Case report: A rare combination of aldosterone-secreting adrenocortical carcinoma and papillary thyroid carcinoma with Graves' disease.

Adrenocortical carcinoma (ACC) is a rare malignancy originating in the adrenal glands, aldosterone-producing ACC, even rarer. Papillary thyroid carcinoma (PTC), by contrast, accounts for the majority of thyroid carcinomas. We herein describe the first reported case of a female with comorbidities of aldosterone-producing ACC, PTC, and Graves' Disease(GD). The patient achieved transient clinical remission following adrenalectomy. However, three months later, aldosterone-producing ACC lung metastases emerged. Subsequently, within another three-month interval, she developed thyroid eye disease(TED). The patient died roughly one year after the adrenal operation. Exome sequencing did not reveal associations between aldosterone-producing ACC, PTC, and GD, and the underlying concurrence mechanism has yet to be elucidated. Further research of similar cases are needed to confirm potential links between the three pathologies.

Circulating microRNA-33b levels are associated with the presence and severity of coronary heart disease.

MicroRNA-33b (miR-33b) affected various biological pathways in regulating cholesterol homeostasis which may link to the pathogenesis of atherosclerotic lesions. However, whether this marker is associated with the presence and severity of coronary heart disease (CHD) is undetermined. We aim to explore the diagnostic value of circulating miR-33b level in the presence and severity of CHD. Altogether 320 patients were enrolled, including 240 patients diagnosed with CHD while 80 were classified as controls after CAG examination. Circulating miR-33b level was analyzed in all subjects, the Gensini score was calculated to assess the severity of stenotic lesions. The association between miR-33b and the presence and severity of CHD was analyzed, and the diagnostic potential of miR-33b of CHD was performed by the receiver operating characteristic (ROC) analysis. The CHD group had higher miR-33b levels (p < 0.001), and the miR-33b content significantly elevated following an increasing Gensini score (p for trend < 0.001). After adjustments for potential risk factors, such as several blood lipid markers, miR-33b remained a significant determinant for CHD (p < 0.001). ROC analysis disclosed that the AUC was 0.931. The optimal cutoff value of miR-33b was with a sensitivity of 81.3% and a specificity of 98.7% in differentiating CHD. It can prognosticate that the higher level of miR-33b was linked to increased severity of disease in CHD patients. Thus, the application of this marker might assist in the diagnosis and classification of CHD patients. Nevertheless, additional studies with larger sample sizes will be required to verify these results.

[Triptolide reduces neuronal damage in cerebral ischemia-reperfusion rats by promoting microglial M2 polarization].

Objective To investigate the effects of triptolide (TP) on microglial M1/M2 polarization after cerebral ischemia-reperfusion (I/R) injury in rats and the underlying molecular mechanism. Methods A rat model of middle cerebral artery occlusion (MCAO) was established. TP was administered to rats at doses of 0.1 and 0.2 mg/kg, with a sham surgery group as the control group. Longa scoring was performed to grade neurological deficits in rats; HE staining was used to observe the morphology of neurons in ischemic brain tissues; neuron-specific nuclear protein (NeuN) immunofluorescence staining was used to measure the number of neurons; and Western blot analysis was used to measure the expression levels of ionised calcium-binding adaptor molecule-1 (Iba1), inducible nitric oxide synthase (iNOS), arginase 1 (Arg1), Toll-like receptor 4 (TLR4), nuclear factor κB (NF-κB), NeuN and caspase-3 in ischemic-brain tissues. The protein levels of interleukin 1ß (IL-1ß) and IL-10 were measured by ELISA. Immunofluorescence double labelling was performed to detect the expression of Arg1 and TLR4 in microglia. Results Compared with the model group, the neurological score of the TP treatment group was significantly reduced and the neuronal damage was significantly alleviated. IL-1ß levels decreased while IL-10 levels increased. The expression levels of iNOS, TLR4, NF-κB and caspase-3 decreased, while the expression levels of Arg1 and NeuN increased. Conclusion TP treatment ameliorates cerebral I/R injury in rats, which may be attributed to the promotion of microglial M2 polarization, thereby reducing the release of inflammatory factors and inhibiting apoptosis.

Impact of Immune Cells on Stroke Limited to Specific Subtypes: Evidence from Mendelian Randomization Study.

INTRODUCTION: Stroke is one of the common diseases that pose a severe threat to human health, with immune cells playing a crucial role in its onset and recovery. However, the specific mechanisms and causal relationships of different immune cell groups in various clinical stroke subtypes are unclear. This study explored the causal relationship between immune cells and stroke and its subtypes using Mendelian randomization (MR) analysis. METHODS: Data from genome-wide association studies were analyzed using inverse-variance weighted (IVW), MR-Egger, and weighted median methods for MR analysis, along with heterogeneity tests, sensitivity analysis, and pleiotropy analysis. RESULTS: CD45RA+CD28-CD8+ T cell %T cell (OR 1.002, 95% CI 1.001-1.003; PFDR = 0.02), CD27 on CD24+CD27+ B cell (OR 1.127, 95% CI 1.061-1.198; PFDR = 0.04), CD27 on IgD-CD38dim B cell (OR 1.138, 95% CI 1.076-1.203; PFDR = 0.005), and CD27 on switched memory B cell (OR 1.144, 95% CI 1.076-1.216; PFDR = 0.01) were found to increase the risk of large artery stroke. Switched memory B cell %lymphocyte (OR 1.206, 95% CI 1.103-1.318; PFDR = 0.02) increased the risk of small vessel stroke. Reverse MR analysis did not reveal any reverse causal associations. Furthermore, by substituting the outcome data, a secondary MR analysis was conducted to validate the primary findings. CONCLUSION: Our study reveals several causal links between immune phenotypes and stroke and its different subtypes, highlighting the complex interactions between the immune system and stroke. These findings provide new directions for further uncovering the biological basis of stroke and assist in advancing research on early interventions and treatment strategies.

Proteomic analysis of milk fat globule membrane proteins in mature human milk of women with and without gestational diabetes mellitus.

Milk fat globule membrane proteins (MFGMP) in human milks have positive effects on infant's health. As gestational diabetes mellitus (GDM) causes variations in MFGMP, it is essential to understand the effects of GDMon MFGMP. This study aims to investigate and compare the MFGMP (>3 months postpartum) of GDM and non-GDM (NGDM) women using four-dimensional-data-independent-acquisition proteomics technology. Principal component analysis shows significant differences in the MFGMP of GDM and NGDM women. A total of 4747 MFGMP were identified in maturehuman milk of GDM and NGDM women. Among these proteins, 174 differentially expressed proteins (DEPs) were identified in MFGM of GDM and NGDM women. Albumin (FC = 7.96) and transthyretin (FC = 2.57) which are related to insulin resistance and involved in thyroid hormone synthesis, are significantly up-regulated in MFGMP of GDM mothers indicating insulin resistance, imbalance of glucose homeostasis and poor glucose metabolism might persist in postpartum period.

Photoinduced [3+2] Cycloaddition of Alkyl-Acceptor Diazoalkanes: Diversity-Oriented Synthesis of Pyrazolines Containing a Quaternary Center.

We present a new [3+2] cycloaddition reaction between alkyl-acceptor diazoalkanes under visible light irradiation. By employing easily accessible alkyl-acceptor-type diazoalkanes or their precursor hydrazones as both 1,3-dipoles and dipolarophiles, a diverse range of pyrazoline derivatives featuring a quaternary center have been efficiently synthesized in a predictable manner, with excellent functional group tolerance and good yields. Furthermore, scale-up experiments and downstream transformations of the product were also detailed.

Triptolide promotes nerve repair after cerebral ischemia reperfusion injury by regulating the NogoA/NgR/ROCK pathway.

Activation of the NogoA/NgR/ROCK pathway limits nerve repair after brain ischemia-reperfusion (I/R) injury. Triptolide displays anti-inflammatory, anti-oxidant, and immunosuppressive effects and is derived from the traditional Chinese medicine Tripterygium wilfordii Hook F. This agent can also penetrate the blood-brain barrier, where it has a neuroprotective effect and ameliorates cerebral I/R injury via an as yet unknown mechanism(s). Here, an animal model of middle cerebral artery occlusion and reperfusion (MCAO/R) was employed to assess triptolide's therapeutic impact on brain I/R injury and the possible mechanism of action. The results indicate that triptolide treatment can decrease cerebral infarction and nerve injury after cerebral I/R injury. Importantly, in vivo and in vitro experiments revealed that treatment with triptolide decreased NogoA, NgR, p75NTR and ROCK2 expression, and upregulated the expression of GAP43 and PSD-95, thus suggesting improved synaptic function. These results indicate that triptolide can promote nerve repair following brain I/R injury by inhibiting NogoA/NgR/ROCK signalling.

Contribution of body mass index, waist circumference, and 25-OH-D3 on the risk of pre-diabetes mellitus in the Chinese population.

This study aimed to investigate the associations between body mass index (BMI), waist circumference (WC), 25-hydroxy-vitamin D3 (25-OH-D3), and the risk of pre-diabetes mellitus (PDM), as well as their predictive values in identifying PDM. A total of 1688 participants were included in this cross-sectional investigation. Spearman's correlation analysis was used to assess the relationships between candidate indicators and PDM. The impact of indicators on PDM risk was determined by multivariate logistic regression. The receiver operating characteristic (ROC) analysis was performed to evaluate the prognostic value of indicators. Our study indicated a positive correlation between WC, BMI, and 25-OH-D3 and PDM. WC (OR = 1.05, 95% CI = 1.04-1.06, p < 0.001), BMI (OR = 1.11, 95% CI = 1.08-1.15, p < 0.001), and 25-OH-D3 (OR = 1.01, 95% CI = 1.00-1.02, p = 0.037) and an increased risk of PDM. Additionally, the ROC analysis demonstrated that WC (AUC = 0.651, Specificity = 55.00%, Sensitivity = 67.900%) had a higher diagnostic value for predicting PDM compared to the other variables (BMI, 25-OH-D3, TG, TC, LDL-C, HDL-C, and UA). A cut-off value of WC > 80.5 cm predicted PDM with both good sensitivity and specificity. Additionally, the cut-off value of waist circumference (WC) for men with prediabetes was 86.500, while for women with prediabetes, it was 76.500.

Carbon Quantum Dots/Cu2O Photocatalyst for Room Temperature Selective Oxidation of Benzyl Alcohol.

The luminescence properties and excellent carrier transfer ability of carbon quantum dots (CQDs) have attracted much attention in the field of photocatalysis. In this work, we loaded the CQDs on the surface of Cu2O to enhance the visible-light property of Cu2O. Furthermore, the composite was used for selective oxidation of benzyl alcohol to benzaldehyde. The composite catalyst achieved high selectivity (90%) for benzaldehyde at room temperature, leveraging its visible-light-induced electron transfer properties and its photocatalytic activity for hydrogen peroxide decomposition. ·OH was shown to be the main reactive oxygen species in the selective oxidation reaction of benzyl alcohol. The formation of heterostructures of CQDs/Cu2O promoted charge carrier separation and provided a fast channel for photoinduced electron transfer. This novel material exhibited enhanced levels of activity and stability for selective oxidation of benzyl alcohol. Potential applications of carbon quantum dot composites in conventional alcohol oxidation reactions are shown.

A genome-wide association study identifies 25(OH)D3-associated genetic variants in the prediabetic Chinese population.

OBJECTIVES: Diabetes mellitus has been a significant public health problem, associated with high rates of morbidity, disability, and mortality. Prediabetes is a crucial period for preventing and managing diabetes. 25(OH)D3 is an important risk factor for prediabetes. However, there is limited genetic knowledge of 25(OH)D3 in the Chinese population. This study was designed to identify genetic variants associated with 25(OH)D3 and explore the potential pathogenesis of prediabetes. METHODS: In this study, 451 individuals with prediabetes were recruited to determine the genetic variants associated with 25(OH)D3 through a genome-wide association study (GWAS). Gene mapping and overrepresentation analysis (ORA) were further performed to explore the candidate genes and their biological mechanisms. RESULTS: In this study, we identified two independent significant loci (rs9457733 and rs11243373, p < 5 × 10-6 and r2 < 0.6) and 37 candidate genes associated with 25(OH)D3 in prediabetes. Furthermore, the ORA analysis revealed that two genes in the gene sets, SLC22A1 and SLC22A3, were found to be significantly enriched in monoamine transmembrane transporter activity and quaternary ammonium group transmembrane transporter activity, as determined by WebGestalt and g:Profiler (padj < 0.05). CONCLUSION: The identification of potential genes associated with 25(OH)D3 provides a foundation for a better understanding of the pathogenesis, diagnosis, and treatment of prediabetes.

Design and synthesis of novel 3-amino-5-phenylpyrazole derivatives as tubulin polymerization inhibitors targeting the colchicine-binding site.

As the basic unit of microtubules, tubulin is one of the most important targets in the study of anticarcinogens. A novel series of 3-amino-5-phenylpyrazole derivatives were designed and synthesized, and evaluates for their biological activities. Among them, a majority of compounds exerted excellent inhibitory activities against five cancer cell lines in vitro. Especially, compound 5b showed a strong antiproliferative activity against MCF-7 cells, with IC50 value of 38.37 nM. Further research indicated that compound 5b can inhibit the polymerization of tubulin targeting the tubulin colchicine-binding sites. Furthermore, 5b could arrest MCF-7 cells at the G2/M phase and induce MCF-7 cells apoptotic in a dose-dependent and time-dependent manners, and regulate the level of related proteins expression. Besides, compound 5b could inhibit the cancer cell migration and angiogenesis. In addition, 5b could inhibit tumor growth in MCF-7 xenograft model without obvious toxicity. All these results indicating that 5b could be a promising antitumor agent targeting tubulin colchicine-binding site and it was worth further study.

Compound Kushen injection combined with transarterial chemoembolization for hepatocellular carcinoma: An evidence map and overview of systematic reviews.

ETHNOPHARMACOLOGICAL RELEVANCE: For the treatment of hepatocellular carcinoma (HCC), compound Kushen injection (CKi) is commonly used in combination with transarterial chemoembolization (TACE). AIMS OF THE STUDY: Our objective was to evaluate the reporting quality, methodological quality, risk of bias, and certainty of evidence for CKi combined with TACE for the treatment of patients with HCC by conducting systematic reviews (SRs). The purpose of this study was to improve the clinical application of CKis, strengthen clinical decision-making regarding CKis, and inform future research. MATERIALS AND METHODS: We used eight databases to systematically search SRs of CKi combined with TACE for HCC through February 21, 2023. The quality of reporting of SRs was evaluated using the 2009 Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, methodological quality using A MeaSurement Tool to Assess systematic Reviews 2, risk of bias using the Risk of Bias in Systematic Review, and certainty of evidence using the Grading of Recommendations Assessment. Finally, the assessment results were visualized by the evidence mapping method. This overview has been registered on PROSPERO with the registration title "Compound Kushen injection for hepatocellular carcinoma: An overview of systematic reviews" and registration number CRD42022369120. RESULTS: A total of 12 SRs meeting the inclusion criteria were included. In terms of reporting quality, 42% of SRs reported relatively complete reports and 58% had certain deficiencies. The methodological quality of all SRs was " critically low". The risk of bias was evaluated as low in 33% of SRs and high in 67% of SRs. The results of the evidence synthesis showed that, in the "moderate" level of evidence, CKi combined with TACE resulted in a 12.7%-21.5% benefit for one-year survival rate, 11.7%-17.2% benefit for objective response rate (ORR), 20.5%-27.1% benefit for quality of life, 22.2% benefit for nausea and vomiting, and 24.7%-27.4% benefit for leukopenia in HCC patients. CONCLUSION: In conclusion, CKi combined with TACE improved survival, ORR and quality of life in patients with HCC, and reduced adverse events. The results should be interpreted with caution due to the low methodological quality of the included SRs. The clinical efficacy of CKis must be confirmed in a large number of randomized controlled trials.

Enhanced stability and bioavailability of mulberry anthocyanins through the development of sodium caseinate-konjac glucomannan nanoparticles.

This study was carried out to improve the stability of anthocyanins (ACNs) by developing MA-SC-KGM nanoparticles using a self-assembly method that involved the combination of sodium caseinate (SC) and konjac glucomannan (KGM) with mulberry anthocyanin extract (MA). Atomic force microscopy (AFM) analysis showed SC encapsulated MA successfully. Multispectral techniques demonstrated the presence of hydrogen bonds and hydrophobic interactions in the nanoparticles. MA-SC-KGM ternary mixture improved storage stability, color stability and anthocyanin retention better compared to the MA-SC binary mixture. Notably, MA-SC-KGM nanoparticles significantly inhibited the thermal degradation of ACNs, improved pH stability, and showed stability and a slow-release effect in gastrointestinal digestion experiments. In addition, MA-SC-KGM nanoparticles were effective in scavenging DPPH· and ABTS+ free radicals, with enhanced stability and antioxidant capacity even during the heating process. This study successfully developed a novel MA-SC-KGM protein-polysaccharide composite material that effectively stabilized natural ACNs, expanding the application of ACNs in various industries.

Design, synthesis, and biological evaluation of harmine derivatives as topoisomerase I inhibitors for cancer treatment.

A series of ß-carboline derivatives were designed and synthesized by introducing the chalcone moiety into the harmine. The synthesized derivatives were evaluated their anti-proliferative activities against six human cancer cell lines (MCF-7, MDA-MB-231, HepG2, HT29, A549, and PC-3) and one normal cell line (L02). Among them, compound G11 exhibited the potent anti-proliferative activity against MCF-7 cell line, with an IC50 value of 0.34 µM. Further biological studies revealed that compound G11 inhibited colony formation of MCF-7 cells, suppressed MCF-7 cell migration by downregulating migration-associated protein MMP-2. In addition, it could induce apoptosis of MCF-7 cells by downregulating Bcl-2 and upregulating Cleaved-PARP, Bax, and phosphorylated Bim proteins. Furthermore, compound G11 can act as a Topo I inhibitor, affecting DNA synthesis and transcription, thereby inhibiting cancer cell proliferation. Moreover, compound G11 inhibited tumor growth in 4T1 syngeneic transplant mice with an inhibition rate of 43.19 % at a dose of 10 mg/kg, and 63.87 % at 20 mg/kg, without causing significant toxicity to the mice or their organs, achieving the goal of reduced toxicity and increased efficacy. All these results indicate of G11 has enormous potential as an anti-tumor agent and merits further investigation.

[Eriodictyol improves cognitive function in 5×FAD mice of Alzheimer's disease by inhibiting the microglia NLRP3 inflammasome signaling pathway].

Objective To investigate the therapeutic effects of eriodictyol on transgenic mice with five familial Alzheimer's disease (5×FAD) and the modulation of NOD-like receptor-pyrin domain containing 3 (NLRP3) inflammasome in microglia. Methods The 8-month-old 5×FAD mice were randomly divided into AD model group and eriodictyol-treated AD group. Same-aged wild-type C57BL/6J mice were randomly divided into wild-type (WT) control group and eriodictyol-treated WT group. Morris water maze and Y-maze experiments were performed to assess the cognitive function of each group of mice. Immunofluorescence histochemical staining was performed to detect the expression of NLRP3, caspase-1 and interleukin 18 (IL-18) in mouse brain tissue, and Western blot was performed to detect the protein levels of NLRP3, apoptosis-associated speckle-like protein containing a CARD (ASC), caspase-1, IL-18, IL-1ß and ion calcium-binding adaptor molecule 1 (Iba-1) in mouse brain tissue. Results Compared with the WT group and the eriodictyol-treated WT group, cognitive function was significantly impaired in the AD group mice, and the expression of NLRP3, caspase-1, IL-18, ASC, IL-1ß and Iba1 were increased in microglia of mouse brain tissue. After eriodictyol treatment, learning memory and cognitive function were improved, and the expression of NLRP3, ASC, caspase-1, IL-1ß, IL-18 and Iba1 were all down-regulated in the eriodictyol-treated AD group mice compared with the AD group mice. Conclusion Eriodictyol may improve cognitive function in animal models of AD by inhibiting the activation of the NLRP3 signaling pathway in microglia.

A genomic catalogue of soil microbiomes boosts mining of biodiversity and genetic resources.

Soil harbors a vast expanse of unidentified microbes, termed as microbial dark matter, presenting an untapped reservo)ir of microbial biodiversity and genetic resources, but has yet to be fully explored. In this study, we conduct a large-scale excavation of soil microbial dark matter by reconstructing 40,039 metagenome-assembled genome bins (the SMAG catalogue) from 3304 soil metagenomes. We identify 16,530 of 21,077 species-level genome bins (SGBs) as unknown SGBs (uSGBs), which expand archaeal and bacterial diversity across the tree of life. We also illustrate the pivotal role of uSGBs in augmenting soil microbiome's functional landscape and intra-species genome diversity, providing large proportions of the 43,169 biosynthetic gene clusters and 8545 CRISPR-Cas genes. Additionally, we determine that uSGBs contributed 84.6% of previously unexplored viral-host associations from the SMAG catalogue. The SMAG catalogue provides an useful genomic resource for further studies investigating soil microbial biodiversity and genetic resources.

Astragaloside IV inhibits experimental autoimmune encephalomyelitis by modulating the polarization of both microglia/macrophages and astrocytes.

Astragaloside IV (AST IV), a major saponin component and active ingredient isolated from Astragalus membranaceus, has been well known to exhibit neuroprotective effects on diverse models of neurological diseases. Accumulating evidence suggests that dynamic balance of microglia/macrophages and astrocytes plays a vital role in neuroprotection and remyelination. However, dysregulation of microglia/macrophages and astrocytes orchestrate the pathogenesis of nervous system disorders. Therefore, we hypothesized that switching the transformation of microglia/macrophages and astrocytes into the neuroprotective M2 and A2 phenotypes, respectively, could be a potential target for therapeutic intervention. In the present study, we evaluate the efficacy of AST IV intervention on the effects of microglia/macrophages and astrocytes in an experimental autoimmune encephalomyelitis (EAE) model. AST IV improved paralysis and pathology of EAE by inhibiting the neurotoxic M1 microglia/macrophage phenotype, promoting M2 phenotype, shifting astrocytes towards a neuroprotective A2 phenotype, and protecting neurons from apoptosis through inhibition of TLR4/Myd88/NF-kB signalling pathway. Our study showed that AST IV could be a potential and promising drug for multiple sclerosis treatment.

MRPS6 modulates glucose-stimulated insulin secretion in mouse islet cells through mitochondrial unfolded protein response.

Lack of efficient insulin secretion from the pancreas can lead to impaired glucose tolerance (IGT), prediabetes, and diabetes. We have previously identified two IGT-associated single nucleotide polymorphisms (SNPs) rs62212118 and rs13052524 located at two overlapping genes: MRPS6 and SLC5A3. In this study, we show that MRPS6 but not SLC5A3 regulates glucose-stimulated insulin secretion (GSIS) in primary human ß-cell and a mouse pancreatic insulinoma ß-cell line. Data mining and biochemical studies reveal that MRPS6 is positively regulated by the mitochondrial unfolded protein response (UPRmt), but feedback inhibits UPRmt. Disruption of such feedback by MRPS6 knockdown causes UPRmt hyperactivation in high glucose conditions, hence elevated ROS levels, increased apoptosis, and impaired GSIS. Conversely, MRPS6 overexpression reduces UPRmt, mitigates high glucose-induced ROS levels and apoptosis, and enhances GSIS in an ATF5-dependent manner. Consistently, UPRmt up-regulation or down-regulation by modulating ATF5 expression is sufficient to decrease or increase GSIS. The negative role of UPRmt in GSIS is further supported by analysis of public transcriptomic data from murine islets. In all, our studies identify MRPS6 and UPRmt as novel modulators of GSIS and apoptosis in ß-cells, contributing to our understanding of the molecular and cellular mechanisms of IGT, prediabetes, and diabetes.