and applications.

Multifunctional fibers represent a cornerstone of human civilization, playing a pivotal role in numerous aspects of societal development. Natural biomaterials, in contrast to synthetic alternatives, offer environmental sustainability, biocompatibility, and biodegradability. Among these biomaterials, natural silk is favored in biomedical applications and smart fiber technology due to its accessibility, superior mechanical properties, diverse functional groups, controllable structure, and exceptional biocompatibility. This review delves into the intricate structure and properties of natural silk fibers and their extensive applications in biomedicine and smart fiber technology. It highlights the critical significance of silk fibers in the development of multifunctional materials, emphasizing their mechanical strength, biocompatibility, and biodegradability. A detailed analysis of the hierarchical structure of silk fibers elucidates how these structural features contribute to their unique properties. The review also encompasses the biomedical applications of silk fibers, including surgical sutures, tissue engineering, and drug delivery systems, along with recent advancements in smart fiber applications such as sensing, optical technologies, and energy storage. The enhancement of functional properties of silk fibers through chemical or physical modifications is discussed, suggesting broader high-end applications. Additionally, the review addresses current challenges and future directions in the application of silk fibers in biomedicine and smart fiber technologies, underscoring silk's potential in driving contemporary technological innovations. The versatility and sustainability of silk fibers position them as pivotal elements in contemporary materials science and technology, fostering the development of next-generation smart materials.

Revealing the Limitation Induced by Hydroxyl in Regulating Solvation Structure of Zn2+ and Overcoming Challenges with Hybrid Additives towards Highly Stable Zinc Anodes.

In the field of electrolyte design for aqueous zinc-ion batteries (AZIBs), additives containing hydroxyl have been demonstrated to effectively modulate the solvation structure of Zn2+. However, reported studies typically focus solely on the effectiveness of hydroxyl while neglecting the issues that emerge during solvation structure regulation. The strong electron-attracting capability of Zn2+ attracts electrons from the oxygen in hydroxyl, thereby weakening the strength of hydroxyl, the hydrogen evolution reaction (HER) is also pronounced. This work innovatively reveals the limitation of hydroxyl-containing additives and proposes a synergistic regulation strategy based on hybrid additives. Arginine with a high isoelectric point is introduced into the electrolyte system containing hydroxyl additives. The protonation effect and electrostatic attraction of arginine enable it to absorb protons at the anode released by the weakened hydroxyl, thereby compensating for the limitation of hydroxyl additives. Under the synergistic action of hybrid additives, the Zn|Zn battery achieved stable deposition/stripping for over 1200 hours under 10 mA cm-2 and 10 mAh cm-2. Moreover, the Zn|Cu battery cycled for over 570 hours with a high Coulombic efficiency of 99.82%. This study presents a pioneering perspective for the further application of AZIBs.

α-Ketoglutarate plays an inflammatory inhibitory role by regulating scavenger receptor class a expression through N6-methyladenine methylation during sepsis.

Sepsis arises from an uncontrolled inflammatory response triggered by infection or stress, accompanied by alteration in cellular energy metabolism, and a strong correlation exists between these factors. Alpha-ketoglutarate (α-KG), an intermediate product of the TCA cycle, has the potential to modulate the inflammatory response and is considered a crucial link between energy metabolism and inflammation. The scavenger receptor (SR-A5), a significant pattern recognition receptor, assumes a vital function in anti-inflammatory reactions. In the current investigation, we have successfully illustrated the ability of α-KG to mitigate inflammatory factors in the serum of septic mice and ameliorate tissue damage. Additionally, α-KG has been shown to modulate metabolic reprogramming and macrophage polarization. Moreover, our findings indicate that the regulatory influence of α-KG on sepsis is mediated through SR-A5. We also elucidated the mechanism by which α-KG regulates SR-A5 expression and found that α-KG reduced the N6-methyladenosine level of macrophages by up-regulating the m6A demethylase ALKBH5. α-KG plays a crucial role in inhibiting inflammation by regulating SR-A5 expression through m6A demethylation during sepsis. The outcomes of this research provide valuable insights into the relationship between energy metabolism and inflammation regulation, as well as the underlying molecular regulatory mechanism.

High methionine intake alters gut microbiota and lipid profile and leads to liver steatosis in mice.

Methionine is an important sulfur-containing amino acid. Health effects of both methionine restriction (MR) and methionine supplementation (MS) have been studied. This study aimed to investigate the impact of a high-methionine diet (HMD) (1.64% methionine) on both the gut and liver functions in mice through multi-omic analyses. Hepatic steatosis and compromised gut barrier function were observed in mice fed the HMD. RNA-sequencing (RNA-seq) analysis of liver gene expression patterns revealed the upregulation of lipid synthesis and degradation pathways, cholesterol metabolism and inflammation-related nucleotide-binding oligomerization domain (NOD)-like receptor signaling pathway. Metagenomic sequencing of cecal content demonstrated a shift in gut microbial composition with an increased abundance of opportunistic pathogens and gut microbial functions with up-regulated lipopolysaccharide (LPS) biosynthesis in mice fed HMD. Metabolomic study of cecal content showed an altered gut lipid profile and the level of bioactive lipids, including docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), palmitoylethanolamide (PEA), linoleoyl ethanolamide (LEA) and arachidonoyl ethanolamide (AEA), that carry anti-inflammatory effects significantly reduced in the gut of mice fed the HMD. Correlation analysis demonstrated that gut microbiota was highly associated with liver and gut functions and gut bioactive lipid content. In conclusion, this study suggested that the HMD exerted negative impacts on both the gut and liver, and an adequate amount of methionine intake should be carefully determined to ensure normal physiological function without causing adverse effects.

[Research Progress of Helicobacter pylori-Associated Extragastric Diseases].

Helicobacter pylori (Hp) is a common Gram-negative bacillus causing gastrointestinal infections.It mainly exists on the surface of gastric epithelial cells and in mucus and is associated with gastric ulcers,gastric cancer,and gastric mucosa-associated lymphomas.Studies have shown that Hp can induce or exacerbate certain extragastric diseases and is associated with the occurrence of coronavirus disease 2019.It is hypothesized that Hp may be indirectly or directly involved in the occurrence and development of diseases by stimulating the production of inflammatory cytokines or inducing cross-immune reactions.In addition,Hp can enter Candida to release toxins continuously and play a role in escaping the recognition of the host immune system and the bactericidal effect of drugs.This article reviews the research progress in Hp-associated extragastric diseases in recent years,aiming to draw the attention of clinical workers to Hp-associated extragastric diseases and enrich the knowledge about Hp infection for formulating countermeasures to avoid the aggravation or triggering of other diseases by Hp.

Psathrosterols C-E, highly conjugated ergosterol derivatives from Psathyrella rogueiana with anti-inflammatory and immunosuppressive activity.

Three new ergosterols featuring with a highly conjugated ring system, psathrosterols C-E (1-3), have been isolated from the fungus Psathyrella rogueiana. The structures with the absolute configurations were elucidated by means of spectroscopic methods and single crystal X-ray diffraction. Compounds 1-3 exhibit inhibitory activity against NO production with IC50 values ranging from 8.4 to 21.8 µM. Compound 1 inhibits the LPS-induced proliferation of B lymphocyte cells with an IC50 value of 12.3 µM.

Silicon dioxide nanoparticles induce anxiety-like behavior in a size-specific manner via the microbiota-gut-brain axis.

The impacts of silicon dioxide nanoparticles (SiO2-NPs) on human health have attracted increasing interest due to their widespread utilization in medicine and food additives. However, the size-dependent effects of SiO2-NPs on brain health remain sparse. Herein we investigated alterations in behavioral patterns, the gut microbiota, inflammation and oxidative stress of mice after a 12-week exposure to SiO2-NPs with either small size (NP-S) or large size (NP-L). A more pronounced deleterious effect of NP-S was found on anxiety-like behavior in mice relative to NP-L. We also found that SiO2-NPs exposure induced inflammation and oxidative stress in the colon, hippocampus and cortex of mice in a size-specific manner. Correlation network analysis revealed potential links between anxiety-like behavior and SiO2-NPs-induced shifts in the gut microbiota including Parvibacter, Faecalibaculum, Gordonibacter and Ileibacterium. Furthermore, anxiety-like behavior caused by SiO2-NPs exposure exhibited correlations with decreased levels of hippocampal IL-10 and cortex Nqo1 as well as increased levels of intestinal Acox1 and hippocampal TNF-α. Therefore, our findings suggest that exposure to SiO2-NPs promoted anxiety-like behavior through the mediation of interplay between the gut and the brain, and SiO2-NPs of smaller size may generate a more adverse effect on brain health.

Immunobiology of COVID-19: Mechanistic and therapeutic insights from animal models.

The distribution of the immune system throughout the body complicates in vitro assessments of coronavirus disease 2019 (COVID-19) immunobiology, often resulting in a lack of reproducibility when extrapolated to the whole organism. Consequently, developing animal models is imperative for a comprehensive understanding of the pathology and immunology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. This review summarizes current progress related to COVID-19 animal models, including non-human primates (NHPs), mice, and hamsters, with a focus on their roles in exploring the mechanisms of immunopathology, immune protection, and long-term effects of SARS-CoV-2 infection, as well as their application in immunoprevention and immunotherapy of SARS-CoV-2 infection. Differences among these animal models and their specific applications are also highlighted, as no single model can fully encapsulate all aspects of COVID-19. To effectively address the challenges posed by COVID-19, it is essential to select appropriate animal models that can accurately replicate both fatal and non-fatal infections with varying courses and severities. Optimizing animal model libraries and associated research tools is key to resolving the global COVID-19 pandemic, serving as a robust resource for future emerging infectious diseases.

Urolithin A promotes atherosclerotic plaque stability by limiting inflammation and hypercholesteremia in Apolipoprotein E-deficient mice.

Urolithin A (UroA), a dietary phytochemical, is produced by gut bacteria from fruits rich in natural polyphenols ellagitannins (ETs). The efficiency of ETs metabolism to UroA in humans depends on gut microbiota. UroA has shown a variety of pharmacological activities. In this study we investigated the effects of UroA on atherosclerotic lesion development and stability. Apolipoprotein E-deficient (ApoE-/-) mice were fed a high-fat and high-cholesterol diet for 3 months to establish atherosclerosis model. Meanwhile the mice were administered UroA (50 mg·kg-1·d-1, i.g.). We showed that UroA administration significantly decreased diet-induced atherosclerotic lesions in brachiocephalic arteries, macrophage content in plaques, expression of endothelial adhesion molecules, intraplaque hemorrhage and size of necrotic core, while increased the expression of smooth muscle actin and the thickness of fibrous cap, implying features of plaque stabilization. The underlying mechanisms were elucidated using TNF-α-stimulated human endothelial cells. Pretreatment with UroA (10, 25, 50 µM) dose-dependently inhibited TNF-α-induced endothelial cell activation and monocyte adhesion. However, the anti-inflammatory effects of UroA in TNF-α-stimulated human umbilical vein endothelial cells (HUVECs) were independent of NF-κB p65 pathway. We conducted RNA-sequencing profiling analysis to identify the differential expression of genes (DEGs) associated with vascular function, inflammatory responses, cell adhesion and thrombosis in UroA-pretreated HUVECs. Human disease enrichment analysis revealed that the DEGs were significantly correlated with cardiovascular diseases. We demonstrated that UroA pretreatment mitigated endothelial inflammation by promoting NO production and decreasing YAP/TAZ protein expression and TEAD transcriptional activity in TNF-α-stimulated HUVECs. On the other hand, we found that UroA administration modulated the transcription and cleavage of lipogenic transcription factors SREBP1/2 in the liver to ameliorate cholesterol metabolism in ApoE-/- mice. This study provides an experimental basis for new dietary therapeutic option to prevent atherosclerosis.

Restricted intake of sulfur-containing amino acids reversed the hepatic injury induced by excess Desulfovibrio through gut-liver axis.

Diet is a key player in gut-liver axis. However, the effect of different dietary patterns on gut microbiota and liver functions remains unclear. Here, we used rodent standard chow and purified diet to mimic two common human dietary patterns: grain and plant-based diet and refined-food-based diet, respectively and explored their impacts on gut microbiota and liver. Gut microbiota experienced a great shift with notable increase in Desulfovibrio, gut bile acid (BA) levels elevated significantly, and liver inflammation was observed in mice fed with the purified diet. Liver inflammation and elevated gut BA levels also occurred in mice fed with the chow diet after receiving Desulfovibrio desulfuricans ATCC 29,577 (DSV). Restriction of sulfur-containing amino acids (SAAs) prevented liver injury mainly through higher hepatic antioxidant and detoxifying ability and reversed the elevated BA levels due to excess Desulfovibrio. Ex vivo fermentation of human fecal microbiota with primary BAs demonstrated that DSV enhanced production of secondary BAs. Higher concentration of both primary and secondary BAs were found in the gut of germ-free mice after receiving DSV. In conclusion, Restriction of SAAs in diet may become an effective dietary intervention to prevent liver injury associated with excess Desulfovibrio in the gut.

Effects of high-intensity ultrasound on physicochemical and gel properties of myofibrillar proteins from the bay scallop (Argopecten irradians).

Myofibrillar proteins (MPs) have a notable impact on the firmness and flexibility of gel-based products. Therefore, enhancing the gelation and emulsification properties of scallop MPs is of paramount significance for producing high-quality scallop surimi products. In this study, we investigated the effects of high-intensity ultrasound on the physicochemical and gelation properties of MPs from bay scallops (Argopecten irradians). The carbonyl content of MPs significantly increased with an increase in ultrasound power (150, 350, and 550 W), indicating ultrasound-induced MP oxidation. Meanwhile, high-intensity ultrasound treatment (550 W) enhanced the emulsifying capacity and the short-term stability of MPs (up to 72.05 m2/g and 153.05 min, respectively). As the ultrasound power increased, the disulfide bond content and surface hydrophobicity of MPs exhibited a notable increase, indicating conformational changes in MPs. Moreover, in the secondary structure of MPs, the α-helix content significantly decreased, whereas the ß-sheet content increased, thereby suggesting the ultrasound-induced stretching and flexibility of MP molecules. Sodium-dodecyl sulfate-polyacrylamide gel electrophoresis and scanning electron microscopy analysis further elucidated that high-intensity ultrasound induced MP oxidation, leading to modification of amino acid side chains, intra- and intermolecular cross-linking, and MP aggregation. Consequently, high-intensity ultrasound treatment was found to augment the viscoelasticity, gel strength, and water-holding capacity of MP gels, because ultrasound treatment facilitated the formation of a stable network structure in protein gels. Thus, this study offers theoretical insights into the functional modification of bay scallop MPs and the processing of its surimi products.

Natural selection shaped the protective effect of the mtDNA lineage against obesity in Han Chinese populations.

Mitochondria play a key role in lipid metabolism, and mitochondrial DNA (mtDNA) mutations are thus considered to affect obesity susceptibility by altering oxidative phosphorylation and mitochondrial function. In this study, we investigated mtDNA variants that may affect obesity risk in 2,877 Han Chinese individuals from three independent populations. The association analysis of 16 basal mtDNA haplogroups with body mass index (BMI), waist circumference (WC) and waist-to-hip ratio (WHR) revealed that only haplogroup M7 was significantly negatively correlated with all three adiposity-related anthropometric traits in the overall cohort (P=0.003 for BMI, P=1×10-5 for WC, P=0.005 for WHR), which was verified by the analysis of a single population, i.e., the Zhengzhou population. Furthermore, subhaplogroup analysis suggested that M7b1a1 was the most likely haplogroup associated with a decreased obesity risk, and the variation T12811C (causing Y159H in ND5) harbored in M7b1a1 may be the most likely candidate for altering mitochondrial function. Specifically, we found that proportionally more nonsynonymous mutations accumulated in M7b1a1 carriers, indicating that M7b1a1 was either under positive selection or subject to a relaxation of selective constraints. We also found that nuclear variants, especially in DACT2 and PIEZO1, may functionally interact with M7b1a1.

ARMC10 regulates mitochondrial dynamics and affects mitochondrial function via the Wnt/ß-catenin signalling pathway involved in ischaemic stroke.

Mitochondrial dynamics has emerged as an important target for neuronal protection after cerebral ischaemia/reperfusion. Therefore, the aim of this study was to investigate the mechanism by which ARMC10 regulation of mitochondrial dynamics affects mitochondrial function involved in ischaemic stroke (IS). Mitochondrial morphology was detected by laser scanning confocal microscopy (LSCM), and mitochondrial ultrastructural alterations were detected by electron microscopy. The expression of mitochondrial dynamics-related genes Drp1, Mfn1, Mfn2, Fis1, OPA1 and ARMC10 and downstream target genes c-Myc, CyclinD1 and AXIN2 was detected by RT-qPCR. Western blot was used to detect the protein expression of ß-catenin, GSK-3ß, p-GSK-3ß, Bcl-2 and Bax. DCFH-DA fluorescent probe was to detect the effect of ARMC10 on mitochondrial ROS level, Annexin V-FITC fluorescent probe was to detect the effect of ARMC10 on apoptosis, and ATP assay kit was to detect the effect of ARMC10 on ATP production. Mitochondrial dynamics was dysregulated in clinical IS samples and in the OGD/R cell model, and the relative expression of ARMC10 gene was significantly decreased in IS group (p < 0.05). Knockdown and overexpression of ARMC10 could affect mitochondrial dynamics, mitochondrial function and neuronal apoptosis. Agonist and inhibitor affected mitochondrial function and neuronal apoptosis by targeting Wnt/ß-Catenin signal pathway. In the OGD/R model, ARMC10 affected mitochondrial function and neuronal apoptosis through the mechanism that regulates Wnt/ß-catenin signalling pathway. ARMC10 regulates mitochondrial dynamics and protects mitochondrial function by activating Wnt/ß-catenin signalling pathway, to exert neuroprotective effects.

Integrated whole-exome and bulk transcriptome sequencing delineates the dynamic evolution from preneoplasia to invasive lung adenocarcinoma featured with ground-glass nodules.

OBJECTIVE: The genomic and molecular ecology involved in the stepwise continuum progression of lung adenocarcinoma (LUAD) from adenocarcinoma in situ (AIS) to minimally invasive adenocarcinoma (MIA) and subsequent invasive adenocarcinoma (IAC) remains unclear and requires further elucidation. We aimed to characterize gene mutations and expression landscapes, and explore the association between differentially expressed genes (DEGs) and significantly mutated genes (SMGs) during the dynamic evolution from AIS to IAC. METHODS: Thirty-five patients with ground-glass nodules (GGNs) lung adenocarcinomas were enrolled. Whole-exome sequencing (WES) and transcriptome sequencing (RNA-Seq) were conducted on all patients, encompassing both tumor samples and corresponding noncancerous tissues. Data obtained from WES and RNA-Seq were subsequently analyzed. RESULTS: The findings from WES delineated that the predominant mutations were observed in EGFR (49%) and ANKRD36C (17%). SMGs, including EGFR and RBM10, were associated with the dynamic evolution from AIS to IAC. Meanwhile, DEGs, including GPR143, CCR9, ADAMTS16, and others were associated with the entire process of invasive LUAD. We found that the signaling pathways related to cell migration and invasion were upregulated, and the signaling pathways of angiogenesis were downregulated across the pathological stages. Furthermore, we found that the messenger RNA (mRNA) levels of FAM83A, MAL2, DEPTOR, and others were significantly correlated with CNVs. Gene set enrichment analysis (GSEA) showed that heme metabolism and cholesterol homeostasis pathways were significantly upregulated in patients with EGFR/RBM10 co-mutations, and these patients may have poorer overall survival than those with EGFR mutations. Based on the six calculation methods for the immune infiltration score, NK/CD8+ T cells decreased, and Treg/B cells increased with the progression of early LUAD. CONCLUSIONS: Our findings offer valuable insights into the unique genomic and molecular features of LUAD, facilitating the identification and advancement of precision medicine strategies targeting the invasive progression of LUAD from AIS to IAC.