Pioglitazone use increases risk of Alzheimer's disease in patients with type 2 diabetes receiving insulin.

Pioglitazone is an insulin resistance inhibitor widely used as monotherapy or combined with metformin or insulin in treating type 2 diabetes mellitus (T2DM). This study further investigated the relationship between pioglitazone use and the risk of developing Alzheimer's disease (AD) in patients newly diagnosed with T2DM, and examined the potential impact of insulin use on this association. Data were extracted from the National Health Insurance Research Database (NHIRD) of Taiwan. Our data exhibited that the risk of developing AD in the pioglitazone group was 1.584-fold (aHR = 1.584, 95% CI 1.203-1.967, p < 0.05) higher than that in the non-pioglitazone controls. Compared to patients without both insulin and pioglitazone, higher cumulative risk of developing AD was found in patients receiving both insulin and pioglitazone (aHR = 2.004, 95% CI = 1.702-2.498), pioglitazone alone (aHR = 1.596, 95% CI = 1.398-1.803), and insulin alone (aHR = 1.365, 95% CI = 1.125-1.572), respectively (all p < 0.05). A similar observation also found in the evaluation the use of diabetic drugs with a cumulative defined daily dose (cDDD). No interaction between pioglitazone and major risk factors (comorbidities) of AD was observed. In conclusion, alternative drug therapies may be an effective strategy for reducing risk of developing AD in T2DM patients.

Inactivation of mitochondrial pyruvate carrier promotes NLRP3 inflammasome activation and gout development via metabolic reprogramming.

The nucleotide-binding and oligomerization domain, leucine-rich repeats, and pyrin domain-containing protein 3 (NLRP3) inflammasome plays a crucial role in innate immunity and is involved in the pathogenesis of autoinflammatory diseases. Glycolysis regulates NLRP3 inflammasome activation in macrophages. However, how lactic acid fermentation and pyruvate oxidation controlled by the mitochondrial pyruvate carrier (MPC) affect NLRP3 inflammasome activation and autoinflammatory disease remains elusive. We found that the inactivation of MPC with genetic depletion or pharmacological inhibitors, MSDC-0160 or pioglitazone, increased NLRP3 inflammasome activation and IL-1ß secretion in macrophages. Glycolytic reprogramming induced by MPC inhibition skewed mitochondrial ATP-associated oxygen consumption into cytosolic lactate production, which enhanced NLRP3 inflammasome activation in response to monosodium urate (MSU) crystals. As pioglitazone is an insulin sens MSDC-itizer used for diabetes, its MPC inhibitory effect in diabetic individuals was investigated. The results showed that MPC inhibition exacerbated MSU-induced peritonitis in diabetic mice and increased the risk of gout in patients with diabetes. Altogether, we found that glycolysis controlled by MPC regulated NLRP3 inflammasome activation and gout development. Accordingly, prescriptions for medications targeting MPC should consider the increased risk of NLRP3-related autoinflammatory diseases.

Association between trichomoniasis and prostate and bladder diseases: a population-based case-control study.

Trichomonas vaginalis infection is one of the most widespread sexually transmitted infections in the world. There are approximately 276 million cases worldwide. Most men remain undiagnosed and untreated because they are asymptomatic. The chronic inflammation induced by persistent infection may increase the risk of developing genitourinary cancers. In this study, we aimed to investigate the association between trichomoniasis and benign prostate hyperplasia (BPH), prostate cancer (PCa), and bladder cancer (BC) in Taiwan. We designed a case-control study by using the database of the National Health Insurance program in Taiwan. We used the International Classification of Diseases, 9th Revision classifications to classify all the medical conditions in the case and control groups. All odds ratios (ORs) and 95% confidence intervals (CIs) were analyzed using multivariable logistic regression to adjust for all comorbidities and variables. From 2000 to 2015, we enrolled a total of 62,544 individuals as the case group and 187,632 as the control group. Trichomoniasis exposure had a significant association with BPH and PCa (adjusted OR: BPH = 2.685, 95% CI = 1.233-4.286, P = 0.013; PCa = 5.801, 95% CI = 1.296-26.035, P = 0.016). The relative risk was much higher if patients had both trichomoniasis and depression (adjusted OR = 7.682, 95% CI = 5.730-9.451, P < 0.001). Men with trichomoniasis had a significantly higher risk of developing BPH and PCa than those without. Healthcare professionals should not only pay more attention to disease treatment, but also to public health education.

Trichomonas infection in pregnant women: a nationwide cohort study.

Trichomoniasis is the most prevalent sexually transmitted infection worldwide, and is associated with adverse pregnancy outcomes. However, Trichomonas vaginalis (TV) has received little public health attention, and only limited data are available on prevalence of TV and other Trichomonas-associated syndromes in pregnant women. This study aimed to determine associations between pregnancy and incident trichomoniasis-related diseases. Data of pregnant women were extracted from the National Health Insurance Research Database (NHIRD) of Taiwan. The pregnant cohort included 113,781 women, and cases were randomly matched by age, and index year with those of non-pregnant women (n = 113,781). Risk of incident trichomoniasis-related diseases was also not significantly different between pregnant and non-pregnant women. However, after stratifying by age or level of care, the younger subgroup among pregnant women had a higher risk of incident trichomoniasis-related diseases than did the younger subgroup in non-pregnant women, while the elder subgroup among pregnant women had a lower risk of incident trichomoniasis-related diseases than did the same subgroup in non-pregnant women (all p < 0.05). The higher level of care (medical center) subgroup among pregnant women had a lower risk of incident trichomoniasis-related diseases than did the same subgroup in non-pregnant women. In conclusions, although pregnancy is not significantly associated with risk of trichomoniasis-related diseases, data of the present study support an enhanced high level of medical care for pregnant women, emphasizing the potential of high medical care in reduced incidence of trichomoniasis-related diseases. This may be an effective strategy for reducing various pregnancy complications associated with trichomoniasis-related diseases.

Associations between Diabetes Mellitus and Nontuberculous Mycobacterium-Caused Diseases in Taiwan: A Nationwide Cohort Study.

Patients with diabetes mellitus (DM) are at greater risk of developing active tuberculosis and other intracellular bacterial infections, although the risk of acquiring infections from nontuberculous Mycobacterium (NTM) remains undefined. This study evaluated associations between DM and incidence of NTM infection-caused pulmonary and cutaneous diseases. Data for DM patients were extracted from the National Health Insurance Research Database of Taiwan. The DM cohort included 136,736 patients, and cases were matched randomly by age, gender, and index year with non-DM patients. Multivariate Cox proportional hazards regression was used to calculate adjusted hazard ratios of incident NTM-caused diseases in the DM cohort compared with non-DM control subjects. The frequency of incident NTM-caused diseases was significantly greater in DM patients (0.12%) than in non-DM patients (0.08%) (P < 0.05), including patients with type 1 DM (0.12%) and type 2 DM (0.12%) (all P < 0.05). Adjusted multivariate Cox regression analysis revealed that the incidence of NTM-caused diseases in DM patients was 1.43-fold greater than that in non-DM patients overall (P < 0.05), particularly in pulmonary (1.13-fold), other specific (excluding pulmonary, cutaneous, and disseminated diseases; 3.88-fold), and unspecific (atypical NTM infection; 1.54-fold) diseases (all P < 0.05). In conclusion, both type 1 DM and type 2 DM patients have high risk of NTM-caused diseases, suggesting that physicians need to pay more attention to this issue concerning the high risk of NTM-caused infection in DM patients.

Proteomic signatures of metronidazole-resistant Trichomonas vaginalis reveal novel proteins associated with drug resistance.

BACKGROUND: Trichomoniasis is the most common non-viral sexually transmitted disease caused by the protozoan parasite Trichomonas vaginalis. Metronidazole (MTZ) is a widely used drug for the treatment of trichomoniasis; however, increased resistance of the parasite to MTZ has emerged as a highly problematic public health issue. METHODS: We conducted iTRAQ-based analysis to profile the proteomes of MTZ-sensitive (MTZ-S) and MTZ-resistant (MTZ-R) parasites. STRING and gene set enrichment analysis (GESA) were utilized to explore the protein-protein interaction networks and enriched pathways of the differentially expressed proteins, respectively. Proteins potentially related to MTZ resistance were selected for functional validation. RESULTS: A total of 3123 proteins were identified from the MTZ-S and MTZ-R proteomes in response to drug treatment. Among the identified proteins, 304 proteins were differentially expressed in the MTZ-R proteome, including 228 upregulated and 76 downregulated proteins. GSEA showed that the amino acid-related metabolism, including arginine, proline, alanine, aspartate, and glutamate are the most upregulated pathways in the MTZ-R proteome, whereas oxidative phosphorylation is the most downregulated pathway. Ten proteins categorized into the gene set of oxidative phosphorylation were ATP synthase subunit-related proteins. Drug resistance was further examined in MTZ-S parasites pretreated with the ATP synthase inhibitors oligomycin and bafilomycin A1, showing enhanced MTZ resistance and potential roles of ATP synthase in drug susceptibility. CONCLUSIONS: We provide novel insights into previously unidentified proteins associated with MTZ resistance, paving the way for future development of new drugs against MTZ-refractory trichomoniasis.

The fabrication and preservation of nanostructures on silicon wafers with a native oxide layer.

This study used nano-oxidation lithography to create oxidized circular nanostructures on a silicon wafer with a native oxide layer (NOL). We also investigated the impact of wet etching on the size of circular oxidized nanostructures and examined how the method and duration of preservation affect them. Experimental results show that the height and width of oxidized circular nanostructures increase proportionally with applied voltage. After wet etching, an increase in applied voltage resulted in a marked increase in the width of the circular nanostructures, a decrease in the inner diameter, and little variation in height. We further demonstrated that in a moist environment, the oxidation process continues, resulting in a further increase in height and width. During the initial stages of preservation, these changes occurred rapidly; however, the increase was negligible after 30 days. We propose the concept of reaction area (RA) ratio to explain the above phenomenon and provide evidence to support these claims. Our results led us to a simple and yet effective method of preserving oxidized circular nanostructures, called the electrostatic patch preservation (EPP) method, to overcome problems associated with changes in size occurring during the preservation of silicon nanostructure molds.