Fast Skeletal Muscle Troponin and Tropomyosin as a Dietary Source of Antidiabetic and Antihypertensive Bioactive Peptides: An In Silico Study / Troponina y Tropomiosina de Músculo Esquelético como Fuente Alimentaria de Péptidos Bioactivos Antidiabéticos y Antihipertensivos: Estudio In Silico

Background: The nutraceutical properties of food hydrolysates rely on multiple biochemical interactions involving the modulation of enzymes and cellular receptors. Numerous bioactive peptides released from troponin and tropomyosin digestion have been identified. Their characterization has mostly been performed by hydrolysis catalyzed by proteases unrelated to the human digestive system. Objective: This study aimed to determine the bioactive profile of beef, pork, and chicken meat by analyzing the frequency and pharmacokinetics of biopeptides released from troponin and tropomyosin. Methods:In silico digestion and biopeptide release frequency were studied by three parameters; bioactive fragments release frequency (AE), frequency percentage (W), and mean occurrence (AS), all stated on the BIOPEP-UWM platform. Further on, hydrolysis end-products were screened based on gastrointestinal-absorption probability and pharmacokinetic profiling performed on SwissADME, SwissTargetPrediction, and ADME/Tlab bioinformatics web tools. Statistical analyses were performed using a one-way ANOVA test. Results: Dipeptidyl peptidase-IV (DPP-IV) and angiotensin-converting enzyme (ACE) inhibiting biopeptides exhibited the highest release frequency. Moreover, W and ASparameters showed no significant difference (p>0.05) between the myofibrillar isoforms assessed. Seven biopeptides were classified as highly absorbable and reported optimal drug-likeness compliance. Although biopeptides hold good pharmacokinetic properties, the therapeutic potency of biopeptides showed to be lower than those of DPP-IV and ACE-inhibiting drugs. Conclusions: Troponin and tropomyosin are rich dietary sources of bioactive peptides, mainly DPP-IV and ACE inhibitors. Digestion end-products are mainly dipeptides with optimal pharmacokinetic and drug-like properties, suggesting a potential therapeutic application in hypertensive and hyperglycemic disorders

Antecedentes: Las propiedades nutracéuticas de los hidrolizados de alimentos dependen de múltiples interacciones bioquímicos que involucran la modulación de enzimas y receptores celulares. Se han identificado numerosos péptidos bioactivos liberados de la digestión de troponina y tropomiosina, pero su caracterización se ha llevado a cabo principalmente por hidrólisis catalizada por proteasas ajenas al sistema digestivo humano. Objetivo: Este estudio tuvo como objetivo determinar el perfil bioactivo de la carne de res, cerdo y pollo mediante el análisis de la frecuencia y farmacocinética de los biopéptidos liberados de la troponina y la tropomiosina. Métodos: Se estudió la digestión in silico y la frecuencia de liberación de biopéptidos mediante dos parámetros; frecuencia de liberación de fragmentos bioactivos (AE), frecuencia porcentual (W) y ocurrencia media (AS), ambos indicados en la plataforma BIOPEP-UWM. Más adelante, los productos finales de la hidrólisis se examinaron en función de la probabilidad de absorción gastrointestinal y el perfil farmacocinético realizado en las herramientas bioinformáticas SwissADME, SwissTargetPrediction y ADME/Tlab. El análisis estadístico se llevó a cabo mediante una prueba ANOVA de una vía. Resultados: Los biopéptidos inhibidores de la dipeptidil peptidasa IV (DPP-IV) y la enzima convertidora de angiotensina (ECA) exhibieron la mayor frecuencia de liberación. Además, los parámetros W y ASno mostraron diferencias significativas (p> 0.05) entre las isoformas miofibrilares evaluadas. Siete biopéptidos se clasificaron como altamente absorbibles e informaron un cumplimiento óptimo de similitud con el fármaco. Aunque los biopéptidos tienen propiedades farmacocinéticas adecuadas, su potencia terapéutica demostró ser menor que la de los fármacos inhibidores de la DPP-IV y la ACE. Conclusiones: La troponina y la tropomiosina son una fuente dietética rica en péptidos bioactivos, principalmente DPP-IV e inhibidores de la ACE. Los productos finales de la digestión son principalmente dipéptidos con propiedades farmacocinéticas óptimas y similares a la de los fármacos, lo que sugiere una aplicación terapéutica factible en trastornos hipertensivos e hiperglicémicos

Research progress of targeted degradation of Mycobacterium tuberculosis proteins / 药学学报

Tuberculosis (TB), an infectious disease caused by Mycobacterium tuberculosis (Mtb), is still one of the significant threats to human life. In recent years, the continuous exploration of small molecule inhibitors represented by bedaquinoline has brought new vitality into the field of tuberculosis. However, small molecule inhibitors will inevitably occur acquired drug resistance during clinical medication. As a new pharmacological mechanism, targeted protein degradation (TPD) achieves efficacy by destroying rather than inhibiting protein targets. It might be an excellent strategy to develop anti-tuberculosis drugs based on the TPD concept to solve drug resistance. This article reviews the protein degradation pathways of Mtb, such as the Pup proteasome system and the ClpP-ClpC1 complex enzyme system. The future development of these strategies into TPD drugs was prospected and summarized.

Cinnamomi Cortex Regulates Incretin Effect in Diabetic Rats / 中国实验方剂学杂志

ObjectiveTo observe the pharmacodynamic effects of Cinnamomi Cortex on the incretin effect in the rat model of diabetes mellites （DM） induced by streptozotocin （STZ） and explore the underlying mechanism from glucagon-like peptide-1 （GLP-1） and dipeptidyl peptidase-4 （DPP-4）. MethodForty SD rats were randomly assigned into blank， model， sitagliptin （0.1 g·kg-1）， and low- and high-dose Cinnamomi Cortex （0.45 and 0.9 g·kg-1， respectively） groups. The DM rat model was established by a high-fat diet combined with intraperitoneal injection of 40 mg·kg-1 STZ in other groups except the blank group. The intervention lasted for 8 weeks. The status， body weight， water intake， food intake， and fasting blood glucose （FBG） of the rats were observed and determined. Hematoxylin-eosin staining was employed to reveal the pathological changes of the pancreas， and immunohistochemistry to detect the expression of glucagon in the pancreas. Biochemical assay was employed to measure the serum levels of lipid metabolism indexes such as total cholesterol （TC）， triglyceride （TG）， low-density lipoprotein （LDL）， and high-density lipoprotein （HDL）. Enzyme-linked immunosorbent assay was employed to determine the levels of glycosylated hemoglobin， insulin， glucagon， GLP-1， and glucose-dependent insulinotropic polypeptide （GIP） in rat serum， and Western blot to determine the protein levels of GLP-1 and DPP-4 in the pancreas. ResultAfter 8 weeks of intervention， the model group showed higher body weight， FBG， TC， TG， LDL， glycosylated hemoglobin， glucagon， insulin， and insulin resistance index and lower HDL， GLP-1， and GIP than the blank group （P<0.05， P<0.01）. The Cinnamomi Cortex groups showed lower body weight， FBG， TC， TG， LDL， glycosylated hemoglobin， glucagon， insulin， and insulin resistance index and higher HDL， GLP-1， and GIP than the model group （P<0.05， P<0.01）. The Cinnamomi Cortex groups showed recovered morphology of islet cells and no nucleus aggregation. Compared with the model group， the Cinnamomi Cortex groups showed declined levels of glucagon in the center of islet cells. Compared with the blank group， the model group showed up-regulated protein level of DPP-4 and down-regulated protein level of GLP-1 （P<0.01）. Compared with the model group， the high-dose Cinnamomi Cortex groups showed down-regulated protein level of DPP-4 and up-regulated protein level of GLP-1 （P<0.05）. ConclusionCinnamomi Cortex may reduce blood glucose and improve incretin effect to lower the blood glucose level by regulating DPP-4 and GLP-1 in DM rats.

La dipeptidil peptidasa 4 y su función frente a la COVID-19 / Dipeptidyl peptidase 4 and its function against COVID-19

Ante la aparición de un nuevo virus en la ciudad de Wuhan-China, llamado SARS-CoV-2, causante del conocido síndrome agudo respiratorio severo (COVID-19), muchos de científicos tratan de hallar una solución contra el virus que ha ocasionado una pandemia. En esta búsqueda, se encontró a una glicoproteína de transmembrana llamada dipeptidil peptidasa 4 o DPP-4 presente en la superficie de diferentes tipos de células y diana en la infección por el MERS-Co-V que abre una esperanza al sospechar que la DPP-4 puede ser un blanco en diferentes coronavirus al servir como estrategia terapéutica. A ello se suman resultados que encuentran la DPP-4 elevada en pacientes con complicaciones graves ante COVID-19, lo que puede ser un posible marcador de gravedad. Sin embargo, aún existe poco énfasis en la identificación y asociación de esta glicoproteína a la COVID-19. Para ello, se realizó una revisión bibliográfica sobre los aspectos más significativos de la Dipeptidil Peptidasa 4 y su función frente a la COVID-19(AU)

Given the appearance of a new virus in the of Wuhan city, China, called SARS-CoV-2, which causes the well-known severe acute respiratory syndrome (COVID-19), many scientists are trying to find a solution against the virus that has caused a pandemic. In this search, a transmembrane glycoprotein called dipeptidyl peptidase 4 or DPP-4 was found present on the surface of different types of cells and a target in MERS-Co-V infection, which opens hope by suspecting that DPP- 4 can be a target in different coronaviruses by serving as a therapeutic strategy. Added to this, there are results that find elevated DPP-4 in patients with severe complications from COVID-19, which may be a possible marker of severity. However, there is still little emphasis on the identification and association of this glycoprotein with COVID-19. To this effect, a bibliographic review was carried out on the most significant aspects of Dipeptidyl Peptidase 4 and its function against COVID-19(AU)

Prescription of DPP4 inhibitors: Indication and effect on glycosylated hemoglobin in a primary care institution of Colombia / Prescripción de inhibidores de la DPP-4: indicación y efecto sobre la hemoglobina glicosilada en un primer nivel de Colombia

Abstract Introduction and objective: In Colombia, Dipeptidyl-Peptidase IV (DPP4) inhibitors are recommended as second-best choice for type 2 diabetes mellitus treatment. However, no evaluation of the accomplishment or impact of this recommendation was performed. The objective was to determine the prescription of the DPP4 inhibitor according to the Colombian Clinicial Practice Guide regarding type 2 diabetes mellitus treatment, and its effects on glycosylated hemoglobin (HbAlc). Materials and methods: A descriptive study that included patients with type 2 diabetes mellitus who attended a first level between 2016 and 2018, had a prescription for DPP4 inhibitor and at least two control appointments. Variables included were sociodemographic, clinics, treatment and comorbidities. The unadjusted prescription was defined as the lack of accomplishment of Colombian guidelines. Descriptive statistics and X2 test were used for the comparison of categorical variables. A binary logistic regression model was applied. Results: 112 out of 207 patients accomplished inclusion criteria, of which 77 were women (68.8%). Also, 68.8% of the patients had an unadjusted prescription of the iDPP4. There was a 0.21% total reduction in HbA1c levels, with a mean of 198.2 ± 124 days between the first and second control measurement (reduction of 0.55% when the prescription was adjusted to the guidelines and 0.05% if it was unadjusted). Conclusion: There is a limited impact of DPP4 inhibitors regarding the reduction of HbA1c and metabolic control, and there is a slight follow-up to the Colombian guidelines in patients who attend a first level.

Resumen Introducción y Objetivo: En Colombia se recomiendan los inhibidores de la Dipeptidil Peptidasa-IV (iDPP4) como segunda opción para el manejo de la diabetes mellitus tipo 2. No se ha evaluado el cumplimiento e impacto de esta recomendación. Como objetivo se buscó determinar la prescripción de los iDPP4 según las recomendaciones de la Guía de Práctica Clínica colombiana, y su efecto sobre la hemoglobina glicosilada (HbA1c). Materiales y métodos: Estudio descriptivo que incluyó pacientes con diabetes mellitus tipo 2 que consultaron a un primer nivel entre 2016 y 2018, y tenían formulado un iDPP4, con al menos dos consultas de seguimiento. Se incluyeron variables sociodemográficas, clínicas, tratamiento y comorbilidades. La prescripción no ajustada se definió como la falta de cumplimento de la recomendación de la guía colombiana. Se empleó estadística descriptiva y pruebas X2 para la comparación de variables categóricas. Se aplicó un modelo de regresión logística binaria. Resultados: Hubo 207 pacientes de los cuales 112 cumplieron criterios de inclusión, 77 eran mujeres (68,8%). El 68,8% de los pacientes presentaron una prescripción no ajustada del iDPP4. Hubo una reducción total de 0,21%, con una media de 198,2±124 días entre la primera y segunda medición de HbA1c de control (reducción de 0,55% cuando la prescripción se ajustaba a la guía colombiana y 0,05% cuando no). Conclusión: Hay un limitado impacto de los iDPP4 frente a la reducción de HbA1c y poco seguimiento de la guía colombiana en pacientes de primer nivel de atención.

Repositioning drug strategy against Trypanosoma cruzi: lessons learned from HIV aspartyl peptidase inhibitors

Chagas disease (CD) is an old neglected problem that affects more than 6 million people through 21 endemic countries in Latin America. Despite being responsible for more than 12 thousand deaths per year, the disease disposes basically of two drugs for its treatment, the nitroimidazole benznidazole and the nitrofuran nifurtimox. However, these drugs have innumerous limitations that greatly reduce the chances of cure. In Brazil, for example, only benznidazole is available to treat CD patients. Therefore, some proof-of-concept phase II clinical trials focused on improving the current treatment with benznidazole, also comparing it with repositioned drugs or combining them. Indeed, repositioning already marketed drugs in view of combating neglected tropical diseases is a very interesting approach in the context of decreased time for approval, better treatment options and low cost for development and implementation. After the introduction of human immunodeficiency virus aspartyl peptidase inhibitors (HIV-PIs) in the treatment of acquired immune deficiency syndrome (AIDS), the prevalence and incidence of parasitic, fungal and bacterial co-infections suffered a marked reduction, making these HIV-PIs attractive for drug repositioning. In this line, the present perspective presents the promising and beneficial data concerning the effects of HIV-PIs on the clinically relevant forms of Trypanosoma cruzi (i.e., trypomastigotes and amastigotes) and also highlights the ultrastructural and physiological targets for the HIV-PIs on this parasite. Therefore, we raise the possibility that HIV-PIs could be considered as alternative treatment options in the struggle against CD.

A haplotype in the dipeptidyl peptidase 4 gene impacts glycemic-related traits of Brazilian older adults

Dipeptidyl peptidase 4 (DPP4) regulates various physiological pathways and has a pivotal role in glucose homeostasis. The objective of this study was to verify the association of a haplotype constituted by two single nucleotide polymorphisms (rs2268894 and rs6741949) in the DPP4 gene with type 2 diabetes mellitus (T2DM) and fasting glycemia-related variables in a sample of Brazilian older adults, taking serum levels and enzymatic activity of DPP4 into account. Clinical, biochemical, and anthropometric characteristics as well as DPP4 serum levels and enzymatic activity were determined in 800 elderly (≥60 years old) individuals. Assessment of polymorphic sites was performed by real-time PCR whereas haplotypes were inferred from genotypic frequencies. Statistical analyses compared measures and proportions according to T2DM diagnosis and DPP4 haplotypic groups. The most common haplotype consisted of the T-rs2268894/G-rs6741949 string, which was 20% more frequent among non-diabetics. Considering non-diabetic patients alone, carriers of the T/G haplotype had significantly lower levels of blood glucose, insulin, HOMA-IR index, and DPP4 activity. Among diabetic patients, the T/G haplotype was associated with lower DPP4 levels whereas glycemic scores were not affected by allelic variants. Our results suggested that the genetic architecture of DPP4 affects the glycemic profile and DPP4 serum levels and activity among elderly individuals according to the presence or absence of T2DM, with a possible implication of the T/G haplotype to the risk of T2DM onset.

Ubiquitin-specific peptidase 22 (USP22) regulates the level and function of hepatitis B virus X protein / 中华微生物学和免疫学杂志

Objective:To investigate the effects of the interaction between ubiquitin-specific peptidase 22 (USP22) and hepatitis B virus X protein (HBx) on the protein level and the biological function of HBx.Methods:The interactions between HBx and USP22 were analyzed by GST pull-down, co-immunoprecipitation assay and confocal laser scanning assay. USP22 recombinant plasmids or specific siRNA were transiently co-transfected with HBx plasmids. Western blot were used to detect the protein level of HBx. The half-life and degradation pathway of HBx in the transfected cells treated with cycloheximide (CHX) or proteasome inhibitor MG132 were detected. In vivo ubiquitination assay was used to detect the ubiquitination of HBx with USP22 overexpression. Moreover, dual-luciferase reporter assay and colony formation assay were used to analyze the effects of USP22 on the biological function of HBx. Results:USP22 could interact with HBx in vivo and in vitro. USP22 significantly increased the stability of HBx and inhibited the proteasome-mediated degradation of HBx protein by reducing the ubiquitination of HBx, thereby enhancing the biological function of HBx. Conclusions:USP22 inhibited HBx protein degradation through ubiquitin-dependent proteasome pathway, thus enhancing the stability and biological function of HBx.

High-temperature requirement A serine peptidase 1-related cerebral small vessel disease / 中华神经科杂志

The high-temperature requirement A serine peptidase 1 (HTRA1) gene mutation results in cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy and autosomal dominant cerebral small vessel disease (CSVD). This article described the definition, clinical features, magnetic resonance imaging manifestations, genetic and pathological examinations and treatment plans of HTRA1 related CSVD and highlighted the distinction between HTRA1 related CSVD and other inherited disorders with white matter involvement, and proposed a diagnostic pathway for timely recognition of HTRA1 related CSVD in a routine clinical environment. Ultimately, in addition to the conventional treatment of CSVD, effective targeted treatment methods still need to be established.

Secretory leukocyte peptidase inhibitor inhibits the inflammatory response and apoptosis of lipopolysaccharide-induced human proximal renal tubular cells / 中华危重病急救医学

Objective:To screen out the potential key genes of sepsis-associated acute kidney injury (AKI), and provide theoretical and experimental evidence for the treatment of sepsis-associated AKI.Methods:① Bioinformatics analysis: two gene expression datasets (GSE30718 and GSE53773) were downloaded for bioinformatics analysis from the Gene Expression Omnibus (GEO). These two datasets recorded mRNA microarray data from kidney biopsies before and after kidney transplantation, and a subset of patients developed AKI after kidney transplantation. Differential analysis was conducted, and the genes with the same differential expression and a higher area under the receiver operator characteristic curve (AUC) in both databases were used as the target gene for subsequent cell experiments. ② Cell validation experiment: human proximal renal tubular cells HK2 were cultured in vitro, and lipopolysaccharide (LPS) was used for establishing LPS-HK2 cell model (LPS 10 mg/L for 6 hours, LPS model group), and the blank control group was set. Then, small interfering RNA (siRNA) technology was used to knock down the target gene obtained by bioinformatics analysis in LPS-HK2 cells (gene knockdown group), and a gene negative control group was set. The real-time fluorescent quantitative reverse transcription-polymerase chain reaction (RT-qPCR) technique was used to detect the expression of the target gene in HK2 cells. Enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of inflammatory factors in the cell supernatants. Western blotting was used to detect the expressions of key apoptosis proteins. Results:① Results of bioinformatics analysis: 325 genes in the two datasets showed the same expression trend, of which 144 were significantly down-regulated and 181 were significantly up-regulated, while the expression difference of secretory leukocyte protease inhibitor (SLPI) in the two datasets was both statistically significant. Further receiver operator characteristic curve (ROC curve) analysis confirmed that the SLPI expression in GSE30718 and GSE53773 datasets had a high diagnostic efficiency for AKI, with AUC of 0.83 and 0.92, respectively. Therefore, SLPI was selected as the target gene for subsequent cell validation experiment. ② Cell validation experiment: the RT-qPCR analysis showed that the expression of SLPI in LPS-HK2 cells of the LPS model group was significantly higher than that of the blank control group (2 -ΔΔCT: 1.80±0.14 vs. 1.00±0.11, P < 0.01), and the change trend was the same with the results of bioinformatics analysis. Furthermore, knockdown SLPI gene analysis showed that the levels of inflammatory factors in LPS-HK2 cells supernatants in the gene knockdown group were significantly higher than those in the negative control group [Interleukin-6 (IL-6, ng/L): 509.58±27.08 vs. 253.87±75.83, IL-1β (ng/L): 490.99±49.52 vs. 239.67±26.97, tumor necrosis factor-α (TNF-α, ng/L): 755.22±48.66 vs. 502.06±10.92, all P < 0.01]. The above results indicated that SLPI could inhibit the inflammatory response of HK2 cells induced by LPS. The expressions of key apoptosis proteins Bax and caspase-3 in LPS-HK2 cells in the gene knockdown group were significantly higher than those in the negative control group [Bax protein (Bax/GAPDH): 1.38±0.12 vs. 1.00±0.10, caspase-3 protein (caspase-3/GAPDH): 1.44±0.15 vs. 1.00±0.11, both P < 0.05], and Bcl-2 expression was significantly decreased (Bcl-2/GAPDH: 0.83±0.08 vs. 1.00±0.05, P < 0.05), the above results indicated that SLPI could inhibit the apoptosis of cells in the inflammatory response. Conclusion:SLPI can inhibit the inflammatory response and apoptosis of HK2 cells induced by LPS, which may be involved in the protective mechanism of renal tubular cells in the response to sepsis, and is a potential target for the treatment of sepsis-associated AKI.

Non-alcoholic fatty liver disease: Epidemiology, pathophysiology and an update on the therapeutic approaches

Non-alcoholic fatty liver disease (NAFLD) denotes a spectrum of fatty liver disease in individuals without significant alcohol consumption. NAFLD is set to be the most common etiology of serious liver diseases in numerous nations when accompanied by obesity and type 2 diabetes. It is further histologically categorized into the non-alcoholic fatty liver (NAFL; steatosis without hepatocellular injury) and non-alcoholic steatohepatitis (NASH) which is characterized by the coexistence of hepatic steatosis and inflammation and is accompanied by hepatocyte injury (ballooning), either with or without fibrosis. NAFL is considered the benign and reversible stage arising from the excessive accumulation of triglycerides in hepatocytes. However, NASH is a more progressive stage of NAFLD, due to the increased risks of evolving more serious diseases such as cirrhosis, hepatocellular carcinoma. This concept, however, has been lately challenged by a hypothesis of multiple parallel hits of NAFLD, in which steatosis and NASH are separate entities rather than two points of the NAFLD spectrum, not only from a set of histological patterns but also from a pathophysiological perspective. The current review highlights the epidemiology and pathophysiology of NAFLD, and its progression towards steatohepatitis, with special focus on the novel imminent therapeutic approaches targeting the molecular aspects and the pathogenic pathways involved in the development, and progression of NAFLD.

Analysis of clinical characteristics of bullous pemphigoid developing after the treatment with dipeptidyl peptidase-Ⅳ inhibitors in 32 patients with diabetes mellitus / 中华皮肤科杂志

Objective:To investigate clinical characteristics of bullous pemphigoid (BP) developing after the treatment with dipeptidyl peptidase-Ⅳ inhibitors (DPP4i) in patients with diabetes mellitus.Methods:A total of 116 inpatients with BP complicated by diabetes mellitus were collected from the Seventh People′s Hospital of Shenyang between January 2014 and December 2020, and divided into 2 groups: DPP4i-BP group treated with DPP4i before the onset of BP, and general BP group receiving no treatment with DPP4i. General clinical data, skin lesion area, laboratory indicators, treatment regimens, and prognosis were analyzed and compared between the above 2 groups, the time interval from the administration of DPP4i to the diagnosis of BP was recorded in the DPP4i-BP group. One-way analysis of variance was used to compare measurement data among multiple groups, two-independent-sample t test was used for comparisons between two groups, and paired t-test for intra-group comparisons before and after treatment; chi-square test was used to compare enumeration data between groups. Results:There were 32 patients aged 77.17 ± 15.32 years in the DPP4i-BP group, with a male-to-female ratio being 15∶17; there were 84 patients aged 76.65 ± 19.32 years in the general BP group, with a male-to-female ratio being 43∶41. The time interval from the administration of DPP4i to the diagnosis of BP was 14.61 ± 3.93 months in the DPP4i-BP group. The time interval for vildagliptin was the shortest (5.42 ± 2.84 months) , and there was a significant difference in the time interval among vildagliptin, sitagliptin, linagliptin and saxagliptin ( F= 8.93, P < 0.001) . The proportion of patients with severe BP was significantly higher in the DPP4i-BP group (16 cases, 50%) than in the general BP group (25 cases, 29.76%; Z= 2.63, P= 0.008) . There was no significant difference in the positivity rate of anti-BP180 antibody between the two groups ( χ2= 0.03, P= 0.870) . However, the level of anti-BP180 antibody was significantly higher in the DPP4i-BP group than in the general BP group before and after treatment ( P= 0.015, < 0.001, respectively) , and the decrease in the level of anti-BP180 antibody was significantly less in the DPP4i-BP group than in the general BP group after treatment ( t= 5.11, P < 0.001) . There was no significant difference in the average effective dose of glucocorticoids required to control the disease between the two groups ( t= 1.00, P= 0.322) . However, the DPP4i-BP group showed a significant increase in the average time required to control the disease and in the proportion of patients requiring combined treatment with immunosuppressants or other drugs compared with the general BP group ( t= 6.72, 10.05, P < 0.001,= 0.002, respectively) . Within 6 months after the start of systemic treatment, the recurrence rate was significantly higher in the general BP group (17 cases, 27.86%) than in the DPP4i-BP group (2 cases, 7.69%; χ2= 4.35, P= 0.037) ; at 6 months, the average dose of glucocorticoids was also significantly higher in the general BP group than in the DPP4i-BP group ( t= 7.04, P < 0.001) . Conclusions:Among the DPP4i hypoglycemic drugs, vildagliptin was the most common drug administrated by patients before the onset of BP, with the shortest interval from the administration to the onset of BP. DPP4i-BP may be difficult to control at the early stage, but the prognosis is good.

Research progress of the relationship between the effect of laparoscopic sleeve gastrectomy on blood glucose and GLP-1/DPP-4 pathway in obese patients with type 2 diabetes mellitus / 中国医师杂志

Obesity and type 2 diabetes (T2DM) are all the metabolic diseases with high incidence rate. There is a clear correlation between the them. Weight-loss surgery is the important treatment of surgical method for obesity and T2DM.However, the mechanism of T2DM for weight loss surgery is not yet clear.The secretion level of glucagon like peptide-1 (GLP-1) was affected after weight loss surgery. The secretion of GLP-1 can delay gastric emptying, increase satiety, improve insulin resistance (IR) and promote β insulin release, inhibition of glucagon synthesis and secretion, and improvement of pancreatic function β cell function. All of these changes were conducive to glycemic control. Therefore, this paper aims to summarize and describe the relationship between the effect of laparoscopic sleeve gastrectomy (LSG) on blood glucose and GLP-1/dipeptidyl peptidase-4 (DPP-4) pathway in obese T2DM patients.

Gliptins vs. Milk-derived Dipeptidyl-Peptidase IV Inhibiting Biopeptides: Physicochemical Characterization and Pharmacokinetic Profiling / Gliptinas vs. Biopéptidos Inhibidores de Dipeptidil-Peptidasa IV Derivados de la Leche: Caracterización Fisicoquímica y Perfil Farmacocinético

Background: Milk-derived biopeptides have reported in vitro dipeptidyl-peptidase IV (DPP-IV) inhibition, suggesting a glycemic-regulatory effect in Type 2 Diabetes Mellitus (T2DM). Nonetheless, the therapeutic application of these nutraceuticals is limited by the scarcity of knowledge regarding their pharmacokinetic profile. Objective: This study aimed to characterize and assess the pharmacokinetics of milk-derived biopeptides. Through an in silico comparative analysis with gliptins, we expected to identify enhanced properties in food-hydrolysates and suitable DPP-IV inhibiting peptides as candidates for T2DM therapy. Methods: A comparison between gliptins and biopeptides was conducted based on in silico evaluation of drug-likeness, physicochemical properties, pharmacokinetics, and synthetic accessibility. Suitable target proteins for gastrointestinal-absorbable biopeptides were determined as well. Data collection was performed on SwissADME, ADMETlab, DrugBank, SwissTargetPrediction, ChemDes, and BIOPEP-UWM platforms. Statistical analysis was carried out using a one-way ANOVA test. Results: Drug-likeness compliance showed no significant difference between gliptins and biopeptides (p>0.05) in three out of nine assessed rules, though gastrointestinal-absorbable biopeptides exhibited no significant difference with gliptins in five drug-likeness guidelines. The physicochemical evaluation revealed a significant difference (p<0.05) between both groups, with peptides exhibiting enhanced solubility, flexibility, and polarity. Nine out of thirty-six assessed biopeptides reported being likely gastrointestinal-absorbable molecules, from which six displayed ≥30% predicted bioavailability, two reported CYP450 interactions, and all were determined to be blood confined. Biopeptides showed a slightly lower clearance than gliptins yet counteracted by a significantly lower half-life. Moreover, synthetic accessibility scores indicated higher synthetic ease for biopeptides. In addition, absorbable bioactive peptides reported a considerable binding affinity to DPP-IV and Calpain-I. Conclusions: Compared to gliptins, gastrointestinal-absorbable biopeptides exhibit superior physicochemical properties (higher solubility, flexibility, and polarity), lesser CYP450 interactions, higher synthetic ease, and some reported an important affinity for DPP-IV and Calpain-I. Only a small fraction of milk-derived biopeptides are suitable drug-like compounds and feasible candidates for T2DM therapy; yet, testing their therapeutic potency remains subject to further studies

Antecedentes: Los biopéptidos derivados de la leche han mostrado inhibir la dipeptidil-peptidasa IV (DPP-IV) en ensayos in vitro, lo que sugiere una regulación de la glicemia en la Diabetes Mellitus Tipo 2 (DM2). Sin embargo, su uso terapéutico está limitado por el escaso conocimiento de sus propiedades farmacológicas. Objetivo: Caracterizar y evaluar el perfil farmacocinético de los biopéptidos derivados de la leche. Por medio de un análisis comparativo in silico, se buscó identificar propiedades de carácter superior a las gliptinas en los biopéptidos inhibidores de DPP-IV, así como posibles candidatos a agentes terapéuticos en la DMT2. Métodos: Se llevó a cabo una comparación entre las Gliptinas y los biopéptidos basada en la evaluación in silicode las características "d r ug - li ke", propiedades fisicoquímicas, farmacocinética y accesibilidad sintética. Adicionalmente, se determinaron posibles proteínas diana para los biopéptidos de alta probabilidad de absorción gastrointestinal. Los datos se obtuvieron en SwissADME, ADMETlab, DrugBank, SwissTargetPrediction, ChemDes y BIOPEP-UWM. El análisis estadístico se basó en un análisis de varianza (one-way ANOVA test). Resultados: El cumplimiento de las reglas de "drug-likeness" no mostró diferencias significativas entre las gliptinas y los biopéptidos (p>0.05) en tres de las nueve normas evaluadas, empero, los biopéptidos absorbibles no mostraron diferencias significativas con las gliptinas en cinco de estas. La evaluación fisicoquímica reveló una diferencia significativa (p>0.05) entre ambos grupos y una mayor solubilidad, flexibilidad y polaridad para los biopéptidos. Nueve de los treinta y seis biopéptidos estudiados reportaron alta probabilidad de absorción gastrointestinal, de los cuales seis presentaron una biodisponibilidad predicha ≥30%, dos reportaron interacciones con el CYP450, y todos mostraron permanecer confinados en sangre. Los biopéptidos mostraron una tasa de aclaramiento inferior a las gliptinas, sin embargo, contrarrestado por una vida-media significativamente menor. Los valores de accesibilidad sintética indicaron una mayor facilidad de síntesis para los biopéptidos. Por último, los biopéptidos absorbibles mostraron una considerable afinidad por la DPP-IV y la Calpaína-I. Conclusiones: Frente a las gliptinas, los biopéptidos absorbibles presentan: propiedades fisicoquímicas superiores (mayor solubilidad, flexibilidad y polaridad), menores interacciones con el CYP450, mayor facilidad de síntesis y algunos una importante afinidad por la DPP-IV y la Calpaína-I. Una mínima fracción de biopéptidos derivados de la leche son candidatos viables para la terapia de DM2; sin embargo, la determinación de su efectividad terapéutica permanece sujeta a futuros estudios

Effects of Incretin - based Therapy on High - sensitivity C - reactive Protein in Patients with Type 2 Diabetes: A Systematic Review and Meta - Analysis

ABSTRACT Background: Recently, studies had shown that incretin-based therapies could reduce the levels of pro-inflammatory markers. The data on the effects of incretin-based therapies on serum high-sensitivity C-reactive protein (hs-CRP) in type 2 diabetes (T2DM) were inconsistent. Objective: The objective of the study was to assess the effects of incretin-based therapies on hs-CRP in patients with T2DM by meta-analysis. Methods: We searched PubMed, EMBASE, the Cochrane Collaboration Library, and Web of Science to identify the eligible randomized clinical trials until August 2019. The pooled standard mean differences (SMD) were calculated by random-effects model using STATA 11.0. Results: Twenty-five studies with 28 randomized controlled trials were finally included into the meta-analysis. Meta-analysis revealed a significant reduction in hs-CRP following treatment with incretin-based regimens compared to controls (SMD = −0.452, p < 0.001). Subgroup analysis of different class of incretin-based drugs showed that therapy with both dipeptidyl peptidase 4 inhibitors (DPP-4Is, SMD = −0.338, p = 0.026) and glucagon-like peptide 1 receptor agonists (GLP-1 RAs, SMD = −0.544, p = 0.003) caused significant reductions in hs-CRP. Besides, there was a significant reduction in hs-CRP with an intervention duration more than 24 weeks (SMD = −0.465, p = 0.001), while no significant difference with <24 weeks. Meta-regression analyses showed that better glycemic control and more body mass index (BMI) decline were associated with hs-CRP reduction after incretin-based therapies. Conclusions: This meta-analysis suggests that incretin-based therapies, both GLP-1 RAs and DPP-4Is, can cause a significant reduction in hs-CRP in patients with T2DM, which is related to long intervention duration, better glycemic control, and more BMI decline.

Efficacy and Safety Comparison between Pioglitazone and Linagliptin in Combination with Metformin among Patients with Type 2 Diabetes Mellitus: A Meta-Analysis of Randomized Controlled Trials

Objective: To compare the safety and efficacy of linagliptin with pioglitazone in combination therapy of metformin for the management of type2 diabetes mellitus (T2DM). Materials and Methods: A meta-analayis research design is applied to evaluate the primary and secondary outcomes. Literature search was carried out using databases such as PubMed, Cochrane Library, MEDLINE Complete, Scopus, Clinical Trial Registry, and Web of Science. Studies were considered eligible if the eligibility criteria were met. Cochrane Collaboration Tool was used to assess the risk of bias in randomized clinical trials. Results: A total of 170 citations were identified during the database search. Further evaluation of articles confirmed 16 clinical trials suitable for the research which were randomized, double-blinded, and published as full articles. The articles were evaluated with low risk of bias and high-quality evidence. The mean baseline hemoglobin A1c(HbA1c) ranged from 6.93% to 9.99% and 7.1% to 8.89% for linagliptin with metformin and pioglitazone with metformin groups, respectively. Two among the 12 groups show a slight increase in the mean HbA1c levels which is nonsignificant due to their sample size. Overall, the combination therapy of linagliptin with metformin led to a reduction of 1.35% which is significantly higher than pioglitazone combined with metformin which led to a 1.27% reduction. The mean baseline values of fasting plasma glucose levels varied from 158.2 mg/dl to 198.0 mg/dl in linagliptin plus metformin group, whereas in pioglitazone plus metformin group, the values varied from 137.0 mg/dL to 212.4 mg/dL. The high heterogeneity could refer to the inconsistencies between the studies. The combination of linagliptin with metformin showed a significant reduction of 0.56% in body mass index, whereas pioglitazone with metformin led to a 0.37% reduction.Conclusion: The findings showed better efficacy profiling of lingaliptin–metformin combination compared with pioglitazone combination therapy.

Comparison of Protein Binding Rate of DPP- 4 Inhibitor LGT- 6 in Different Species of Plasma / 中国药房

OBJECTIVE：To establish the method for determining protein binding rate of dipeptidyl peptidase- 4 inhibitor LGT- 6 in different species of plasma ，and to compare their difference. METHODS ：By equilibrium dialysis ，LGT-6（3，30，300，3 000 nmol/L）was equilibrated in rat ，monkey and human plasma （i. e. internal dialysis solution ）for 48 h，using phosphate buffer as the external dialysis solution. The concentration of LGT- 6 in internal and external dialysis solution was determined by UPLC-MS/MS using tolbutamide as internal standard ，and the plasma protein binding rate was calculated. The determination was performed on ACQUITY UPLC HSS T 3 column with water （containing 0.01％ formic acid ）-acetonitrile（containing 0.01％ formic acid ）as mobile phase at the flow rate of 0.6 mL/min. The column temperature was 40 ℃，and the sample size was 2 μL. The ion source was electrospray ion source ，and the multiple ion monitoring mode was used to carry out positive ionization scanning. The ion pairs for quantitative analysis were m/z 487.0→434.3（LGT-6），m/z 271.1→172.0（internal standard ），respectively. RESULTS ：At the concentrations of 3，30，300，and 3 000 nmol/L，the protein binding rates of LGT- 6 in rat plasma were （96.25±0.97）％，（84.16± 1.24）％，（78.25±0.61）％，（66.63±0.95）％；the protein protein binding rates in monkey plasma were （98.54±0.58）％，（87.27± 1.01）％，（79.35±0.86）％，（66.69±0.54）％；the protein binding rates in human plasma were （99.40±1.03）％，（84.48± 1.15）％，（77.62±0.77）％，（66.93±0.48）％. At the same concentration ，the protein binding rates of LGT- 6 in rat ，monkey and human plasma had no significant difference （P＞0.05）. In the same species of plasma ，there were significant differences in the plasma protein binding rates of different concentration of LGT-6 among those groups （P＜0.05），and it decreased with 才〔2016〕4015） the increase of drug concentration. CONCLUSIONS ： The method for the determination of plasma protein binding rate of LGT-6 is successfully established. The data revealed that the protein binding rate of LGT- 6 is concentration-dependent ， there was no obvious spec ies difference on protein binding rates of LGT- 6 in rat ，monkey and human plasma under the same concentration.

Antihyperglycaemic activity of ethylacetate extract of Chlorophytum alismifolium in type 2 diabetes: The involvement of peroxisome proliferator-activated receptor-γ and dipeptidyl peptidase-4 / 中西医结合学报

OBJECTIVE@#This research is to investigate the antihyperglycaemic activity and the underlying mechanisms of action of the ethylacetate extract of Chlorophytum alismifolium (EACA) tubers in a type 2 diabetes model.@*METHODS@#The tubers were processed and sequentially extracted in hexane followed by ethylacetate, using a Soxhlet apparatus, and subjected to gas chromatography-mass spectrometry (GC-MS). The acute toxicity of EACA was investigated in albino Wistar rats. An antihyperglycaemic study was carried out using high-fat diet (pelletized diet and margarine in the ratio of 10:1 and 20% fructose solution) and streptozotocin-induced hyperglycaemic Wistar rats. The effects of the extract (150, 300 and 600 mg/kg) on blood glucose level, insulin, peroxisome proliferator-activated receptor-γ (PPAR-γ) and dipeptidyl peptidase-4 (DPP-4) were evaluated using enzyme-linked immunosorbent assay.@*RESULTS@#The oral median lethal dose in Wistar rats was estimated to be > 5000 mg/kg. Treatment with EACA at all doses significantly reduced the fasting blood glucose levels, compared to the hyperglycaemic control, and over time. Administration of EACA increased the serum insulin and PPAR-γ levels while decreasing DPP-4 levels. GC-MS analysis revealed the presence of 13 compounds, with isothiazole and isoxazolidine covering total area of 24.6% and 22.69%, respectively.@*CONCLUSION@#The findings from this study showed that EACA has important compounds with beneficial effect in type 2 diabetes and acts by increasing insulin secretion and PPAR-γ level and decreasing DPP-4 activity.

The Effect of DPP4 Inhibitor on Glycemic Variability in Patients with Type 2 Diabetes treated with twice-daily Premixed Human Insulin / Journal of the ASEAN Federation of Endocrine Societies

Objective@#To evaluate the effect of adding DPP4 inhibitor (DPP4-i) on glycemic variability (GV) in patients with type 2 diabetes mellitus (T2DM) treated with premixed human insulin (MHI).@*Methodology@#We conducted a prospective study in patients with T2DM on twice-daily MHI with or without metformin therapy. Blinded continuous glucose monitoring was performed at baseline and following 6 weeks of Vildagliptin therapy.@*Results@#Twelve patients with mean (SD) age of 55.8 (13.1) years and duration of disease of 14.0 (6.6) years were recruited. The addition of Vildagliptin significantly reduced GV indices (mmol/L): SD from 2.73 (IQR 2.12-3.66) to 2.11 (1.76-2.55), p=0.015; mean amplitude of glycemic excursions (MAGE) 6.94(2.61) to 5.72 (1.87), p=0.018 and CV 34.05 (8.76) to 28.19 (5.36), p=0.010. In addition, % time in range (3.9-10 mmol/l) improved from 61.17 (20.50) to 79.67 (15.33)%, p=0.001; % time above range reduced from 32.92 (23.99) to 18.50 (15.62)%, p=0.016; with reduction in AUC for hyperglycemia from 1.24 (1.31) to 0.47 (0.71) mmol/day, p=0.015. Hypoglycemic events were infrequent and the reduction in time below range and AUC for hypoglycemia did not reach statistical significance.@*Conclusion@#The addition of DPP4-I to commonly prescribed twice-daily MHI in patients with T2DM improves GV and warrants further exploration.

Assessment of risk conferred by coding and regulatory variations of TMPRSS2 and CD26 in susceptibility to SARS-CoV-2 infection in human

At present, more than 200 countries and territories are directly affected by the coronavirus disease-19 (COVID-19) pandemic. Incidence and case fatality rate are significantly higher among elderly individuals (age [60 years), type 2 diabetes and hypertension patients. Cellular receptor ACE2, serine protease TMPRSS2 and exopeptidase CD26 (also known as DPP4) are the three membrane bound proteins potentially implicated in SARS-CoV-2 infection. We hypothesised that common variants from TMPRSS2 and CD26 may play critical role in infection susceptibility of predisposed population or group of individuals. Coding (missense) and regulatory variants from TMPRSS2 and CD26 were studied across 26 global populations. Two missense and five regulatory SNPs were identified to have differential allelic frequency. Significant linkage disequilibrium (LD) signature was observed in different populations. Modelled protein–protein interaction (PPI) predicted strong molecular interaction between these two receptors and SARS-CoV-2 spike protein (S1 domain). However, two missense SNPs, rs12329760 (TMPRSS2) and rs1129599 (CD26), were not found to be involved physically in the said interaction. Four regulatory variants (rs112657409, rs11910678, rs77675406 and rs713400) from TMPRSS2 were found to influence the expression of TMPRSS2 and pathologically relevant MX1. rs13015258 a 50 UTR variant from CD26 have significant role in regulation of expression of key regulatory genes that could be involved in SARS-CoV-2 internalization. Overexpression of CD26 through epigenetic modification at rs13015258-C allele was found critical and could explain the higher SARS-CoV-2 infected fatality rate among type 2 diabetes.