Financial Benefits of Renal Dose-Adjusted Dipeptidyl Peptidase-4 Inhibitors for Patients with Type 2 Diabetes and Chronic Kidney Disease.

Background: Dipeptidyl peptidase-4 (DPP4) inhibitors are frequently prescribed for patients with type 2 diabetes; however, their cost can pose a significant barrier for those with impaired kidney function. This study aimed to estimate the economic benefits of substituting non-renal dose-adjusted (NRDA) DPP4 inhibitors with renal dose-adjusted (RDA) DPP4 inhibitors in patients with both impaired kidney function and type 2 diabetes. Methods: This retrospective cohort study was conducted from January 1, 2012 to December 31, 2018, using data obtained from common data models of five medical centers in Korea. Model 1 applied the prescription pattern of participants with preserved kidney function to those with impaired kidney function. In contrast, model 2 replaced all NRDA DPP4 inhibitors with RDA DPP4 inhibitors, adjusting the doses of RDA DPP4 inhibitors based on individual kidney function. The primary outcome was the cost difference between the two models. Results: In total, 67,964,996 prescription records were analyzed. NRDA DPP4 inhibitors were more frequently prescribed to patients with impaired kidney function than in those with preserved kidney function (25.7%, 51.3%, 64.3%, and 71.6% in patients with estimated glomerular filtration rates [eGFRs] of ≥60, <60, <45, and <30 mL/min/1.73 m2, respectively). When model 1 was applied, the cost savings per year were 7.6% for eGFR <60 mL/min/1.73 m2 and 30.4% for eGFR <30 mL/min/1.73 m2. According to model 2, 15.4% to 51.2% per year could be saved depending on kidney impairment severity. Conclusion: Adjusting the doses of RDA DPP4 inhibitors based on individual kidney function could alleviate the economic burden associated with medical expenses.

The impact of dipeptidyl peptidase 4 inhibitors on health-related quality of life in patients with type 2 diabetes mellitus: a systematic review and meta-analysis.

PURPOSE: To evaluate the impact of dipeptidyl peptidase 4 (DPP-4) inhibitors on Health-related quality of life (HRQOL) in patients with type 2 diabetes mellitus (T2DM) compared with other hypoglycemic agents. METHODS: A systematic review and meta-analysis based on randomized controlled trials was conducted following the Cochrane Handbook and PRISMA. Studies were identified by searching PubMed (MEDLINE), EMBASE, Web of Science, CNKI, WANGFANG DATA, VIP DATABASE, Google Scholar, and Cochrane Central Register of Controlled Trials from database inception to Dec 30, 2023. The main result was HRQOL scores. The outcomes were extracted using the mean difference (MD) from each study. Sensitivity analysis and subgroup analysis were also performed. RESULTS: Forty studies (4,579 participants) were included, with 32 pooled for meta-analysis. DPP-4 inhibitors alongside conventional treatment significantly enhanced HRQOL compared to conventional treatment alone (MD = 9.85, 95% CI [7.98-11.71], P < 0.001; heterogeneity, I2 = 94%, P < 0.001), as assessed by SF-36 using a random-effects model. No additional benefit was found when measured by DTR-QOL using a fixed-effects model (MD = 2.29, 95% CI [-0.06-4.64], P = 0.06; heterogeneity, I2 = 49%, P = 0.1) and compared to SGLT-2 inhibitors. Subgroup analysis indicated that DPP-4 inhibitors favored patients ≥ 60 years old on medication for ≥ 6 months. CONCLUSIONS: DPP-4 inhibitors were superior for T2DM HRQOL improvement. More long-term, multicenter evidence is needed to generalize findings and compare them with newer hypoglycemic agents. SYSTEMATIC REVIEW REGISTRATION: PROSPERO: CRD42023440134.

Assessing the Metabolic and Physical Effects of Combined DPP4 and SGLT2 Inhibitor Therapy in Patients with Type-2 Diabetes Mellitus: An Observational Prospective Pilot Study.

Introduction: This study aimed to assess the efficacy of combined administration of dipeptidyl peptide-4 (DPP4) and sodium-glucose cotransporter-2 (SGLT2) inhibitors on metabolic disorders and their preferable and complementary effects. Methods: The effectiveness of a 24-week intervention on metabolic parameters (including glucose profile), physical functions (grip strength and calf circumference), and health-related quality of life (HR-QOL) was analyzed using the International Physical Activity Questionnaire and Geriatric Depression Scale 5. A total of 39 patients with type-2 diabetes mellitus (T2DM) treated with the combination of DPP4 and SGLT2 inhibitors were included in this multicenter pilot study. Results: Combination therapy significantly reduced the HbA1c level (median [interquartile range]) after 24 weeks (pretreatment: 7.7% [7.3-8.2] vs. posttreatment: 7.1% [6.6-7.9], P < 0.001). The grip strength significantly increased after 24 weeks (1.7 ± 2.7 kg, P < 0.001), while the mean calf circumference and body mass index significantly decreased. In particular, administration of the SGLT2 inhibitor significantly increased total physical activity in participants aged ≥65 years (P = 0.003), while psychological QOL did not significantly improve. Conclusions: Combination therapy with DPP4 and SGLT2 inhibitors decreased HbA1c levels and improved physical function in patients with T2DM. This study confirmed the effectiveness of combination therapy for metabolic disorders and suggested its beneficial and complementary effects. Therefore, advances in treatment plans to achieve further improvements in glucose profiles using DPP4 and SGLT2 inhibitors are recommended to enhance the QOL of patients with T2DM. Clinical trial number: University Hospital Medical Information Network Center: UMIN000045375.

A case report of dipeptidyl peptidase 4 inhibitor-related kidney disease combined with renal cancer.

A kidney biopsy was performed in a 64-year-old woman with type 2 diabetes mellitus and less than 1 g of proteinuria who rapidly progressed to end-stage renal failure after approximately 2 years of treatment with two dipeptidyl peptidase 4 (DPP-4) inhibitors for type 2 diabetes mellitus. The biopsy revealed not only a coincidental diagnosis of renal cell carcinoma, which was not evident on pre-biopsy computed tomography, but also severe thrombotic microangiopathy (TMA)-like glomerular endothelial cell damage in the noncancerous areas. These results suggest that DPP4 inhibitors may have been involved in two kidney diseases.

Pharmacological inhibition of USP14 delays proteostasis-associated aging in a proteasome-dependent but foxo-independent manner.

Aging is often accompanied by a decline in proteostasis, manifested as an increased propensity for misfolded protein aggregates, which are prevented by protein quality control systems, such as the ubiquitin-proteasome system (UPS) and macroautophagy/autophagy. Although the role of the UPS and autophagy in slowing age-induced proteostasis decline has been elucidated, limited information is available on how these pathways can be activated in a collaborative manner to delay proteostasis-associated aging. Here, we show that activation of the UPS via the pharmacological inhibition of USP14 (ubiquitin specific peptidase 14) using IU1 improves proteostasis and autophagy decline caused by aging or proteostatic stress in Drosophila and human cells. Treatment with IU1 not only alleviated the aggregation of polyubiquitinated proteins in aging Drosophila flight muscles but also extended the fly lifespan with enhanced locomotive activity via simultaneous activation of the UPS and autophagy. Interestingly, the effect of this drug disappeared when proteasomal activity was inhibited, but was evident upon proteostasis disruption by foxo mutation. Overall, our findings shed light on potential strategies to efficiently ameliorate age-associated pathologies associated with perturbed proteostasis.

Fabrication of novel vildagliptin loaded ZnO nanoparticles for anti diabetic activity.

Diabetes mellitus (DM) is a rapidly prevailing disease throughout the world that poses boundless risk factors linked to several health problems. Vildagliptin is the standard dipeptidyl peptidase-4 (DPP-4) inhibitor type of medication that is used for the treatment of diabetes anti-hyperglycemic agent (anti-diabetic drug). The current study aimed to synthesize vildagliptin-loaded ZnO NPs for enhanced efficacy in terms of increased retention time minimizing side effects and increased hypoglycemic effects. Herein, Zinc Oxide (ZnO) nanoparticles (NPs) were constructed by precipitation method then the drug vildagliptin was loaded and drug loading efficiency was estimated by the HPLC method. X-ray diffraction analysis (XRD), UV-vis spectroscopy, FT-IR, scanning electron microscope (SEM), and EDX analysis were performed for the characterization of synthesized vildagliptin-loaded ZnO NPs. The UV-visible spectrum shows a distinct peak at 363 nm which confirms the creation of ZnO NPs and SEM showed mono-dispersed sphere-shaped NPs. EDX analysis shows the presence of desired elements along with the elemental composition. The physio-sorption studies, which used adsorption isotherms to assess adsorption capabilities, found that the Freundlich isotherm model explains the data very well and fits best. The maximum adsorption efficiency of 58.83% was obtained. Further, In vitro, anti-diabetic activity was evaluated by determining the α-amylase and DPP IV inhibition activity of the product formed. The formulation gave maximum inhibition of 82.06% and 94.73% of α-amylase and DPP IV respectively. While at 1000 µg/ml concentration with IC50 values of 24.11 µg/per ml and 42.94 µg/ml. The inhibition of α-amylase can be ascribed to the interactive effect of ZnO NPs and vildagliptin.

A sensitive fluorescence assay of serum dipeptidyl peptidase IV activity to predict the suitability of its inhibitors in patients with type 2 diabetes mellitus.

DPP-IV inhibitors, which are close to the natural hypoglycemic pathway of human physiology and have few side effects, have been extensively employed in the management of type 2 diabetes mellitus (T2DM). However, there are currently no specific blood indicators that can indicate or predict a patient's suitability for DPP-IV inhibitors. In this study, based on the self-developed high-specificity fluorescent substrate glycyl-prolyl-N-butyl-4-amino-1, 8-naphthimide (GP-BAN), a detection method of human serum DPP-IV activity was established and optimized. The method demonstrates a favorable lower limit of detection (LOD) at 0.32 ng/mL and a satisfactory lower limit of quantification (LOQ) of 1.12 ng/mL, and can be used for the detection of DPP-IV activity in trace serum (2 µL). In addition, Vitalliptin and Sitagliptin showed similar IC50 values when human recombinant DPP-IV and human serum were used as enzyme sources, and the intra-day and inter-day precision obtained by the microplate analyzer were less than 15 %. These results indicate that the microplate reader based detection technique has good accuracy, repeatability and reproducibility. A total of 700 volunteers were recruited, and 646 serum samples were tested for DPP-IV activity. The results showed that serum DPP-IV activity was higher in patients with T2DM than in controls (P < 0.01). However, the statistical data of family history of diabetes, gender and age of diabetic patients showed no statistical significance, and there was no contrast difference. The DPP-IV activity of serum in T2DM patients ranged from 2.4 µmol/min/L to 78.6 µmol/min/L, with a huge difference of up to 32-fold. These results suggest that it is necessary to test DPP-IV activity in patients with T2DM when taking DPP-IV inhibitors to determine the applicability of DPP-IV inhibitors in T2DM patients. These results suggest that it is necessary to detect the activity of DPP-IV in blood before taking DPP-IV inhibitors in patients with T2DM to judge the applicability of DPP-IV inhibitors in patients with T2DM.

Efficacy and safety of switching from a dipeptidyl peptidase-4 inhibitor to oral semaglutide in Japanese patients with type 2 diabetes mellitus.

Background: Dipeptidyl peptidase-4 inhibitors (DPP-4is) are the most widely used oral hypoglycemic drugs in Japan. However, once-daily oral semaglutide has been reported to reduce glycated hemoglobin (HbA1c) and body weight (BW) without causing significant hypoglycemia. Here, we aimed to evaluate the efficacy and safety of switching from a DPP-4i to oral semaglutide in Japanese patients with type 2 diabetes (T2D). Methods: We performed a single-center retrospective study of the changes in HbA1c and BW in 68 patients with T2D who were switched from a DPP-4i and took oral semaglutide for ≥ 6 months, without changes in any other oral hypoglycemic agent. Results: Mean HbA1c decreased from 7.8 to 7.0% (p < 0.001) and BW decreased from 74.2 to 71.2 kg (p < 0.001) over 6 months. The decrease in HbA1c was more pronounced in participants with high baseline HbA1c (r = - 0.542, p < 0.001). There was also a trend (r = 0.236, p = 0.052) toward a decrease in BW in individuals with shorter disease duration. There were reductions in either HbA1c or BW in 65 participants (95.6%). In addition, the larger the decrease in HbA1c was, the greater was the decrease in BW (r = 0.480, p < 0.001). Eighteen participants (20.1%) discontinued the drug within 6 months, of whom 10 (11.6% of the total) did so because of suspected adverse effects and the discontinuation rate was the highest in older, non-obese patients. Conclusions: Switching from a DPP-4i to oral semaglutide may be useful for Japanese patients with T2D who have inadequate glycemic or BW control. However, its utility may be limited by gastrointestinal adverse effects in certain patients.

Glycemic control of once-weekly and other administration frequencies for DPP-4 inhibitor in patients with type 2 diabetes: a real-world retrospective cohort study.

Aims: To assess the glycemic control of once-weekly (QW) and other administration frequencies for dipeptidyl peptidase-4 inhibitors (DPP-4i) in patients with type 2 diabetes in a real-world setting. Methods: A retrospective cohort study used Japanese medical claims data and medical check-up data between December 2015 and February 2020. Patients with type 2 diabetes had been newly prescribed a DPP-4i regimen of once-daily (QD), twice-daily (BID), or QW administration and had hemoglobin A1c (HbA1c) values from regular medical check-ups. HbA1c values and proportion of patients achieving their HbA1c target were assessed. Multivariable analyses were conducted to examine the association between DPP-4i regimen and achievement of HbA1c target. Results: Of the analysis population (N = 7229), 6098 patients were prescribed the QD regimen, 772 BID, and 359 QW. Mean HbA1c before exposure to DPP-4i was 7.31 ± 1.20% (mean ± standard deviation) for QD, 7.64 ± 1.47% for BID, and 7.06 ± 0.96% for QW, decreasing after DPP-4i exposure to 6.71 ± 0.78%, 6.77 ± 0.84%, and 6.59 ± 0.67%, respectively. HbA1c < 7% was achieved in 72.1% of patients for QD, 69.0% for BID, and 79.1% for QW. On multivariable analysis, the odds ratio (95% confidence interval) for HbA1c < 7.0% in patients < 65 years of age was 0.97 (0.73-1.30) for BID and 0.90 (0.57-1.42) for QW compared to QD. Similar achievement of HbA1c target was noted in each regimen for patients age ≥ 65 years and for age ≥ 65 years with multimorbidity. Conclusion: In this study under real-world conditions, glycemic control for the DPP-4i QW regimen was similar to that for QD and BID. Supplementary Information: The online version contains supplementary material available at 10.1007/s13340-024-00718-5.

Comparison of medication persistence and adherence in type 2 diabetes using a once-weekly regimen of DPP-4 inhibitor compared with once-daily and twice-daily regimens: a retrospective cohort study of Japanese health insurance claims data.

Aims: Assess medication persistence and adherence for dipeptidyl peptidase-4 inhibitors (DPP-4i) administered once weekly (QW), once daily (QD), and twice daily (BID) among patients with type 2 diabetes (T2D), and explore factors associated with discontinuation and non-adherence for DPP-4i regimens. Methods: This retrospective T2D cohort study used medical claims data for three DPP-4i regimens in patients newly prescribed DPP-4i between December 2016 and February 2019. Medication persistence rates were calculated at 3, 6, and 12 months by the Kaplan-Meier method. Adherence was measured as Proportion of Days Covered (PDC). We used Cox proportional hazards models for DPP-4i discontinuation and logistic regression models for non-adherence. Results: In the analysis population of 52,762 patients, DPP-4i prescriptions were 84.2% QD, 11.8% BID, and 4.0% QW. Medication persistence rates were similar up to 6 months for all regimens: approximately 90% at 3 and 80% at 6 months. The 12-month persistence rates for QD, BID, and QW were 74.8%, 67.5%, and 68.0%, respectively. Median PDC was 94.0% for QD, 91.8% for BID, and 93.2% for QW. Five specific factors were associated with discontinuation: BID or QW regimen, younger age, no concomitant medications, comorbid dementia, and comorbid chronic pulmonary disease. Non-adherence was associated with those factors plus male sex and treatment at clinics with 0-19 beds. Conclusions: The 12-month medication persistence rates were highest for QD, followed by QW and then BID. Adherence was similar for all three regimens. Medication persistence for DPP-4i may be improved by tailoring regimens to patient characteristics and needs. Supplementary Information: The online version contains supplementary material available at 10.1007/s13340-024-00714-9.

Glucagon-like peptide-1 receptor agonists and risk of sight-threatening retinopathy in Taiwanese population: A propensity based cohort study.

AIMS: To compare the risk of vision-threatening retinopathy between glucagon-like peptide-1 receptor agonists (GLP-1 RA) use and no use in patients with type 2 diabetes. METHODS: Using propensity score matching, we identified 27,506 pairs of GLP-1 RA users and non-users, 3904 pairs of GLP-1 RA and dipeptidyl peptidase-4 inhibitors (DPP-4i) users, 10,985 pairs of GLP-1 RA and sodium-glucose cotransporter-2 inhibitors (SGLT2i) users, 2542 pairs of GLP-1 RA and sulfonylurea, respectively, from Taiwan's National Health Insurance Research Database from January 1, 2009 to December 31, 2018. We used Cox proportional hazards models to compare the risk of vision-threatening retinopathy between GLP-1 RA use and other matched groups. RESULTS: In the matched cohorts, the time-varying exposure analysis showed that GLP-1 RA use was not associated with an increased risk of vision-threatening retinopathy compared to GLP-1 RA non-use (aHR 0.96, 95 % CI 0.89-1.03). New-user and active-comparator analyses showed that GLP-1 RA was associated with a significantly lower risk of vision-threatening retinopathy than DPP-4i (aHR 0.8, 95 % CI 0.66-0.97) but had no significant association with this risk compared to SGLT2i (aHR 1.09, 95 % CI 0.96-1.24) or sulfonylureas (aHR 0.79, 95 % CI 0.49-1.06). CONCLUSIONS: This nationwide cohort study showed that GLP-1 RA use was not associated with an increased risk of vision-threatening retinopathy compared to non- GLP-1 RA use, and GLP-1 RA could significantly lower the risk of vision-threatening retinopathy than DPP-4i.

Bis(benzimidazol-2-yl)amine-based DPP-4 Inhibitors Potentially Suitable for Combating Diabetes and Associated Nervous System Alterations.

Bis(benzimidazol-2-yl)amine scaffold is not present in dipeptidyl peptidase-4 (DPP-4) inhibitors published so far. Herein, the inhibitory potential of bis(benzimidazol-2-yl)amine derivatives against DPP-4 was evaluated. In non-competitive inhibition mode, three representatives 5, 6, and 7 inhibited DPP-4 in vitro with IC50 values below 50 µM. The assessed binding pocket of DPP-4 for these benzimidazoles includes the S2 extensive subsite's residues Phe357 and Arg358. None of the lead compounds showed cytotoxicity to human neuroblastoma SH-SY5Y cells at concentrations lower than 10 µM. None showed significant binding affinity for dopamine D2, D3, and histamine H1, H3 receptors, at concentrations lower than 10 µM, leading to preferable outcomes due to mutually opposite effects of these neurotransmitters on each other. The potential beneficial effects on dopamine synthesis and the survival of dopaminergic neurons could be mediated by DPP-4 inhibition. These effective noncompetitive DPP-4 inhibitors, with inhibitory potential better than reference diprotin A (relative inhibitory potency compared to diprotin A is 3.39 and 1.54 for compounds 7 and 5, respectively), with the absence of the cytotoxicity to SH-SY5Y cells, are valuable candidates for further evaluation for the treatment of diabetes and associated disruption of neuronal homeostasis.

Case report: Ofatumumab treatment in anti-DPPX autoimmune encephalitis.

Dipeptidyl peptidase-like protein 6 (DPPX) antibody encephalitis is a rare autoimmune encephalitis. Diagnosis and treatment of DPPX remain challenging, particularly in patients with refractory disease. Herein, we report the first case of anti-DPPX encephalitis treated with ofatumumab. The patient had a chronic insidious onset and predominantly presented with severe neuropsychiatric symptoms and the typical triad of symptoms (weight loss, central nervous system hyperexcitability, and cognitive dysfunction). Positive anti-DPPX antibodies in the serum (1:1,000) and cerebrospinal fluid (CSF) (1:100) were detected at the disease peak. The patient was unresponsive to four types of standard immunotherapies (intravenous globulin, plasma exchange, steroids, and tacrolimus), resulting in a treatment switch to ofatumumab. After five doses of injection and 12 months of follow-up, the patient improved well, with only a mild cognitive deficit.

USP9X inhibits metastasis in pulmonary sarcomatoid carcinoma by regulating epithelial-mesenchymal transition, angiogenesis and immune infiltration.

BACKGROUND: Pulmonary sarcomatoid carcinoma (PSC) is a highly invasive pulmonary malignancy with an extremely poor prognosis. The results of previous studies suggest that ubiquitin-specific peptidase 9X (USP9X) contributes to the progression of numerous types of cancer. Nevertheless, there is little knowledge about the molecular mechanisms and functions of USP9X in the metastasis of PSC. METHODS: Immunohistochemistry and western blotting were used to detect USP9X expression levels in PSC tissues and cells. Wound healing, transwell, enzyme-linked immunosorbent assay (ELISA), tube formation, and aortic ring assays were used to examine the function and mechanism of USP9X in the metastasis of PSC. RESULTS: Expression of USP9X was markedly decreased and significantly correlated with metastasis and prognosis of patients with PSC. Then we revealed that USP9X protein levels were negatively associated with the levels of epithelial-mesenchymal transition (EMT) markers and the migration of PSC cells. It was confirmed that USP9X in PSC cells reduced VEGF secretion and inhibited tubule formation of human umbilical vein endothelial cells (HUVEC) in vitro. USP9X was detected to downregulate MMP9. Meanwhile, MMP9 was positively related to EMT, angiogenesis and was negatively related to immune infiltration in the public databases. USP9X was significantly negatively associated with the expression of MMP9, EMT markers, CD31, and positively associated with CD4, and CD8 in PSC tissues. CONCLUSION: The present study reveals the vital role of USP9X in regulating EMT, angiogenesis and immune infiltration and inhibiting metastasis of PSC via downregulating MMP9, which provides a new effective therapeutic target for PSC.

Pancreatitis and Pancreatic Cancer Risk Among Patients With Type 2 Diabetes Receiving Dipeptidyl Peptidase 4 Inhibitors: An Updated Meta-Analysis of Randomized Controlled Trials.

PURPOSE: This meta-analysis sought to assess the relationship between dipeptidyl peptidase-4 inhibitors (DPP-4) and the risk of pancreatitis and pancreatic cancer by synthesizing data from randomized, controlled trials, in light of the conflicting findings from observational studies and previous meta-analyses. METHODS: Cochrane, Embase, ClinicalTrials.gov, and PubMed databases that compared the use of DPP-4 inhibitors and that reported pancreatitis and pancreatic cancer events in patients with diabetes mellitus Type 2 (T2DM) were searched using specific terms. Studies were included if they satisfied the following inclusion criteria: They were randomized trials comparing DPP-4 inhibitors use in patients with T2DM; The study's duration was longer than 24 weeks; And they reported pancreatitis and pancreatic cancer events. Stata 15 MP was used to analyze the data, and odds ratios (OR) with 95% confidence intervals (CI) were used to represent the results. FINDINGS: A total of 81,737 participants with T2DM were included in the analysis. The results showed that during a mean follow-up period of 24 to 520 weeks, The use of DPP-4 inhibitors was not associated with an increased risk of pancreatitis (Peto-OR 0.97; 95% CI: 0.74, 1.27) or pancreatic cancer (Peto-OR = 0.88; 95% CI: 0.59, 1.30). IMPLICATIONS: Current evidence fails to validate a significant correlation between DPP-4 therapy and pancreatitis or pancreatic cancer. However, subgroup analyses showed that sitagliptin was associated with a significant reduction in pancreatitis risk compared to the control group; furthermore, when comparing different types of control medications, a significant decrease in pancreatic cancer risk was observed among DPP-4 users compared to GLP-1 users.

Risk of Urogenital Bacterial Infection with Sodium-Glucose Cotransporter-2 Inhibitors: A Retrospective Cohort Study Using a Claims Database.

INTRODUCTION: The association between sodium-glucose cotransporter-2 (SGLT2) inhibitors and the risk of urogenital infections remains controversial. This study aimed to investigate the association between SGLT2 inhibitors and the incidence of perineal soft tissue infections, including Fournier's gangrene (FG), genital bacterial infections, and urinary tract infections (UTIs), using administrative claims data in Japan. METHODS: In this retrospective cohort study, we utilized the JMDC Claims Database. The study included patients aged 18 years or older diagnosed with type 2 diabetes mellitus, identified by a diagnostic code, who received new prescriptions for SGLT2 inhibitors or dipeptidyl peptidase 4 (DPP-4) inhibitors between April 2014 and August 2020. Using one-to-one propensity score (PS) matching, we compared the incidence of perineal soft tissue infections, including FG, genital bacterial infection, and UTIs between groups treated with SGLT2 and DPP-4 inhibitors. Hazard ratios (HR) and their 95% confidence intervals (CI) were estimated using the Cox proportional hazards model. RESULTS: We identified 34,897 patients in the SGLT2 inhibitor group and 135,311 patients in the DPP-4 inhibitor group. After one-to-one PS matching, 31,665 pairs were generated. The mean age of the patients was 51 years, with approximately 70% being male. The use of SGLT2 inhibitors was associated with a decreased risk of UTI (HR 0.90, 95% CI 0.83-0.98) and an increased risk of genital bacterial infection (HR 1.23, 95% CI 1.03-1.46) compared to DPP-4 inhibitors. However, no significant association was observed with perineal soft tissue infection (HR 1.05, 95% CI 0.61-1.81). CONCLUSIONS: SGLT2 inhibitors were associated with a reduced risk of UTI and an increased risk of genital bacterial infection. They showed no significant association with perineal soft tissue infection when compared to DPP-4 inhibitors. Future research should explore broader demographics, focusing on the elderly and achieving gender balance, to gain a comprehensive understanding of infection risks.

Inactive metallopeptidase homologs: the secret lives of pseudopeptidases.

Inactive enzyme homologs, or pseudoenzymes, are proteins, found within most enzyme families, that are incapable of performing catalysis. Rather than catalysis, they are involved in protein-protein interactions, sometimes regulating the activity of their active enzyme cousins, or scaffolding protein complexes. Pseudoenzymes found within metallopeptidase families likewise perform these functions. Pseudoenzymes within the M14 carboxypeptidase family interact with collagens within the extracellular space, while pseudopeptidase members of the M12 "a disintegrin and metalloprotease" (ADAM) family either discard their pseudopeptidase domains as unnecessary for their roles in sperm maturation or utilize surface loops to enable assembly of key complexes at neuronal synapses. Other metallopeptidase families contain pseudopeptidases involved in protein synthesis at the ribosome and protein import into organelles, sometimes using their pseudo-active sites for these interactions. Although the functions of these pseudopeptidases have been challenging to study, ongoing work is teasing out the secret lives of these proteins.

Neuro-molecular perspectives on long COVID-19 impacted cerebrovascular diseases - a role for dipeptidyl peptidase IV.

The coronavirus disease 2019 (COVID-19) has caused immense devastation globally with many outcomes that are now extending to its long-term sequel called long COVID. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects not only lungs, but also the brain and heart in association with endothelial cell dysfunction, coagulation abnormalities, and thrombosis leading to cardio-cerebrovascular health issues. Fatigue, cognitive decline, and brain fog are common neurological symptoms in persisting long COVID. Neurodegenerative processes and SARS-CoV-2 infection manifest overlapping molecular mechanisms, such as cytokine dysregulation, inflammation, protein aggregation, mitochondrial dysfunction, and oxidative stress. Identifying the key molecules in these processes is of importance for prevention and treatment of this disease. In particular, Dipeptidyl peptidase IV (DPPIV), a multifunctional peptidase has recently drawn attention as a potential co-receptor for SARS-CoV-2 infection and cellular entry. DPPIV is a known co-receptor for some other COVID viruses including MERS-Co-V. DPPIV regulates the immune responses, obesity, glucose metabolism, diabetes, and hypertension that are associated with cerebrovascular manifestations including stroke. DPPIV likely worsens persisting COVID-19 by disrupting inflammatory signaling pathways and the neurovascular system. This review highlights the neurological, cellular and molecular processes concerning long COVID, and DPPIV as a potential key factor contributing to cerebrovascular dysfunctions following SARS-CoV-2 infection.

Bismuth Sulfide Nanoflowers Facilitated miR339 Delivery to Overcome Stemness and Radioresistance through Ubiquitin-Specific Peptidase 8 in Esophageal Cancer.

Despite the superior efficacy of radiotherapy in esophageal squamous cell carcinoma (ESCC), radioresistance by cancer stem cells (CSCs) leads to recurrence, metastasis, and treatment failure. Therefore, it is necessary to develop CSC-based therapies to enhance radiotherapy. miR-339-5p (miR339) is involved in stem cell division and DNA damage checkpoint signaling pathways based on ESCC cohort. miR339 inhibited ESCC cell stemness and enhanced radiation-induced DNA damage by targeting USP8, suggesting that it acts as a potential CSC regulator and radiosensitizer. Considering the limited circulating periods and poor tumor-targeting ability of miRNA, a multifunctional nanoplatform based on bismuth sulfide nanoflower (Bi@PP) is developed to efficiently deliver miR339 and improve radioresistance. Intriguingly, Bi@PP encapsulates more miR339 owing to their flower-shaped structure, delivering more than 1000-fold miR339 into cells, superior to free miR339 alone. Besides being used as a carrier, Bi@PP is advantageous for dynamically monitoring the distribution of delivered miR339 in vivo while simultaneously inhibiting tumor growth. Additionally, Bi@PP/miR339 can significantly enhance radiotherapy efficacy in patient-derived xenograft models. This multifunctional platform, incorporating higher miRNA loading capacity, pH responsiveness, hypoxia relief, and CT imaging, provides another method to promote radiosensitivity and optimize ESCC treatment.

The multiple actions of dipeptidyl peptidase 4 (DPP-4) and its pharmacological inhibition on bone metabolism: a review.

BACKGROUND: Dipeptidyl peptidase 4 (DPP-4) plays a crucial role in breaking down various substrates. It also has effects on the insulin signaling pathway, contributing to insulin resistance, and involvement in inflammatory processes like obesity and type 2 diabetes mellitus. Emerging effects of DPP-4 on bone metabolism include an inverse relationship between DPP-4 activity levels and bone mineral density, along with an increased risk of fractures. MAIN BODY: The influence of DPP-4 on bone metabolism occurs through two axes. The entero-endocrine-osseous axis involves gastrointestinal substrates for DPP-4, including glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptides 1 (GLP-1) and 2 (GLP-2). Studies suggest that supraphysiological doses of exogenous GLP-2 has a significant inhibitory effect on bone resorption, however the specific mechanism by which GLP-2 influences bone metabolism remains unknown. Of these, GIP stands out for its role in bone formation. Other gastrointestinal DPP-4 substrates are pancreatic peptide YY and neuropeptide Y-both bind to the same receptors and appear to increase bone resorption and decrease bone formation. Adipokines (e.g., leptin and adiponectin) are regulated by DPP-4 and may influence bone remodeling and energy metabolism in a paracrine manner. The pancreatic-endocrine-osseous axis involves a potential link between DPP-4, bone, and energy metabolism through the receptor activator of nuclear factor kappa B ligand (RANKL), which induces DPP-4 expression in osteoclasts, leading to decreased GLP-1 levels and increased blood glucose levels. Inhibitors of DPP-4 participate in the pancreatic-endocrine-osseous axis by increasing endogenous GLP-1. In addition to their glycemic effects, DPP-4 inhibitors have the potential to decrease bone resorption, increase bone formation, and reduce the incidence of osteoporosis and fractures. Still, many questions on the interactions between DPP-4 and bone remain unanswered, particularly regarding the effects of DPP-4 inhibition on the skeleton of older individuals. CONCLUSION: The elucidation of the intricate interactions and impact of DPP-4 on bone is paramount for a proper understanding of the body's mechanisms in regulating bone homeostasis and responses to internal stimuli. This understanding bears significant implications in the investigation of conditions like osteoporosis, in which disruptions to these signaling pathways occur. Further research is essential to uncover the full extent of DPP-4's effects on bone metabolism and energy regulation, paving the way for novel therapeutic interventions targeting these pathways, particularly in older individuals.