Xianlian Jiedu Decoction alleviates colorectal cancer by regulating metabolic profiles, intestinal microbiota and metabolites.

BACKGROUND: Xianlian Jiedu Decoction (XLJDD) has been used for the treatment of colorectal cancer (CRC) for several decades because of the prominent efficacy of the prescription. Despite the clear clinical efficacy of XLJDD, the anti-CRC mechanism of action is still unclear. PURPOSE: The inhibitory effect and mechanism of XLJDD on CRC were investigated in the azoxymethane/dextran sulfate sodium (AOM/DSS)-induced mice. METHODS: The AOM/DSS-induced mice model was adopted to evaluate the efficacy after administering the different doses of XLJDD. The therapeutic effects of XLJDD in treating AOM/DSS-induced CRC were investigated through histopathology, immunofluorescence and ELISA analysis methods. In addition, metabolomics profile and 16S rRNA analysis were used to explore the effective mechanisms of XLJDD on CRC. RESULTS: The results stated that the XLJDD reduced the number of tumor growth on the inner wall of the colon and the colorectal weight/length ratio, and suppressed the disease activity index (DAI) score, meanwhile XLJDD also increased body weight, colorectal length, and overall survival rate. The treatment of XLJDD also exhibited the ability to lower the level of inflammatory cytokines in serum and reduce the expression levels of ß-catenin, COX-2, and iNOS protein in colorectal tissue. The findings suggested that XLJDD has anti-inflammatory properties and may provide relief for those suffering from inflammation-related conditions. Mechanistically, XLJDD improved gut microbiota dysbiosis and associated metabolic levels of short chain fatty acids (SCFAs), sphingolipid, and glycerophospholipid. This was achieved by reducing the abundance of Turicibacter, Clostridium_sensu_stricto_1, and the levels of sphinganine, LPCs, and PCs. Additionally, XLJDD increased the abundance of Enterorhabdus and Alistipes probiotics, as well as the content of butyric acid and isovaleric acid. CONCLUSION: The data presented in this article demonstrated that XLJDD can effectively inhibit the occurrence of colon inner wall tumors by reducing the level of inflammation and alleviating intestinal microbial flora imbalance and metabolic disorders. It provides a scientific basis for clinical prevention and treatment of CRC.

Salvianolic acid B and tanshinone IIA synergistically improve early diabetic nephropathy through regulating PI3K/Akt/NF-κB signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Diabetic nephropathy (DN) is one of the most common and serious complications of diabetes, which lacks effective treatment. Salviae Miltiorrhizae Radix Et Rhizoma is one of the key compatible traditional Chinese medicine in the prescription for the treatment of DN. Salvianolic acid B and tanshinone IIA are two monomer active components with high content and clear structure in Salvia miltiorrhiza, which can effectively improve early (DN), respectively. AIM OF THE STUDY: To evaluate the compatible effect of salvianolic acid B and tanshinone IIA on early DN rats and elucidate the mechanism. METHODS: Early DN rats were induced by streptozotocin combined with high glucose and high fat diet, and intervened by salvianolic acid B, tanshinone IIA and their combinations. The pathological sections of kidney, liver and biochemical indexes were analyzed. Network pharmacology method was used to predict the possible mechanism. The mechanisms were elucidated by metabolomics, Elisa, and Western blot. RESULTS: Given our analysis, salvianolic acid B and tanshinone IIA can synergistically regulate 24 h UTP, Urea and Scr and improve kidney damage in early DN rats. The metabolic abnormalities of early DN rats were improved by regulating the biosynthesis of saturated fatty acids, glycerol phospholipid metabolism, steroid biosynthesis, alanine, and arachidonic acid. Salvianolic acid B combined with tanshinone IIA at a mass ratio of 13.4:1 can significantly reduce kidney inflammation, up-regulate p-PI3K/PI3K and p-Akt/Akt and down-regulate p-NF-κB/NF-κB, which better than the single-used group and can be reversed by PI3K inhibitor LY294002. CONCLUSION: Salvianolic acid B and tanshinone IIA can synergistically improve glucose and lipid disorders, liver and kidney damage, and resist kidney inflammation in early DN rats, and the mechanism may be related to regulating PI3K/Akt/NF-κB signaling pathway.

Clinical application of repetitive transcranial magnetic stimulation in improving functional impairments post-stroke: review of the current evidence and potential challenges.

In recent years, the stroke incidence has been increasing year by year, and the related sequelae after stroke, such as cognitive impairment, motor dysfunction, and post-stroke depression, seriously affect the patient's rehabilitation and daily activities. Repetitive transcranial magnetic stimulation (rTMS), as a safe, non-invasive, and effective new rehabilitation method, has been widely recognized in clinical practice. This article reviews the application and research progress of rTMS in treating different functional impairments (cognitive impairment, motor dysfunction, unilateral spatial neglect, depression) after stroke in recent years, and preliminary summarized the possible mechanisms. It has been found that the key parameters that determine the effectiveness of rTMS in improving post-stroke functional impairments include pulse number, stimulated brain areas, stimulation intensity and frequency, as well as duration. Generally, high-frequency stimulation is used to excite the ipsilateral cerebral cortex, while low-frequency stimulation is used to inhibit the contralateral cerebral cortex, thus achieving a balance of excitability between the two hemispheres. However, the specific mechanisms and the optimal stimulation mode for different functional impairments have not yet reached a consistent conclusion, and more research is needed to explore and clarify the best way to use rTMS. Furthermore, we will identify the issues and challenges in the current research, explore possible mechanisms to deepen understanding of rTMS, propose future research directions, and offer insightful insights for better clinical applications.

Upregulation of miR-21-5p rescues the inhibition of cardiomyocyte proliferation induced by high glucose through negative regulation of Rhob.

Increasing evidence shows that maternal hyperglycemia inhibits cardiomyocyte (CM) proliferation and promotes cell apoptosis during fetal heart development, which leads to cardiac dysplasia. Accumulating evidence suggests that the overexpression of miR-21 in CMs has a protective role in cardiac function. Therefore, we investigated whether miR-21 can rescue CM injury caused by high glucose. First, we performed biological function analysis of miR-21-5p overexpression in H9c2 cells treated with high glucose. We found that the proliferation of H9c2 cells treated with high glucose decreased significantly and was rescued after overexpression of miR-21-5p. CCK-8 and EdU incorporation assays were performed to assess cell proliferation. The cell proliferation of the miR-21-5p mimic transfection group was improved compared with that of the NC mimic group (*p < 0.05, miR-21-5p mimics vs. NC mimics) when the proliferation of H9c2 cells was reduced by high glucose (****p < 0.0001, high glucose (HG) vs. normal glucose (NG)). Then, we verified the targeted and negative regulation of miR-21-5p on Rhob using a dual-luciferase activity assay and RT-qPCR, respectively. We further demonstrated that miR-21-5p regulates Rhob to rescue the inhibition of CM proliferation induced by high glucose. The CCK-8 results showed that the cell proliferation of the siRNA-Rhob group was higher than that of the NC mimic group (***p < 0.001) and that of the cotransfection group with Up-Rhob plasmids and miR-21-5p mimics was lower than that of the miR-21-5p mimic group (*p < 0.05). Conclusion: Overexpression of miR-21-5p rescues the inhibition of high glucose-induced CM proliferation through regulation of Rhob.

Proteome profiling of early gestational plasma reveals novel biomarkers of congenital heart disease.

Prenatal diagnosis of congenital heart disease (CHD) relies primarily on fetal echocardiography conducted at mid-gestational age-the sensitivity of which varies among centers and practitioners. An objective method for early diagnosis is needed. Here, we conducted a case-control study recruiting 103 pregnant women with healthy offspring and 104 cases with CHD offspring, including VSD (42/104), ASD (20/104), and other CHD phenotypes. Plasma was collected during the first trimester and proteomic analysis was performed. Principal component analysis revealed considerable differences between the controls and the CHDs. Among the significantly altered proteins, 25 upregulated proteins in CHDs were enriched in amino acid metabolism, extracellular matrix receptor, and actin skeleton regulation, whereas 49 downregulated proteins were enriched in carbohydrate metabolism, cardiac muscle contraction, and cardiomyopathy. The machine learning model reached an area under the curve of 0.964 and was highly accurate in recognizing CHDs. This study provides a highly valuable proteomics resource to better recognize the cause of CHD and has developed a reliable objective method for the early recognition of CHD, facilitating early intervention and better prognosis.

miR-136 Regulates the Proliferation and Adipogenic Differentiation of Adipose-Derived Stromal Vascular Fractions by Targeting HSD17B12.

Fat deposition involves the continuous differentiation of adipocytes and lipid accumulation. Studies have shown that microRNA miR-136 and 17ß-hydroxysteroid dehydrogenase type 12 (HSD17B12) play important roles in lipid accumulation. However, the regulatory mechanism through which miR-136 targets HSD17B12 during ovine adipogenesis remains unclear. This study aimed to elucidate the role of miR-136 and HSD17B12 in adipogenesis and their relationship in ovine adipose-derived stromal vascular fractions (SVFs). The target relationship between miR-136 and HSD17B12 was predicted and confirmed using bioinformatics and a dual-luciferase reporter assay. The results showed that miR-136 promoted proliferation and inhibited adipogenic differentiation of ovine SVFs. We also found that HSD17B12 inhibited proliferation and promoted adipogenic differentiation of ovine SVFs. Collectively, our results indicate that miR-136 facilitates proliferation and attenuates adipogenic differentiation of ovine SVFs by targeting HSD17B12. These findings provide a theoretical foundation for further elucidation of the regulatory mechanisms of lipid deposition in sheep.

Noninvasive Characterization of Metabolic Changes in Ischemic Stroke Using Z-spectrum-fitted Multiparametric Chemical Exchange Saturation Transfer-weighted Magnetic Resonance Imaging.

OBJECTIVE: This study aimed to noninvasively characterize the metabolic alterations in ischemic brain tissues using Z-spectrum-fitted multiparametric chemical exchange saturation transfer-weighted magnetic resonance imaging (CEST-MRI). METHODS: Three sets of Z-spectrum data with saturation power (B1) values of 1.5, 2.5, and 3.5 µT, respectively, were acquired from 17 patients with ischemic stroke. Multiple contrasts contributing to the Z-spectrum, including fitted amide proton transfer (APTfitted), +2 ppm peak (CEST@2ppm), concomitantly fitted APTfitted and CEST@2ppm (APT&CEST@2ppm), semisolid magnetization transfer contrast (MT), aliphatic nuclear Overhauser effect (NOE), and direct saturation of water (DSW), were fitted with 4 and 5 Lorentzian functions, respectively. The CEST metrics were compared between ischemic lesions and contralateral normal white matter (CNWM), and the correlation between the CEST metrics and the apparent diffusion coefficient (ADC) was assessed. The differences in the Z-spectrum metrics under varied B1 values were also investigated. RESULTS: Ischemic lesions showed increased APTfitted, CEST@2ppm, APT&CEST@2ppm, NOE, and DSW as well as decreased MT. APT&CEST@2ppm, MT, and DSW showed a significant correlation with ADC [APT&CEST@2ppm at the 3 B1 values: R=0.584/0.467/0.551; MT at the 3 B1 values: R=-0.717/-0.695/-0.762 (4-parameter fitting), R=-0.734/-0.711/-0.785 (5-parameter fitting); DSW of 4-/5-parameter fitting: R=0.794/0.811 (2.5 µT), R=0.800/0.790 (3.5 µT)]. However, the asymmetric analysis of amide proton transfer (APTasym) could not differentiate the lesions from CNWM and showed no correlation with ADC. Furthermore, the Z-spectrum contrasts varied with B1. CONCLUSION: The Z-spectrum-fitted multiparametric CEST-MRI can comprehensively detect metabolic alterations in ischemic brain tissues.

Detection of CYFRA 21-1 in human serum by an electrochemical immunosensor based on UiO-66-NH2@CMWCNTs and CS@AuNPs.

In this study, an electrochemical immunosensor was constructed to detect the cytokeratin 19 fragment antigen 21-1 (CYFRA 21-1) in human serum. CYFRA 21-1 is the most sensitive tumor marker of non-small cell lung cancer (NSCLC), its content in normal human serum should be less than 3.3 ng/mL. When lung cancer cells dissolve or die, a myriad of CYFRA 21-1 is released into a tumor patient's blood circulation, and its serum content elevates strikingly. Consequently, detecting CYFRA 21-1 by an electrochemical biosensor is expected to provide a new method for the early detection and prevention of lung cancer. In this study, a composite of UiO-66-NH2 and carboxylated multi-walled carbon nanotubes (CMWCNTs) was used as the substrate material of a sensor; the resulting sensor had a large specific surface area and strong electrical conductivity. Moreover, gold nanoparticles (AuNPs) were used to bind to antibodies through an Au-S bonds. Also, a supersensitive detection of CYFRA 21-1 was achieved through the specific bindings of antigens and antibodies. Under optimal detection conditions, the change of current signal intensity of the immunosensor was proportional to the logarithm of CYFRA 21-1 concentration and had a linear relation in the range of 0.005-400 ng/mL, while the detection limit was 1.15 pg/mL (S/N = 3). The proposed immunosensor had high precision, stability, and selectivity. More importantly, the sensor was been successfully applied to detect CYFRA 21-1 in human serum with high recovery, providing a new method for early screening and dynamic monitoring of lung cancer.

Insights into the in vitro digestibility of pork myofibrillar protein with different ionic polysaccharides from the perspective of gel characteristics.

In this work, the simulated gastrointestinal digestion of myofibrillar protein gels (MPGs) with anionic xanthan (XMP) and sodium alginate (SMP)/cationic chitosan (CSMP)/neutral curdlan (CMP) and konjac (KMP) was investigated to develop muscle-gelled foods with good qualities before and after eating. The results indicated that the neutral CMP and KMP groups had higher gel strength and protein digestibility than the CSMP group. Xanthan and sodium alginate facilitated myosin degradation in gastrointestinal digestion because of the weak wraps between protein and anionic polysaccharides, gaining plentiful peptides (1790 and 1692 respectively) with molecular weights below 2000 Da. Chitosan and neutral curdlan could improve the strength of MP gel but inhibited proteolysis and resulted in low contents of released amino acids via the strong cross-linked network blocking trypsin contact. This work provides a theoretical basis for developing low-fat meat products with good qualities and digestion behaviors by simply controlling the ionic types of polysaccharides.

A scientometrics and visualization analysis of oxidative stress modulator Nrf2 in cancer profiles its characteristics and reveals its association with immune response.

Background: Nrf2, an essential and fascinating transcription factor, enjoys a dual property in the occurrence and development of inflammation and cancer. For over two decades, numerous studies regarding Nrf2 in cancer have been reported, whereas there is still a lack of a scientometrics and visualization analysis of Nrf2 in cancer. Hence, a scientometric study regarding the oxidative stress modulator Nrf2 was implemented. Methods: After the quality screening, we defined 7168 relevant studies from 2000 to 2021. CiteSpace, VOSviewer, R software, and GraphPad Prism were used for the following scientometric study and visualization analysis, including field profiles, research hotspots, and future predictions. Results: The total number of publications and citations are 1058 and 54,690, respectively. After polynomial fitting curve analysis, two prediction functions of the annual publication number (y = 3.3909x2 - 13585x + 1 E+07) and citation number (185.45x2 - 743669x + 7 E+08) were generated. After scientometric analysis, we found that Biochemistry Molecular Biology correlates with Nrf2 in cancer highly, and Free Radical Biology and Medicine is a good choice for submitting Nrf2-related manuscripts. The current research hotspots of Nrf2 in cancer mainly focus on cancer therapy and its cellular and molecular mechanisms. "antioxidant response element (87.5)", "gene expression (43.98)", "antioxidant responsive element (21.14)", "chemoprevention (20.05)", "carcinogenesis (19.2)", "cancer chemoprevention (18.45)", "free radical (17.15)", "response element (14.17)", and "chemopreventive agent (14.04)" are important for cancer therapy study. In addition, "glutathione-S-transferase (47)", "keap1 (15.39)", and "heme oxygenase 1 gene (24.35)" are important for inflammation and cell fate study. More interestingly, by performing an "InfoMap" algorithm, the thematic map showed that the "immune response" is essential to oxidative stress modulator Nrf2 but not well developed, indicating it deserves further exploration. Conclusion: This study revealed field profiles, research hotspots, and future directions of oxidative stress modulator Nrf2 in inflammation and cancer research, and our findings will offer a vigorous roadmap for further studies in this field.

[Mechanism of Sijunzi Decoction in treatment of Alzheimer's disease based on UPLC-Q-TOF-MS, network pharmacology, and experimental verification].

The study identified the blood-entering components of Sijunzi Decoction after gavage administration in rats by UPLC-Q-TOF-MS/MS, and investigated the mechanism of Sijunzi Decoction in treating Alzheimer's disease by virtue of network pharmacology, molecular docking, and experimental verification. The blood-entering components of Sijunzi Decoction were identified based on the mass spectra and data from literature and databases. The potential targets of the above-mentioned blood-entering components in the treatment of Alzheimer's disease were searched against PharmMapper, OMIM, DisGeNET, GeneCards, and TTD. Next, STRING was employed to establish a protein-protein interaction(PPI) network. DAVID was used to perform the Gene Ontology(GO) annotation and the Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment. Cytoscape 3.9.0 was used to carry out visual analysis. AutoDock Vina and PyMOL were used for molecular docking of the blood-entering components with the potential targets. Finally, the phosphatidylinositol 3-kinase(PI3K)/protein kinase B(Akt) signaling pathway enriched by the KEGG analysis was selected for validation by animal experiments. The results showed that 17 blood-entering components were detected in the serum samples after administration. Among them, poricoic acid B, liquiritigenin, atractylenolide Ⅱ, atractylenolide Ⅲ, ginsenoside Rb_1, and glycyrrhizic acid were the key components of Sijunzi Decoction in treating Alzheimer's disease. HSP90AA1, PPARA, SRC, AR, and ESR1 were the main targets for Sijunzi Decoction to treat Alzheimer's disease. Molecular docking showed that the components bound well with the targets. Therefore, we hypothesized that the mechanism of Sijunzi Decoction in treating Alzheimer's disease may be associated with the PI3K/Akt, cancer treatment, and mitogen-activated protein kinase(MAPK) signaling pathways. The results of animal experiments showed that Sijunzi Decoction significantly attenuated the neuronal damage in the hippocampal dentate gyrus area, increased the neurons, and raised the ratios of p-Akt/Akt and p-PI3K/PI3K in the hippocampus of mice. In conclusion, Sijunzi Decoction may treat Alzheimer's disease by activating the PI3K/Akt signaling pathway. The findings of this study provide a reference for further studies about the mechanism of action and clinical application of Sijunzi Decoction.

Nuclear ATR lysine-tyrosylation protects against heart failure by activating DNA damage response.

Dysregulated amino acid increases the risk for heart failure (HF) via unclear mechanisms. Here, we find that increased plasma tyrosine and phenylalanine levels are associated with HF. Increasing tyrosine or phenylalanine by high-tyrosine or high-phenylalanine chow feeding exacerbates HF phenotypes in transverse aortic constriction and isoproterenol infusion mice models. Knocking down phenylalanine dehydrogenase abolishes the effect of phenylalanine, indicating that phenylalanine functions by converting to tyrosine. Mechanistically, tyrosyl-tRNA synthetase (YARS) binds to ataxia telangiectasia and Rad3-related gene (ATR), catalyzes lysine tyrosylation (K-Tyr) of ATR, and activates the DNA damage response (DDR) in the nucleus. Increased tyrosine inhibits the nuclear localization of YARS, inhibits the ATR-mediated DDR, accumulates DNA damage, and elevates cardiomyocyte apoptosis. Enhancing ATR K-Tyr by overexpressing YARS, restricting tyrosine, or supplementing tyrosinol, a structural analog of tyrosine, promotes YARS nuclear localization and alleviates HF in mice. Our findings implicate facilitating YARS nuclear translocation as a potential preventive and/or interfering measure against HF.

Folic acid protects against age-associated apoptosis and telomere attrition of neural stem cells in senescence-accelerated mouse prone 8.

Folic acid (FA) could improve cognitive performance and attenuate brain cell injury in the aging brain; FA supplementation is also associated with inhibiting neural stem cell (NSC) apoptosis. However, its role in age-associated telomere attrition remains unclear. We hypothesized that FA supplementation attenuates age-associated apoptosis of NSCs in mice via alleviating telomere attrition in senescence-accelerated mouse prone 8 (SAMP8). In this study, 4-month-old male SAMP8 mice were assigned equal numbers to four different diet groups (n = 15). Fifteen age-matched senescence-accelerated mouse resistant 1 mice, fed with the FA-normal diet, were used as the standard aging control group. After FA treatment for 6 months, all mice were sacrificed. NSC apoptosis, proliferation, oxidative damage, and telomere length were evaluated by immunofluorescence and Q-fluorescent in situ hybridization. The results showed that FA supplementation inhibited age-associated NSC apoptosis and prevented telomere attrition in the cerebral cortex of SAMP8 mice. Importantly, this effect might be explained by the decreased levels of oxidative damage. In conclusion, we demonstrate it may be one of the mechanisms by which FA inhibits age-associated NSC apoptosis by alleviating telomere length shortening.

Proteogenomic characterization of cholangiocarcinoma.

BACKGROUND AND AIMS: Cholangiocarcinoma (CCA) is a highly heterogeneous cancer with limited understanding and few effective therapeutic approaches. We aimed at providing a proteogenomic CCA characterization to inform biological processes and treatment vulnerabilities. APPROACH AND RESULTS: Integrative genomic analysis with functional validation uncovered biological perturbations downstream of driver events including DPCR1 , RBM47 mutations, SH3BGRL2 copy number alterations, and FGFR2 fusions in CCA. Proteomic clustering identified three subtypes with distinct clinical outcomes, molecular features, and potential therapeutics. Phosphoproteomics characterized targetable kinases in CCA, suggesting strategies for effective treatment with CDK and MAPK inhibitors. Patients with CCA with HBV infection showed increased antigen processing and presentation (APC) and T cell infiltration, conferring a favorable prognosis compared with those without HBV infection. The characterization of extrahepatic CCA recommended the feasible application of vascular endothelial-derived growth factor inhibitors. Multiomics profiling presented distinctive molecular characteristics of the large bile duct and the small bile duct of intrahepatic CCA. The immune landscape further revealed diverse tumor immune microenvironments, suggesting immune subtypes C1 and C5 might benefit from immune checkpoint therapy. TCN1 was identified as a potential CCA prognostic biomarker, promoting cell growth by enhancing vitamin B12 metabolism. CONCLUSIONS: We characterized the proteogenomic landscape of 217 CCAs with 197 paired normal adjacent tissues and identified their subtypes and potential therapeutic targets. The multiomics analyses with other databases and some functional validations have indicated strategies regarding the clinical, biological, and therapeutic approaches to the management of CCA.

Value of whole-body dynamic 18F-FMISO PET/CT Patlak multi-parameter imaging for evaluating the early radiosensitizing effect of oleanolic acid on C6 rat gliomas.

The purpose of this study was to investigate the value of tumour-to-muscle (T/M) ratios and Patlak Ki images extracted from whole-body dynamic 18F-fluoromisonidazole (FMISO) PET/CT Patlak multi-parameter imaging for evaluating the early radiosensitizing effect of oleanolic acid (OA). Twenty-four rats with C6 gliomas were divided into 4 groups and treated with OA (group B), radiotherapy (group C), both (group D) or neither (group A). Whole-body dynamic 18F-FMISO PET/CT scans were performed for 120 min before treatment and 24 h following the treatment course. The tumour samples were dissected for hematoxylin and eosin staining, and HIF-1α, Ki-67 and GLUT-1 immunohistochemical staining. PET images were analysed using kinetic modelling (Patlak Ki) and static analysis (T/M ratios), and correlated with immunohistochemical results. The changes in T/M ratios, Ki values and tumour volume before treatment and 24 h following the treatment course were compared, and the survival time of tumour-bearing rats was recorded. Kaplan-Meier analysis showed that OA combined with radiotherapy can inhibit tumour growth and prolong the survival time of tumour-bearing rats. Whole-body dynamic 18F-FMISO PET/CT showed that the Ki values in group D were significantly lower than those in group C, whilst there was no significant difference in T/M ratios between groups C and D. The Pearson correlation coefficient analysis showed that Ki values were significantly related to immunohistochemical results. Our study suggests that Patlak Ki images may add value to PET/CT static images for evaluating the early radio-sensitizing effect of OA.

Prevalence of diabetic retinopathy in patients with newly diagnosed type 2 diabetes: A systematic review and meta-analysis.

AIMS: Type 2 diabetes mellitus (T2DM) can remain undiagnosed for many years, during which micro- and macro-vascular complications may develop. This study aimed to assess the worldwide prevalence of diabetic retinopathy (DR) in patients with newly diagnosed T2DM. MATERIALS AND METHODS: We systematically searched electronic databases for relevant studies published from inception to 01 January 2022. Selected studies reported the prevalence of DR among patients with newly diagnosed T2DM, specifying the case definition used. Random-effects meta-analysis was used to derive the pooled prevalence. Subgroup and meta-regression analyses were used to investigate variations in the prevalence estimates in terms of available variables. RESULTS: Data from 77 studies including 99,847 patients with newly diagnosed T2DM were included from 26 countries. The pooled prevalence of DR among patients with newly diagnosed T2DM was 13.1% (95% CI, 11.1%-15.1%; I2  = 97.0%). DR was higher in clinic-based samples compared with community-based samples (15.0%, 95% CI = 12.4%-17.8% vs. 11.5%, 95% CI = 8.9%-14.5%; p = 0.05; I2  = 97.0%) and was higher in countries in the WHO African 19.2% (95% CI, 14.6%-24.3%; I2  = 76.0%), South-East Asia 15.4% (95% CI, 10.0%-21.6%; I2  = 79.1%), and European 15.0% (95% CI, 11.2%-19.2%; I2  = 82.0%) regions. A higher proportion of female patients was significantly associated with a lower prevalence of DR in patients with newly diagnosed T2DM. We observed that the prevalence of DR in patients with newly diagnosed T2DM has remained unchanged over time. CONCLUSIONS: Globally, DR is a prevalent complication among patients with newly diagnosed T2DM indicating the importance of establishing effective strategies to promote regular screening for the early diagnosis of T2DM alongside routine ophthalmic assessment at the time of T2DM diagnosis to reduce the burden of vision-threatening retinopathy.

AKR1C3-dependent lipid droplet formation confers hepatocellular carcinoma cell adaptability to targeted therapy.

Rationale: Increased lipid droplet (LD) formation has been linked to tumor metastasis, stemness, and chemoresistance in various types of cancer. Here, we revealed that LD formation is critical for the adaptation to sorafenib in hepatocellular carcinoma (HCC) cells. We aim to investigate the LD function and its regulatory mechanisms in HCC. Methods: The key proteins responsible for LD formation were screened by both metabolomics and proteomics in sorafenib-resistant HCC cells and further validated by immunoblotting and immunofluorescence staining. Biological function of AKR1C3 was evaluated by CRISPR/Cas9-based gene editing. Isotopic tracing analysis with deuterium3-labeled palmitate or carbon13-labeled glucose was conducted to investigate fatty acid (FA) and glucose carbon flux. Seahorse analysis was performed to assess the glycolytic flux and mitochondrial function. Selective AKR1C3 inhibitors were used to evaluate the effect of AKR1C3 inhibition on HCC tumor growth and induction of autophagy. Results: We found that long-term sorafenib treatment impairs fatty acid oxidation (FAO), leading to LD accumulation in HCC cells. Using multi-omics analysis in cultured HCC cells, we identified that aldo-keto reductase AKR1C3 is responsible for LD accumulation in HCC. Genetic loss of AKR1C3 fully depletes LD contents, navigating FA flux to phospholipids, sphingolipids, and mitochondria. Furthermore, we found that AKR1C3-dependent LD accumulation is required for mitigating sorafenib-induced mitochondrial lipotoxicity and dysfunction. Pharmacologic inhibition of AKR1C3 activity instantly induces autophagy-dependent LD catabolism, resulting in mitochondrial fission and apoptosis in sorafenib-resistant HCC clones. Notably, manipulation of AKR1C3 expression is sufficient to drive the metabolic switch between FAO and glycolysis. Conclusions: Our findings revealed that AKR1C3-dependent LD formation is critical for the adaptation to sorafenib in HCC through regulating lipid and energy homeostasis. AKR1C3-dependent LD accumulation protects HCC cells from sorafenib-induced mitochondrial lipotoxicity by regulating lipophagy. Targeting AKR1C3 might be a promising therapeutic strategy for HCC tumors.

Effect of Mealworm Powder Substitution on the Properties of High-Gluten Wheat Dough and Bread Based on Different Baking Methods.

Mealworms (Tenebrio molitor) are protein-rich edible insects that have been regarded as novel food ingredients. In this study, high-gluten wheat flour was formulated with dried mealworm powder at various levels (0%, 5%, 10%, 15%, and 20%) to study its influence on the pasting, farinograph, and extensograph properties and microstructure of the dough. A subsequent decrease in the pasting parameters was observed due to starch dilution. The water absorption, dough development time, and dough stability time decreased gradually from 71.9% to 68.67%, 13.6 min to 10.43 min, and 14.1 min to 5.33 min, respectively, with the increase in the substitution of mealworm powder from 0% to 20%. The farinograph characteristics corresponded to a weak gluten network formed through the dilution of gluten by the replacement of wheat flour with a non-gluten ingredient. The stretch ratio of the high-gluten dough increased gradually from 4.37 (M0) to 6.33 (M15). The increased stretching resistance and extensibility of the dough with 5% and 10% mealworm powder indicated that mealworm powder can act as a plasticizer in the gluten network, which might contribute to the decreased strength and increased elasticity and flexibility of the dough network. The bread made with three different baking methods showed similar increases in specific volume and decreased hardness up to the 10% substitution level, owing to the increased elasticity and flexibility of the dough. The GB/T 35869-2018 Rapid-baking method, GB/T 14611-2008 Straight dough method, and automatic bread maker method exhibited the highest specific volumes of 3.70 mL/g, 3.79 mL/g, and 4.14 mL/g when the wheat flour was substituted with 10% mealworm powder. However, 15% and 20% mealworm powder substitution markedly reduced the bread quality owing to the dilution effect and mealworm powder phase separation. These results provide a perspective on the relationship between the rheological properties of mealworm powder-substituted high-gluten dough and application suggestions for insect food development in the food industry.

Inference of pan-cancer related genes by orthologs matching based on enhanced LSTM model.

Many disease-related genes have been found to be associated with cancer diagnosis, which is useful for understanding the pathophysiology of cancer, generating targeted drugs, and developing new diagnostic and treatment techniques. With the development of the pan-cancer project and the ongoing expansion of sequencing technology, many scientists are focusing on mining common genes from The Cancer Genome Atlas (TCGA) across various cancer types. In this study, we attempted to infer pan-cancer associated genes by examining the microbial model organism Saccharomyces Cerevisiae (Yeast) by homology matching, which was motivated by the benefits of reverse genetics. First, a background network of protein-protein interactions and a pathogenic gene set involving several cancer types in humans and yeast were created. The homology between the human gene and yeast gene was then discovered by homology matching, and its interaction sub-network was obtained. This was undertaken following the principle that the homologous genes of the common ancestor may have similarities in expression. Then, using bidirectional long short-term memory (BiLSTM) in combination with adaptive integration of heterogeneous information, we further explored the topological characteristics of the yeast protein interaction network and presented a node representation score to evaluate the node ability in graphs. Finally, homologous mapping for human genes matched the important genes identified by ensemble classifiers for yeast, which may be thought of as genes connected to all types of cancer. One way to assess the performance of the BiLSTM model is through experiments on the database. On the other hand, enrichment analysis, survival analysis, and other outcomes can be used to confirm the biological importance of the prediction results. You may access the whole experimental protocols and programs at https://github.com/zhuyuan-cug/AI-BiLSTM/tree/master.

The predictive accuracy of preoperative erythrocyte count and maximum tumor diameter to maximum kidney diameter ratio in renal cell carcinoma.

Background: The purpose of this study was to investigate the predictive accuracy of erythrocyte count and maximum tumor diameter to maximum kidney diameter ratio (TKR) in patients with renal cell carcinoma (RCC). Methods: We retrospectively analyzed the clinicopathological epidemiological characteristics of patients with RCC in the First Hospital of Shanxi Medical University from 2010 to 2014. Among them, 295 cases with complete follow-up data at the time of visit were selected. We collected data including erythrocyte counts and length of each diameter line of the tumor and kidney. To predict the prognosis of RCC, receiver operating characteristic (ROC) curve analysis was used to calculate the cutoff value of each parameter. Results: Of the 295 included patients, 199 (67.5%) were male, 96 (32.5%) were female, and the mean (± SD) age was 56.45±11.03 years. The area under the curve (AUC) of the erythrocyte count and the TKR for predicting the prognosis of RCC were 0.672 (SD 0.031; P<0.001) and 0.800 (SD 0.030; P<0.001), respectively. When the cutoff value of the erythrocyte count and TKR count were 3.975 and 0.452, the highest Youden index values were 0.309 and 0.685, and the corresponding sensitivity and specificity were 0.826 and 0.685, and 0.483 and 1.000, respectively. Conclusions: An erythrocyte count <3.975×1012/L and a TKR >0.452 were found to be risk factors for poor prognosis in patients with RCC.