The role of microbial metabolites in endocrine tumorigenesis: From the mechanistic insights to potential therapeutic biomarkers.

Microbial metabolites have been indicated to communicate with the host's endocrine system, regulating hormone production, immune-endocrine communications, and interactions along the gut-brain axis, eventually affecting the occurrence of endocrine cancer. Furthermore, microbiota metabolites such as short-chain fatty acids (SCFAs) have been found to affect the tumor microenvironment and boost immunity against tumors. SCFAs, including butyrate and acetate, have been demonstrated to exert anti-proliferative and anti-protective activity on pancreatic cancer cells. The employing of microbial metabolic products in conjunction with radiation and chemotherapy has shown promising outcomes in terms of reducing treatment side effects and boosting effectiveness. Certain metabolites, such as valerate and butyrate, have been made known to improve the efficiency of CAR T-cell treatment, whilst others, such as indole-derived tryptophan metabolites, have been shown to inhibit tumor immunity. This review explores the intricate interplay between microbial metabolites and endocrine tumorigenesis, spanning mechanistic insights to the discovery of potential therapeutic biomarkers.

The effect of green tea supplementation on the anthropometric outcomes in overweight and obese women: a time and dose-response meta-analysis of randomized controlled trials.

Inconsistencies are evident within the literature regarding the role of Green Tea (GT) supplementation on women living with obesity. To address this, we conducted to determine the impact of GT supplementation on the weight, body mass index (BMI), and waist circumference (WC) in overweight and obese women using time and dose-response meta-analysis of randomized controlled trials (RCTs). This meta-analysis searched electronic Scopus, Web of Science, Embase, and PubMed/Medline databases from inception to December 1st, 2022. Data were reported as weighted mean difference (WMD) with 95% confidence interval (CI). A total of 2061 references were identified, and 15 articles with 16 RCT arms on body weight, 17 RCT arms on BMI, and 7 RCT arms on WC were included in the meta-analysis. GT supplementation significantly decreases body weight (WMD: -1.23 kg, 95% CI: -2.13 to -0.33, p = 0.007), BMI (WMD: -0.47 kg/m2, 95% CI: -0.87 to -0.07, p = 0.020) and WC (WMD: -3.46 cm, 95% CI: -6.75 to -0.16, p = 0.040). In subgroup analyses, GT consumption demonstrated lowered body weight with dosaes ≥1000 mg/day (WMD: -1.38 kg), in the RCTs, which lasted ≥8 wk (WMD: -1.24 kg). The non-linear dose-response assessment detected a negative correlation between the changes in body weight and BMI in green tea consumption of more than 1000 (mg/day). The GT supplementation reduced the weight, BMI, and WC in overweight and obese women. In clinical practice, healthcare professionals can recommend using GT with dosages ≥ 1000mg/day and duration ≥ 8 wk in obese women.

A new model for the treatment of type 2 diabetes mellitus based on rhythm regulations under the framework of psychosomatic medicine: a real-world study.

We aimed to explore a new treatment model for type 2 diabetes mellitus (DM) based on rhythm regulation under the framework of psychosomatic medicine. Using psychotropics as rhythm regulators, 178 patients with DM were evaluated and divided into three groups: the antidiabetic treatment group (AT group), psychotropic treatment group (PT group), and combined antidiabetic + psychotropic treatment group (combined group), for a course of 16 weeks. The West China Psychiatry Association (WCPA) Somatic Symptom Classification Scale (SSCS) was used to evaluate each patient. The levels of hormones in the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-thyroid axes and of blood glucose and glycosylated hemoglobin (HbA1c) were evaluated both before and after treatment. After the treatment, the blood glucose and HbA1c levels in all three groups were lower than those at baseline. Furthermore, the incidence of the abnormal HPA axis in the PT group was significantly decreased (P = 0.003), while the incidence of the abnormal HPA axis in the combined group was 0.0%. The five factor scores of the SSCS in the PT and combined groups after treatment were both significantly low (P < 0.01). Both the incidence of abnormal neuroendocrine axes and SSCS scores in the AT group showed no significant difference before and after treatment. "Blood glucose control + rhythm regulation" should be considered as optimised treatment goals for DM. Moreover, some psychotropics could be used as biorhythm regulators, which have good potential value for clinical application.Clinical trial registration number: ChiCTR1800019064. Name of trial registration: Reinterpretation of mechanism and the optimization of treatment for non-infectious chronic diseases under the "stress-dysrhythmia" theory hypothesis. The full trial protocol can be accessed at the Chinese Clinical Trial Registry ( http://www.chictr.org.cn/ ).

Re-interpretation of the mechanism of type 2 diabetes mellitus based on a framework of psychosomatic medicine: a real-world study.

OBJECTIVE: Using bipolar disorder (BD) as a control, we explored the possible developmental process of impaired glucose metabolism rhythm. METHODS: In total, 441 subjects (77, 162, 134, 54, and 14 in the pre-diabetes [pre-DM], DM, BD, BD + pre-DM, and BD + DM groups, respectively) and 160 controls were included. All subjects were assessed using the Neuroticism Extraversion Openness Five-Factor Inventory (NEO-FFI). The hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-thyroid (HPT) axes were measured. RESULTS: Cluster analysis showed that the BD, BD + DM, and DM groups were classified as the 'disease group, the BD + pre-DM group as the 'mixed period group', and the pre-DM group as the 'pre-disease group'. The conscientiousness factor scores of the NEO-FFI in the 'disease group' were higher than the norm but lower than the norm in the 'pre-disease group'. The scores of neurotic factors in the 'pre-disease' and 'mixed period' groups were both significantly higher than that in the 'disease group' (corrected p < 0.001). The incidences of the abnormal HPA axis decreased gradually from the 'pre-disease group' to the 'mixed period group' then to the 'disease group', while those of the HPT axis slightly increased at first and then significantly decreased. The overall prediction rate of the multiple logistic regression model was 92.7%. CONCLUSION: This study suggests that progression of pre-diabetes to DM is a continuous process from local abnormalities to rhythm disorder of glucose metabolism. This understanding can be applied to the whole course management and early intervention of DM and to the future development of optimised treatment based on rhythm regulation. TRIAL REGISTRATION: Clinical trial registration number: ChiCTR1800019064. Name of trial registration: Identify and the optimization of treatment for non-infectious chronic diseases under the "stress-dysrhythmia" theory hypothesis (Registration date: 24/10/2018). The full trial protocol can be accessed at the Chinese Clinical Trial Registry ( http://www.chictr.org.cn/ ).

A panel of rhythm gene polymorphisms is involved in susceptibility to type 2 diabetes mellitus and bipolar disorder.

BACKGROUND: Biological rhythm is closely related to health. We aimed to identify the potential correlations of rhythm gene polymorphisms to type 2 diabetes mellitus (DM) or bipolar disorder (BD), which both have many abnormal rhythmic activities, in a sample of Chinese Han origin. METHODS: A total of 136 patients with BD, 166 patients with DM, and 130 healthy controls were collected. We screened 28 single nucleotide polymorphisms (SNPs) located in rhythm genes CLOCK, ARNTL, PER2, PER3, CRY1, and CRY2 respectively. Snapshot typing technology was used for genotyping. RESULTS: Both the rs10832022-G and rs11022765-A allele frequencies of the ARNTL gene were significantly higher in patients with DM than in those with BD (corrected P=0.03, 0.004, respectively). The frequency of rs10832022-G, rs1022765-A, and rs11022762-T haplotypes, which was significantly lower in patients with BD than in controls (P=0.003, OR =0.579), was significantly higher in patients with DM than in those with BD (P=0.0002, OR =1.878). The rs2292910-CC genotypic frequency of the CRY2 gene was significantly higher in patients with BD than in controls (OR of regression =2.203, P=0.01), while the frequency of the AA genotype was significantly lower than in patients with DM (P=0.01). The frequency of rs1972874-G and rs36124720-G haplotype of the PER2 gene was significantly higher in patients with DM than in controls (P=0.01, OR =1.577). CONCLUSIONS: Our study preliminarily suggested that both BD and type 2 DM could be considered as dysrhythmias with different rhythmic genetic backgrounds, which contribute to the early prediction of an individual's susceptibility to different rhythm disorders and early intervention.

Effects of purslane supplementation on C-reactive protein levels and biomarkers of oxidative stress as marks for metabolic syndrome: A systematic review and meta-analysis of randomized controlled trials.

The antioxidant and antiinflammatory properties of purslane (Portulaca oleracea L.) are known in preclinical studies but further examination is needed to expand their potential into the clinical scenario. A systematic review and meta-analysis of randomized controlled trials were performed to elucidate the effects of purslane supplementation on C-reactive protein (CRP) levels and biomarkers of oxidative stress in metabolic syndrome, its related complications, and other diseases. PubMed/MEDLINE, Web of Science, SCOPUS, and Embase were the databases searched. Heterogeneity was examined using the I-squared (I2 ) statistic, in which the source of heterogeneity was determined if the I2 -value was >50%. After all the screening processes, 10 studies met the eligibility criteria and were analyzed. Following purslane supplementation, CRP levels decreased significantly (weighted mean difference [WMD]: -0.33 mg/dl, 95% confidence interval [CI]: -0.66, -0.004, p = .047) but with significant heterogeneity (I2  = 87.4%, p = .001). Purslane supplementation did not significantly change serum levels of malondialdehyde (MDA) (WMD: -0.353 µm/L; 95% CI: -0.920, 0.213; I2  = 50.7%), total antioxidant capacity (TAC) (WMD: 0.090 mm/L, 95% CI: -0.081, 0.262; I2  = 47.1%), and superoxide dismutase (SOD) (WMD: 6.54 U/ml, 95% CI: -22.150, 35.236; I2  = 70.7%). Thus, this meta-analysis showed a positive effect of purslane supplementation as a tool to decrease CRP levels, but not to MDA, TAC, and SOD levels.

A novel homozygous nonsense mutation in the CA2 gene (c.368G>A, p.W123X) linked to carbonic anhydrase II deficiency syndrome in a Chinese family.

BACKGROUND: Carbonic anhydrase II deficiency syndrome is an autosomal recessive osteopetrosis with renal tubular acidosis and cerebral calcifications. We tried to detect the causative mutation for carbonic anhydrase II deficiency syndrome in a five-generation Chinese family. MATERIALS AND METHODS: Genomic DNA was extracted from whole blood of the proband, his grandmother, parents, aunt, uncle and sister. The exomes were sequenced by whole exon sequencing followed by genetic analysis and Sanger sequencing validation. Then, physical and chemical properties studies and structure analysis were performed on mutated protein. Finally, Minigene model of vector plasmids for wild type and mutant type was constructed and transfected into human embryonic kidney 293T cells to further explore the expression change of CA2 transcript and protein after mutation. RESULTS: Sequencing and genetic analysis have revealed the homozygous nonsense mutation of CA2 gene (c.368G > A, p.W123X) in the exon 4 of chromosome 8 of the proband, while it was not found in his grandmother, parents, aunt, uncle and sister. Furthermore, Sanger sequencing in the proband and his parents validated the mutation. Properties and structure of mutated CA2 proteins changed after mutation, especially in change of protein modification and hindrance of zinc ions binding, which may lead to decreased protein expression level of CA2. CONCLUSIONS: We found a new homozygous nonsense mutation in CA2 gene (c.368G > A, p.W123X), which may be valuable in the early diagnosis and therapy of carbonic anhydrase II deficiency syndrome.

Risk factors for multidrug-resistant bacterial infections in patients with diabetic foot ulcers: a systematic review and meta-analysis.

BACKGROUND: Diabetic foot ulcer (DFU) is one of the main causes of disability and death in diabetic patients, along with the continuous development of relevant research. The purpose of this paper is to study the risk factors of multidrug resistant organisms (MDROs) infection in patients with DFUs by meta-analysis. METHODS: We searched the PubMed, EMBASE, Cochrane library, and Web of Science databases for literature related to the risk factors of MDRO infection in patients with DFUs from the date of establishment of the database to September 2021. Duplicate studies were excluded using Endnote X9 software. Stata 15.1 software was used to meta-analyze the data. Random or fixed effects models were used to combine and analyze the odds ratio (OR) and 95% confidence interval (CI) of the included risk factors. Heterogeneity was analyzed by the Q and I2 tests. Egger's linear regression method was used to evaluate the publication bias of the included articles. Sensitivity analysis was used to analyze the source of heterogeneity. RESULTS: A total of 13 articles were included in the study. Meta-analysis was performed on 15 risk factors. Among them, hospital records before admission (OR =5.18, 95% CI: 1.45-18.51, P=0.011), antibiotic use before admission (OR =2.17, 95% CI: 1.24-3.79, P=0.006), diabetes type (OR =2.44, 95% CI: 1.29-4.64, P=0.006), ulcer type (OR =2.17, 95% CI: 1.06-4.41, P=0.033), ulcer size (OR =2.56, 95% CI: 1.53-4.28, P<0.001), osteomyelitis (OR =3.50, 95% CI: 2.37-5.16, P<0.001), vascular disease (OR =2.37, 95% CI: 1.41-3.99, P=0.001), surgical treatment (OR =4.80, 95% CI: 2.95-7.83, P<0.001), and these meta-analysis results were statistically different and could be considered as risk factors for MDRO infection. CONCLUSIONS: The risk factors of MDRO infection in DFU patients include hospitalization records before admission, antibiotic use before admission, type of diabetes, type of ulcer, size of ulcer, osteomyelitis, vascular lesions, and surgical treatment. This study contributes to the ability of the population of DFU patients infected with MDROs to receive timely treatment at an early stage and delay disease development.

The effects of astaxanthin supplementation on obesity, blood pressure, CRP, glycemic biomarkers, and lipid profile: A meta-analysis of randomized controlled trials.

BACKGROUND AND AIM: Previous studies lack consistent conclusions as to whether astaxanthin is actually linked to various health benefits as claimed. Here, we attempt to unravel the association of astaxanthin consumption with selected health benefits by performing a systematic review and meta-analysis. METHODS: Online literature search databases including Scopus, Web of Science, PubMed/Medline, Embase and Google Scholar were searched to discover relevant articles available up to 17 March 2020. We used mean changes and SD of the outcomes to assess treatment response from baseline and mean difference, and 95 % CI were calculated to combined data and assessment effect sizes in astaxanthin and control groups. RESULTS: 14 eligible articles were included in the final quantitative analysis. Current study revealed that astaxanthin consumption was not associated with FBS, HbA1c, TC, LDL-C, TG, BMI, BW, DBP, and SBP. We did observe an overall increase in HDL-C (WMD: 1.473 mg/dl, 95 % CI: 0.319-2.627, p = 0.012). As for the levels of CRP, only when astaxanthin was administered (i) for relatively long periods (≥ 12 weeks) (WMD: -0.528 mg/l, 95 % CI: -0.990 to -0.066), and (ii) at high dose (> 12 mg/day) (WMD: -0.389 mg/dl, 95 % CI: -0.596 to -0.183), the levels of CRP would decrease. CONCLUSION: In summary, our systematic review and meta-analysis revealed that astaxanthin consumption was associated with increase in HDL-C and decrease in CRP. Significant associations were not observed for other outcomes.

Effect of informatization-based blood glucose team management on the control of hyperglycaemia in noncritical care units.

PURPOSE: To provide a new system of in-hospital blood glucose team management combined with a network blood glucose monitoring system and analyse the effect on hyperglycaemic participants' blood glucose control in noncritical care units. METHODS: Hyperglycaemic participants in noncritical care units were divided into two groups. They underwent active intervention by the hospital's blood glucose management team or the routine consultation group. The better method, based on a shorter length of stay (LOS) and lower hospital cost, could be selected by comparing the two blood glucose management strategies. RESULTS: Compared with the routine consultation group, the team management group had a higher detection rate of hyperglycaemia (18.49% vs 16.17%, P<0.01) and glycosylated haemoglobin (51.53% vs 30.97%, P<0.01) and a lower incidence rate of hyperglycaemia (59.24% vs 61.59%, P<0.01), severe hyperglycaemia (3.56% vs 5.19%, P<0.01) and clinically significant hypoglycaemia (0.26% vs 0.35%, P<0.05). Simultaneously, blood glucose drift (mmol/L) (2.50 (1.83, 3.25) vs 2.76 (2.01, 3.57), P<0.01), blood glucose coefficient of variation (%) (28.86 (22.70, 34.83) vs 29.80 (23.47, 36.13), P<0.01), maximum blood glucose fluctuation (mmol/L) (9.30 (6.20, 13.10) vs 10.10 (7.00, 14.40), P<0.01) and nosocomial infection (5.42% vs 8.05%, P<0.05) were all lower among participants in the team management group. In addition, the LOS (P<0.001) and hospital costs (P<0.001) of participants were lower in the team management group. CONCLUSION: In-hospital blood glucose team management combined with a network blood glucose monitoring system effectively improved the blood glucose control and fluctuation levels of participants who were admitted to noncritical care units, thereby reducing LOS and hospital cost.

Transgenic Mice Overexpressing SREBP-1a in Male ob/ob Mice Exhibit Lipodystrophy and Exacerbate Insulin Resistance.

Sterol regulatory element-binding protein (SREBP)-1a is a key transcription factor that activates the expression of genes involved in the synthesis of fatty acids, triglycerides (TGs), and cholesterol. Transgenic mice that overexpress the nuclear form of SREBP-1a under the control of the phosphoenolpyruvate carboxykinase promoter (Tg-1a) were previously shown to display a lipodystrophic phenotype characterized by enlarged and fatty livers, diminished peripheral white adipose tissue (WAT), and insulin resistance. In the current study, we crossed these Tg-1a mice with genetically obese (ob/ob) mice (Tg-1a;ob/ob) and examined change in fat distribution between liver and adipose tissues in severe obesity and mechanism underlying the lipodystrophic phenotype in mice with Tg-1a. Tg-1a;ob/ob mice developed more severe steatohepatitis but had reduced WAT mass and body weight compared with ob/ob mice. The reduction of WAT mass in Tg-1a and Tg-1a;ob/ob mice was accompanied by enhanced lipogenesis and lipid uptake in the liver, reduced plasma lipid levels, impaired adipocyte differentiation, reduced food intake, enhanced energy expenditure, and extended macrophage infiltration and fibrosis in WAT. Despite the improved glucose tolerance, Tg-1a;ob/ob mice showed severe peripheral insulin resistance. Adenoviral hepatic expression of SREBP-1a mimicked these phenotypes. The "fat steal"-like lipodystrophy phenotype of the Tg-1a;ob/ob model demonstrates that hepatic SREBP-1a activation has a strong impact on the partition of TG accumulation, resulting in adipose-tissue remodeling by inflammation and fibrosis and insulin resistance.

Elovl6 Deficiency Improves Glycemic Control in Diabetic db/db Mice by Expanding ß-Cell Mass and Increasing Insulin Secretory Capacity.

Dysfunctional fatty acid (FA) metabolism plays an important role in the pathogenesis of ß-cell dysfunction and loss of ß-cell mass in type 2 diabetes (T2D). Elovl6 is a microsomal enzyme that is responsible for converting C16 saturated and monounsaturated FAs into C18 species. We previously showed that Elovl6 played a critical role in the development of obesity-induced insulin resistance by modifying FA composition. To further define its role in T2D development, we assessed the effects of Elovl6 deletion in leptin receptor-deficient C57BL/KsJ db/db mice, a model of T2D. The db/db;Elovl6-/- mice had a markedly increased ß-cell mass with increased proliferation and decreased apoptosis, an adaptive increase in insulin, and improved glycemic control. db/db islets were characterized by a prominent elevation of oleate (C18:1n-9), cell stress, and inflammation, which was completely suppressed by Elovl6 deletion. As a mechanistic ex vivo experiment, isolated islets from Elovl6-/- mice exhibited reduced susceptibility to palmitate-induced inflammation, endoplasmic reticulum stress, and ß-cell apoptosis. In contrast, oleate-treated islets resulted in impaired glucose-stimulated insulin secretion with suppressed related genes irrespective of the Elovl6 gene. Taken together, Elovl6 is a fundamental factor linking dysregulated lipid metabolism to ß-cell dysfunction, islet inflammation, and ß-cell apoptosis in T2D, highlighting oleate as the potential culprit of ß-cell lipotoxicity.

Ablation of Elovl6 protects pancreatic islets from high-fat diet-induced impairment of insulin secretion.

ELOVL family member 6, elongation of very long-chain fatty acids (Elovl6) is a microsomal enzyme that regulates the elongation of C12-16 saturated and monounsaturated fatty acids and is related to the development of obesity-induced insulin resistance via the modification of the fatty acid composition. In this study, we investigated the role of systemic Elovl6 in the pancreatic islet and ß-cell function. Elovl6 is expressed in both islets and ß-cell lines. In mice fed with chow, islets of the Elovl6(-/-) mice displayed normal architecture and ß-cell mass compared with those of the wild-type mice. However, when fed a high-fat, high-sucrose (HFHS) diet, the islet hypertrophy in response to insulin resistance observed in normal mice was attenuated and glucose-stimulated insulin secretion (GSIS) increased in the islets of Elovl6(-/-) mice compared with those of the wild-type mice. Enhanced GSIS in the HFHS Elovl6(-/-) islets was associated with an increased ATP/ADP ratio and the suppression of ATF-3 expression. Our findings suggest that Elovl6 could be involved in insulin secretory capacity per ß-cell and diabetes.