Immune checkpoint inhibitor-associated new-onset hypophysitis: a retrospective analysis using the FAERS.

BACKGROUND: Our study aimed to investigate the prevalence and demographic characteristics of immune checkpoint inhibitor-associated hypophysitis (ICI-hypophysitis) using data from the FAERS, and the risk factors of prognosis were explored. METHODS: In this retrospective study, all cases of newly-diagnosed hypophysitis associated with FDA approved ICIs from 1st January 2007 to 31st December 2022 were accumulated using FAERS. Demographic data including age, sex, body weight, the prognosis of cases, and other co-occurred endocrinopathies induced by ICIs were analyzed and compared between different subgroups of immunotherapy. RESULTS: The reporting frequency of ICI-hypophysitis was 1.46% (2343/160089). Patients on the combination therapy had higher risk of hypophysitis reporting, followed by anti-CTLA-4 agent compared with other monotherapies (p < 0.001). Male subjects displayed higher reporting risk of ICI-hypophysitis (p = 0.015). Patients on anti-PD-1 therapy or the combination therapy showed higher occurrence rate of type 1 diabetes (anti-PD-1 vs. anti-PD-L1 vs. anti-CTLA-4 vs. combination therapy, 4.2% vs. 0.7% vs. 0.3% vs. 8.4%, p < 0.001). The occurrence rate of new-onset thyroid diseases in patients receiving combination therapy was higher than anti-PD-1 monotherapy (12.3% vs. 8.4%, p = 0.010). Elder age, lung cancer, and renal cancer emerged to be positively associated with severe clinical outcomes [>65 years, OR 1.042, 95%CI (1.022-1.063), p < 0.001; lung cancer, OR 1.400, 95%CI (1.019-1.923), p = 0.038; renal cancer, OR 1.667, 95%CI (1.153-2.412), p = 0.007]. Anti-CTLA-4 monotherapy was discovered to be a protective factor of severe outcomes [OR 0.433, 95%CI (0.335-0.558), p < 0.001]. Female sex and co-occurrence of ICI-related diabetes exhibited lower risk of death [female, OR 0.571, 95%CI (0.361-0.903), p = 0.017; diabetes, OR 0.090, 95%CI (0.016-0.524), p = 0.007]. CONCLUSIONS: ICI-induced hypophysitis is male-predominant irAE, most commonly seen in patients on anti-CTLA-4 mono- or combination therapy. Awareness among clinicians is critical when patients with elder age, lung or renal cancer develop hypophysitis, which indicates poor clinical outcomes. Female sex, anti-CTLA-4 monotherapy and co-occurrence of ICI-related diabetes are protective risk factors for poor prognosis.

Comparisons of pharmacokinetics and tissue distribution of six major bioactive components of the herbal pair Alpinia officinarum-Cyperus rotundus in normal and primary dysmenorrhea rats.

The Liangfu formula, as described in 'Liangfang Jiye', is well-known for its efficacy in treating stomach pain, abdominal pain, and dysmenorrhea. This research aimed to investigate the pharmacokinetics and tissue distribution of 5-hydroxy-7-(4-hydroxy-3-methoxyphenyl)-1-phenyl-3-heptanone (DPHA), Galangin, Kaempferide, 5-Hydroxy-1,7-diphenyl-3-heptanone (DPHC), α-Cyperone, and Nootkatone in vivo using an LC-MS/MS method. The method successfully separated the six active components and internal standards (Chrysin and Yakuchinone-A) on an XB-C18 column with a mobile phase of 0.2 ‰ formic acid water-acetonitrile. It demonstrated good linearity with a correlation coefficient (r2) ≥ 0.9911 and a lower limit of quantification (LLOQ) of 5-80 ng/mL for the different components. Precision, accuracy, matrix effects, and recovery rates were within acceptable ranges. Pharmacokinetic analysis revealed significant differences in parameters between primary dysmenorrhea (PD) and normal rats (especially AUC, Tmax, and CLz/F). Tissue distribution showed that the six active components of the herbal pair Alpinia officinarum Hance-Cyperus rotundus L. (HPAC) extract was primarily distributed in the liver, lung, and kidney. This study offers valuable insights into the potential mechanisms of action and drug development for treating PD.

Kaempferol from Alpinia officinarum hance induces G2/M cell cycle arrest in hepatocellular carcinoma cells by regulating the ATM/CHEK2/KNL1 pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Alpinia officinarum Hance (A. officinarum), a perennial herb known for its medicinal properties, has been used to treat various ailments, such as stomach pain, abdominal pain, emesis, and digestive system cancers. A. officinarum is extensively cultivated in the Qiongzhong and Baisha regions of Hainan, and it holds substantial therapeutic value for the local Li people of Hainan. Kaempferol, a flavonoid derived from A. officinarum, has demonstrated anticancer properties in various experimental and biological studies. Nevertheless, the precise mechanisms through which it exerts its anti-hepatocellular carcinoma (HCC) effects remain to be comprehensively delineated. AIM OF THE STUDY: This investigation aims to elucidate the anti-HCC effects of kaempferol derived from A. officinarum and to delve into its underlying mechanistic pathways. MATERIALS AND METHODS: Using ultra-high performance liquid chromatography-mass spectrometry/mass spectrometry (UPLC-MS/MS) to identify active compounds in A. officinarum. HCCLM3 and Huh7 cells were used to study the anti-HCC effect of kaempferol from A. officinarum. The cytotoxicity and proliferation of kaempferol and A. officinarum were measured using CCK-8 and EDU staining. Wound-healing assays and three-dimensional tumor spheroid models were further used to evaluate migration and the anti-HCC activity of kaempferol. The cell cycle and apoptosis were evaluated by flow cytometry. Western blot and qRT-PCR were used to detect the expression of proteins and genes associated with the cell cycle checkpoints. Finally, bioinformatics was used to analyze the relationship between the differential expression of core targets in the ATM/CHEK2/KNL1 pathway and a poor prognosis in clinical HCC samples. RESULTS: UPLC-MS/MS was employed to detect five active compounds in A. officinarum, such as kaempferol. The CCK-8 and EDU assays showed that kaempferol and A. officinarum significantly inhibited the proliferation of HCC cells. A wound-healing assay revealed that kaempferol remarkably inhibited the migration of HCC cells. Kaempferol significantly suppressed the growth of tumor spheroids. In addition, kaempferol markedly induced G2/M arrest and promoted apoptosis of HCC cells. Mechanically, kaempferol significantly reduced the protein and mRNA expression levels of ATM, CHEK2, CDC25C, CDK1, CCNB1, MPS1, KNL1, and Bub1. Additionally, the combination of kaempferol and the ATM inhibitor KU55933 had a more significant anti-HCC effect. The results of bioinformatics showed that ATM, CHEK2, CDC25C, CDK1, and KNL1 were highly expressed in patients with HCC and cancer tissues, indicating that these genes have certain value in the clinical diagnosis of HCC. CONCLUSIONS: Collectively, our results revealed that kaempferol from A. officinarum inhibits the cell cycle by regulating the ATM/CHEK2/KNL1 pathway in HCC cells. In summary, our research presents an innovative supplementary strategy for HCC treatment.

Integrating network pharmacology, bioinformatics, and experimental validation to unveil the molecular targets and mechanisms of galangin for treating hepatocellular carcinoma.

BACKGROUND: Galangin, a flavonoid compound, is derived from Alpinia officinarum Hance. Previous studies have shown that galangin can inhibit the proliferation of hepatocellular carcinoma (HCC), but its mechanism is still unclear. This study aims to investigate the potential targets and molecular mechanisms of galangin on HCC through network pharmacology, bioinformatics, molecular docking, and experimental in vitro validation. METHODS: In this study, network pharmacology was used to investigate the targets and mechanisms of galangin in the treatment of HCC. AutoDockTools software was used to simulate and calculate the binding of galangin to its core targets. GO and KEGG enrichment analyses were conducted in the DAVID database to explore the main biological functions and signaling pathways impacted by galangin intervention. In addition, bioinformatics was applied to examine the correlation between the differential expressions of the anti-HCC core targets of galangin and the survival of patients with HCC. Finally, the findings obtained from network pharmacology and bioinformatics were verified in cell experiments. RESULTS: A total of 67 overlapping target genes of galangin and HCC were identified. Through the analysis of the protein-protein interaction (PPI) network, 10 hub genes with the highest degree of freedom were identified, including SRC, ESR1, MMP9, CDK4, CCNB1, MMP2, CDK2, CDK1, CHK1, and PLK1. These genes were found to be closely related to the degradation of the extracellular matrix, signal transduction, and the cell cycle. GO and KEGG enrichment analyses revealed that galangin exerts an anti-HCC role by affecting various signaling pathways, including the cell cycle, pathways in cancer, and the PI3K-Akt signaling pathway. The results of molecular docking indicated a significant interaction between galangin and CCNB1, CDK4, CDK1, and PLK1. Bioinformatics analysis revealed that CCNB1, CDK4, CDK1, and PLK1 were upregulated in the liver of patients with HCC at both the mRNA and protein levels. Flow cytometry analysis showed that galangin induced G0/G1 phase arrest and cell apoptosis in HepG2 and Huh7 cells. Additionally, galangin suppressed the expression of key proteins and mRNAs involved in the cell cycle pathway. CONCLUSIONS: These results suggest that galangin inhibits the growth of HCC cells by arresting the cell cycle at the G0/G1 phase.

TRPV3 facilitates lipolysis and attenuates diet-induced obesity via activation of the NRF2/FSP1 signaling axis.

Transient receptor potential vanilloid (TRPV) ion channels play a crucial role in various cellular functions by regulating intracellular Ca2+ levels and have been extensively studied in the context of several metabolic diseases. However, the regulatory effects of TRPV3 in obesity and lipolysis are not well understood. In this study, utilizing a TRPV3 gain-of-function mouse model (TRPV3G568V/G568V), we assessed the metabolic phenotype of both TRPV3G568V/G568V mice and their control littermates, which were randomly assigned to either a 12-week high-fat diet or a control diet. We investigated the potential mechanisms underlying the role of TRPV3 in restraining obesity and promoting lipolysis both in vivo and in vitro. Our findings indicate that a high-fat diet led to significant obesity, characterized by increased epididymal and inguinal white adipose tissue weight and higher fat mass. However, the gain-of-function mutation in TRPV3 appeared to counteract these adverse effects by enhancing lipolysis in visceral fat through the upregulation of the major lipolytic enzyme, adipocyte triglyceride lipase (ATGL). In vitro experiments using carvacrol, a TRPV3 agonist, demonstrated the promotion of lipolysis and antioxidation in 3T3-L1 adipocytes after TRPV3 activation. Notably, carvacrol failed to stimulate Ca2+ influx, lipolysis, and antioxidation in 3T3-L1 adipocytes treated with BAPTA-AM, a cell-permeable calcium chelator. Our results revealed that TRPV3 activation induced the action of transcriptional factor nuclear factor erythroid 2-related factor 2 (NRF2), resulting in increased expression of ferroptosis suppressor protein 1 (FSP1) and superoxide dismutase2 (SOD2). Moreover, the inhibition of NRF2 impeded carvacrol-induced lipolysis and antioxidation in 3T3-L1 adipocytes, with downregulation of ATGL, FSP1, and SOD2. In summary, our study suggests that TRPV3 promotes visceral fat lipolysis and inhibits diet-induced obesity through the activation of the NRF2/FSP1 signaling axis. We propose that TRPV3 may be a potential therapeutic target in the treatment of obesity.

Diversity analysis of sea anemone peptide toxins in different tissues of Heteractis crispa based on transcriptomics.

Peptide toxins found in sea anemones venom have diverse properties that make them important research subjects in the fields of pharmacology, neuroscience and biotechnology. This study used high-throughput sequencing technology to systematically analyze the venom components of the tentacles, column, and mesenterial filaments of sea anemone Heteractis crispa, revealing the diversity and complexity of sea anemone toxins in different tissues. A total of 1049 transcripts were identified and categorized into 60 families, of which 91.0% were proteins and 9.0% were peptides. Of those 1049 transcripts, 416, 291, and 307 putative proteins and peptide precursors were identified from tentacles, column, and mesenterial filaments respectively, while 428 were identified when the datasets were combined. Of these putative toxin sequences, 42 were detected in all three tissues, including 33 proteins and 9 peptides, with the majority of peptides being ShKT domain, ß-defensin, and Kunitz-type. In addition, this study applied bioinformatics approaches to predict the family classification, 3D structures, and functional annotation of these representative peptides, as well as the evolutionary relationships between peptides, laying the foundation for the next step of peptide pharmacological activity research.

Gestational diabetes mellitus is associated with greater incidence of dementia during long-term post-partum follow-up.

BACKGROUND: The impact of gestational diabetes mellitus (GDM) on incident dementia is unknown. Our aim was to evaluate the relationship between GDM and all-cause dementia and the mediating effects of chronic diseases on this relationship. METHODS: This prospective cohort study included women from the UK Biobank who were grouped based on GDM history. Multivariate Cox proportional hazard models were used to explore the associations between GDM and dementia. We further analysed the mediating effects of chronic diseases on this relationship and the interactions of covariates. RESULTS: A total of 1292 women with and 204,171 women without a history of GDM were included. During a median follow-up period of 45 years after first birth, 2921 women were diagnosed with dementia. Women with a GDM history had a 67% increased risk of incident dementia (hazard ratio 1.67, 95% confidence interval: 1.03-2.69) compared with those without a GDM history. According to mediation analyses, type 2 diabetes, coronary heart disease, chronic kidney disease and comorbidities (diagnosed with any two of the three diseases) explained 34.5%, 8.4%, 5.2% and 18.8% of the mediating effect on the relationship. Subgroup analyses revealed that physical activity modified the association between GDM history and dementia (p for interaction = 0.030). Among physically inactive women, GDM was significantly associated with incident dementia; however, this association was not observed among physically active women. CONCLUSIONS: A history of GDM was associated with a greater risk of incident dementia. Type 2 diabetes partially mediated this relationship. Strategies for dementia prevention might be considered for women with a history of GDM.

Physicochemical Characterization, Antioxidant and Anticancer Activity Evaluation of an Acidic Polysaccharide from Alpinia officinarum Hance.

AHP-3a, a triple-helix acidic polysaccharide isolated from Alpinia officinarum Hance, was evaluated for its anticancer and antioxidant activities. The physicochemical properties and structure of AHP-3a were investigated through gel permeation chromatography, scanning electron microscopy (SEM), Fourier transform infrared spectroscopy, and nuclear magnetic resonance (NMR) spectroscopy. The weight-average molecular weight of AHP-3a was 484 kDa, with the molar percentages of GalA, Gal, Ara, Xyl, Rha, Glc, GlcA, and Fuc being 35.4%, 21.4%, 16.9%, 11.8%, 8.9%, 3.1%, 2.0%, and 0.5%, respectively. Based on the results of the monosaccharide composition analysis, methylation analysis, and NMR spectroscopy, the main chain of AHP-3a was presumed to consist of (1→4)-α-D-GalpA and (1→2)-α-L-Rhap residues, which is a pectic polysaccharide with homogalacturonan (HG) and rhamnogalacturonan-I (RG-I) structural domains containing side chains. In addition, the results of the antioxidant activity assay revealed that the ability of AHP-3a to scavenge DPPH, ABTS, and OH free radicals increased with an increase in its concentration. Moreover, according to the results from the EdU, wound healing, and Transwell assays, AHP-3a can control the proliferation, migration, and invasion of HepG2 and Huh7 hepatocellular carcinoma cells without causing any damage to healthy cells. Thus, AHP-3a may be a natural antioxidant and anticancer component.

Synthesis and Hypoglycemic Effect of Insulin from the Venom of Sea Anemone Exaiptasia diaphana.

Sea anemone venom, abundant in protein and peptide toxins, serves primarily for predatory defense and competition. This study delves into the insulin-like peptides (ILPs) present in sea anemones, particularly focusing on their role in potentially inducing hypoglycemic shock in prey. We identified five distinct ILPs in Exaiptasia diaphana, exhibiting varied sequences. Among these, ILP-Ap04 was successfully synthesized using solid phase peptide synthesis (SPPS) to evaluate its hypoglycemic activity. When tested in zebrafish, ILP-Ap04 significantly reduced blood glucose levels in a model of diabetes induced by streptozotocin (STZ) and glucose, concurrently affecting the normal locomotor behavior of zebrafish larvae. Furthermore, molecular docking studies revealed ILP-Ap04's unique interaction with the human insulin receptor, characterized by a detailed hydrogen-bonding network, which supports a unique mechanism for its hypoglycemic effects. Our findings suggest that sea anemones have evolved sophisticated strategies to activate insulin receptors in vertebrates, providing innovative insights into the design of novel drugs for the treatment of diabetes.

The role of TRPV ion channels in adipocyte differentiation: What is the evidence?

Obesity is a complex disorder, and the incidence of obesity continues to rise at an alarming rate worldwide. In particular, the growing incidence of overweight and obesity in children is a major health concern. However, the underlying mechanisms of obesity remain unclear and the efficacy of several approaches for weight loss is limited. As an important calcium-permeable temperature-sensitive cation channel, transient receptor potential vanilloid (TRPV) ion channels directly participate in thermo-, mechano-, and chemosensory responses. Modulation of TRPV ion channel activity can alter the physiological function of the ion channel, leading to neurodegenerative diseases, chronic pain, cancer, and skin disorders. In recent years, increasing studies have demonstrated that TRPV ion channels are abundantly expressed in metabolic organs, including the liver, adipose tissue, skeletal muscle, pancreas, and central nervous system, which has been implicated in various metabolic diseases, including obesity and diabetes mellitus. In addition, as an important process for the pathophysiology of adipocyte metabolism, adipocyte differentiation plays a critical role in obesity. In this review, we focus on the role of TRPV ion channels in adipocyte differentiation to broaden the ideas for prevention and control strategies for obesity.

Copper(II)-infused porphyrin MOF: maximum scavenging GSH for enhanced photodynamic disruption of bacterial biofilm.

Bacterial biofilm infection is a serious obstacle to clinical therapeutics. Photodynamic therapy (PDT) plays a dynamic role in combating biofilm infection by utilizing reactive oxygen species (ROS)-induced bacterial oxidation injury, showing advantages of mild side effects, spatiotemporal controllability and little drug resistance. However, superfluous glutathione (GSH) present in biofilm and bacteria corporately reduces ROS levels and seriously affects PDT efficiency. Herein, we have constructed a Cu2+-infused porphyrin metal-organic framework (MOF@Cu2+) for the enhanced photodynamic combating of biofilm infection by the maximum depletion of GSH. Our results show that the released Cu2+ from porphyrin MOF@Cu2+ could not only oxidize GSH in biofilm but also consume GSH leaked from ROS-destroyed bacteria, thus greatly weakening the antioxidant system in biofilm and bacteria and dramatically improving the ROS levels. As expected, our dual-enhanced PDT nanoplatform exhibits a strong biofilm eradication ability both in vitro and in an in vivo biofilm-infected mouse model. In addition, Cu2+ can promote biofilm-infected wound closing by provoking cell immigration, collagen sediment and angiogenesis. Besides, no apparent toxicity was detected after treatment with MOF@Cu2+. Overall, our design offers a new paradigm for photodynamic combating biofilm infection.

A. officinarum Hance - P. cablin (Blanco) Benth drug pair improves oxidative stress, intracellular Ca2+ concentrations and apoptosis by inhibiting the AGE/RAGE axis to ameliorate diabetic gastroparesis: In vitro and in vivo studies.

ETHNOPHARMACOLOGICAL RELEVANCE: Alpinia officinarum Hance is a perennial natural medicine herbivorous plant, has been used in the management of treat stomach pain and diabetes, it is abundantly cultivated in Qiongzhong, Baisha and other places. P. cablin (Blanco) Benth, one of the most important traditional Chinese plants, which plays functions in antioxidant and gastrointestinal regulation, has been extensively planted in Hainan, Guangdong and other regions. AIM OF THE STUDY: In this study, we investigated the role and underlying molecular mechanism of AP on diabetic gastroparesis (DGP) in vitro and in vivo. MATERIALS AND METHODS: In this study, using ultra-high performance liquid chromatography-mass spectrometry/mass spectrometry (UPLC-MS/MS) to identify active compounds in A. officinarum Hance-P. cablin (Blanco) Benth drug pair (AP). Molecular docking were utilized to explore the potential mechanism of AP treatment of DGP. In in vitro assays, gastric smooth muscle cells (GSMCs) were treated with 35 mM glucose to promote apoptosis and construct the DGP model, which was treated with different concentrations of AP. Furthermore, transfection technology was used to overexpress RAGE in GSMCs and elucidate the underlying mechanisms of alleviation of DGP by AP. RESULTS: Using UPLC-MS/MS analysis, nine components of AP were identified. We found that AP effectively blocked the increase in apoptosis, oxidative stress, and intracellular Ca2+ concentrations. For in vivo experiments, mice were fed with a high-fat irregular diet to construct DGP model, and AP was co-administered via oral gavage daily to prevent the development of DGP. Compared with DGP mice, AP significantly decreased fasting blood glucose levels and increased gastric emptying levels. Consistent with in vitro experiments, AP also considerably decreased the increase in oxidative stress in DGP mice. Mechanistically, AP alleviates apoptosis and DGP by decreasing oxidative stress and intracellular Ca2+ concentrations via the inhibition of the AGE/RAGE axis. CONCLUSIONS: Collectively, this study has established that AP can improve DGP, and the mechanism may be related to the inhibition the AGE/RAGE axis to mitigate apoptosis and DGP. To summarize, this study provides a novel supplementary strategy for DGP treatment.

Noninvasive detection of diabetes mellitus based on skin fluorescence and diffuse reflectance spectroscopy.

There is an urgent need for a mass population screening tool for diabetes. Skin tissue contains a large number of endogenous fluorophores and physiological parameter markers related to diabetes. We built an excitation-emission spectrum measurement system with the excited light sources of 365, 395, 415, 430, and 455 nm to extract skin characteristics. The modeling experiment was carried out to design and verify the accuracy of the recovery of tissue intrinsic discrete three-dimensional fluorescence spectrum. Blood oxygen modeling experiment results indicated the accuracy of the physiological parameter extraction algorithm based on the diffuse reflectance spectrum. A community population cohort study was carried out. The tissue-reduced scattering coefficient and scattering power of the diabetes were significantly higher than normal control groups. The Gaussian multi-peak fitting was performed on each excitation-emission spectrum of the subject. A total of 63 fluorescence features containing information such as Gaussian spectral curve intensity, central wavelength position, and variance were obtained from each person. Logistic regression was used to construct the diabetes screening model. The results showed that the area under the receiver operating characteristic curve of the model for predicting diabetes was 0.816, indicating a high diagnostic value. As a rapid and non-invasive detection method, it is expected to have high clinical value.

Alpinia officinarum Hance extract ameliorates diabetic gastroparesis by regulating SCF/c-kit signaling pathway and rebalancing gut microbiota.

Diabetic gastroparesis (DGP) is a common complication of type 2 diabetes mellitus (T2DM). Alpinia officinarum Hance (AOH) is one of the most commonly used both as a food and folk medicines, which is rich in diarylheptanoids and flavonoids. The gastroprotection and hypoglycemic effect make AOH has great potential in developing of anti-DGP complementary medicine. However, the molecular mechanisms of AOH that act against DGP are yet to be elucidated. In this study, we evaluated the therapeutic effects, the potential molecular mechanism, and the changes of gut microbiota of AOH in DGP. The 5 components of the AOH were analyzed, and the potential signaling pathway of AOH improving DGP was predicted by molecular docking. Subsequently, DGP rat model was constructed using high-fat-irregular-diet, AOH intervention significantly reduced blood glucose levels, increased gastrointestinal propulsion rate, and improved gastric histological morphology in DGP rats. Meanwhile, AOH has been shown to regulate the SCF/c-kit signaling pathway and rebalance the gut microbiota, which may be closely related to its role in improving DGP. Taken together, AOH may play a protective role on DGP through multiple mechanisms, which might pave the road for development and utilization of AOH.

Gut Microecology May Be Involved in the Pathogenesis of Hashimoto Thyroiditis by Reducing Production of Hydrogen Sulfide.

CONTEXT: Hashimoto thyroiditis (HT) is related to intestinal microbiota alteration, but the causal relationship remains unclear. Hydrogen sulfide (H2S) is a microbiota-derived metabolite. We speculated that abnormal intestinal microbiota might limit H2S production capacity, promoting HT pathogenesis. OBJECTIVE: This work aimed to illustrate that the intestinal microbiota plays important roles in HT pathogenesis via microbiota-derived H2S levels. METHODS: We collected feces from HT patients and healthy donors for fecal microbiota transplantation (FMT). Thirty-six female CBA/J mice were randomly assigned to 4 groups: experimental autoimmune thyroiditis (EAT) group, EAT + Healthy group, EAT + HT group, and EAT + HT + H2S group. 16S ribosomal RNA sequencing was performed to examine gut microbiota alterations and the H2S production pathway. Serum TgAb and H2S levels were assayed by enzyme-linked immunosorbent assay and H2S-selective sensors, respectively. T-cell subpopulations in the spleen were detected by flow cytometry. RESULTS: The gut microbiota was different after FMT among the EAT, EAT + Healthy, and EAT + HT groups. The thyroiditis score assessed by hematoxylin and eosin staining was higher in the EAT + HT group than that in the EAT and EAT + HT + H2S groups. Helper T (Th1) and Th17 cell differentiation ratios were increased in the EAT + HT group compared to the other 3 groups. Serum H2S levels were decreased and the dissimilatory sulfate reduction (DSR) pathway was attenuated in the EAT + HT group compared to the EAT + Healthy group. CONCLUSION: H2S alleviated thyroiditis severity and related immune disorders, which were aggravated by the FMT from HT patients. The attenuated DSR pathway in the gut microbiota from HT patients might be involved in thyroiditis pathogenesis.

A Minimized Measurement Scheme for Predicting HbA1c Using Discrete Self-Monitoring Blood Glucose Data Within 4 Weeks for People with Type 2 Diabetes.

Objective: To establish an accurate and robust calculation model for predicting hemoglobin A1c (HbA1c) for people with type 2 diabetes (T2D) by using the fewest discrete blood glucose values according to an irregular data set and propose an appropriate cost-effective and scientific scheme for routine blood glucose monitoring. Methods: By using two data sets obtained from 2017 to 2022, which involved 2432 people with T2D, ∼420,000 irregular blood glucose values, and 10,000 HbA1c values, multiple blood glucose monitoring schemes were designed and compared to find the optimal one. The data were structured and then fitted using a regularized extreme learning machine, and the results were evaluated on the basis of indicators such as mean absolute error (MAE), root mean square error, and the relevance analysis (R) value; the optimal scheme for routine blood glucose monitoring was determined by combining the accuracy and the cost and was compared with previous studies in terms of accuracy and stability. Results: Data fitting results for the chosen scheme: R = 0.8029 (P < 0.001), MAE = 0.3181% (95% confidence interval, 0.2666-0.3695%). Within the last 4 weeks before the prediction of HbA1c, a minimum of only seven fasting and seven postprandial blood glucose values are needed, of which are one fasting and one postprandial blood glucose values per 4 days. Compared with previous studies, the prediction model shows better accuracy and stability (P < 0.05), especially under the great glucose fluctuation group. Conclusion: A minimized calculation model for accurately and robustly predicting HbA1c using discrete self-monitoring of blood glucose data within 4 weeks for people with T2D has been established and provides a new reference for the design of a scheme for blood glucose monitoring. The diabetes care clinic of Peking University First Hospital (Registration Number: ChiCTR2300068139).

Quantification of Central and Eastern China's atmospheric CH4 enhancement changes and its contributions based on machine learning approach.

Methane is the second largest anthropogenic greenhouse gas, and changes in atmospheric methane concentrations can reflect the dynamic balance between its emissions and sinks. Therefore, the monitoring of CH4 concentration changes and the assessment of underlying driving factors can provide scientific basis for the government's policy making and evaluation. China is the world's largest emitter of anthropogenic methane. However, due to the lack of ground-based observation sites, little work has been done on the spatial-temporal variations for the past decades and influencing factors in China, especially for areas with high anthropogenic emissions as Central and Eastern China. Here to quantify atmospheric CH4 enhancements trends and its driving factors in Central and Eastern China, we combined the most up-to-date TROPOMI satellite-based column CH4 (xCH4) concentration from 2018 to 2022, anthropogenic and natural emissions, and a random forest-based machine learning approach, to simulate atmospheric xCH4 enhancements from 2001 to 2018. The results showed that (1) the random forest model was able to accurately establish the relationship between emission sources and xCH4 enhancement with a correlation coefficient (R²) of 0.89 and a root mean-square error (RMSE) of 11.98 ppb; (2)The xCH4 enhancement only increased from 48.21±2.02 ppb to 49.79±1.87 ppb from the year of 2001 to 2018, with a relative change of 3.27%±0.13%; (3) The simulation results showed that the energy activities and waste treatment were the main contributors to the increase in xCH4 enhancement, contributing 68.00% and 31.21%, respectively, and the decrease of animal ruminants contributed -6.70% of its enhancement trend.

Molecular cytogenetic identification and nutritional composition evaluation of newly synthesized Triticum turgidum-Triticum boeoticum amphiploids (AABBAbAb).

Triticum boeoticum Boiss. (AbAb, 2n = 2x = 14) is a wheat-related species with the blue aleurone trait. In this study, 18 synthetic Triticum turgidum-Triticum boeoticum amphiploids were identified, which were derived from crosses between T. boeoticum and T. turgidum. Three probes (Oligo-pTa535, Oligo-pSc119.2, and Oligo-pTa713) for multicolor fluorescence in situ hybridization (mc-FISH) were combined with genomic in situ hybridization (GISH) to identify chromosomal composition. Seven nutritional indices (anthocyanins, protein, total essential amino acids TEAA, Fe, Zn, Mn and Cu) were measured, and the nutritional components of 18 synthetic amphiploids were comprehensively ranked by principal component analysis (PCA). The results showed that all three synthetic amphiploids used for cytological identification contained 42 chromosomes, including 14 A, 14 B, and 14 Ab chromosomes. The average anthocyanin content was 82.830 µg/g to 207.606 µg/g in the whole meal of the 17 blue-grained lines (Syn-ABAb-1 to Syn-ABAb-17), which was obviously higher than that in the yellow-grained line Syn-ABAb-18 (6.346 µg/g). The crude protein content was between 154.406 and 180.517 g/kg, and the EAA content was 40.193-63.558 mg/g. The Fe, Zn, Mn and Cu levels in the 17 blue-grained lines were 60.55 to 97.41 mg/kg, 60.55-97.41 mg/kg, 35.11 to 65.20 mg/kg and 5.74 to 7.22 mg/kg, respectively, which were higher than those in the yellow-grained line. The contribution of the first three principal components reached 84%. The first principal component was mainly anthocyanins, Fe, Zn and Mn. The second principal component contained protein and amino acids, and the third component contained only Cu. The top 5 Triticum turgidum-Triticum boeoticum amphiploids were Syn-ABAb-11, Syn-ABAb-17, Syn-ABAb-5, Syn-ABAb-8 and Syn-ABAb-4. These amphidiploids exhibited the potential to serve as candidates for hybridization with common wheat, as indicated by comprehensive score rankings, toward enhancing the nutritional quality of wheat.

A Novel Risk Score Model for the Differential Diagnosis of Type 2 Diabetic Nephropathy: A Multicenter Study.

Introduction: DN is a common complication of diabetes. However, diabetes combined with renal injury may involve DN or NDKD, with different treatment schemes. The purpose of our study was to determine the independent risk factors of DN and establish a risk score model to help differentiate DN and NDKD, providing a reference for clinical treatment. Methods: A total of 678 T2D patients who had undergone renal biopsy in four affiliated hospitals of Peking University were consecutively enrolled. Patients were assigned to the DN group and NDKD group according to histopathological results. Seventy percent of patients from PKUFH were randomly assigned to the training group, and the remaining 30% were assigned to the internal validation group. Patients from the other three centers were assigned to the external validation group. We used univariate and multivariate logistic regression analyses to identify independent risk factors of DN in the training group and conducted multivariate logistic regression analysis with these independent risk factors in the training group to find regression coefficients "ß" to establish a risk score model. Finally, we conducted internal and external validation of the model with ROC curves. Results: Diabetic retinopathy, diabetes duration ≥ 5 years, eGFR < 30 ml/min/1.73 m2, 24 h UTP ≥ 3 g, and no hematuria were independent risk factors (P < 0.05), and each factor scored 2, 1, 1, 1, and 1. We assigned the patients to a low-risk group (0-1 points), a medium-risk group (2-3 points), and a high-risk group (4-6 points), representing unlikely DN, possibly DN, and a high probability of DN, respectively. The AUCs were 0.860, 0.924, and 0.855 for the training, internal validation, and external validation groups, respectively. Conclusion: The risk score model could help differentiate DN and NDKD in a noninvasive manner, reduce the number of renal biopsies, and provide a reference for clinical treatment.

Association Between Copper Intake and Migraine: a National Cross-sectional Study.

Migraine is a common clinical neurological disorder that adversely affects humans and society. The relationship between copper intake and migraine has been less studied and controversial. The purpose of this study was to determine the relationship between copper intake and migraine and to guide dietary interventions. The data for this study were obtained from the National Health and Nutrition Examination Survey (NHANES) database from 1999 to 2004, involving a total of 12,724 participants. The relationship between copper intake and migraine was examined using weighted multivariate logistic regression models, and smooth-fit curves were plotted to explore the relationship. After non-linear relationships were found, recursive algorithms and two-stage linear regression models were used to calculate inflection points. Stratified analyses were also performed to explore population differences. In the model corrected for all covariates, the OR (95% CI) of copper intake with migraine was 1.19 (0.97, 1.46), which was not statistically significant. However, the results of the linear trend test suggested that their relationship might be non-linear. Smooth-fit curves confirmed the non-linear relationship between copper intake and migraine, and an inflection point (0.98 mg/day) was identified. There was no statistical significance before the inflection point, but after the inflection point, copper intake was positively associated with migraine attacks. Stratified analyses showed that this non-linear relationship persisted in females, people under 45 years old, and people with BMI less than 30. In this large cross-sectional study, we found a non-linear correlation between copper intake and migraine.