RESUMEN

Meckel syndrome (MKS), also known as the Meckel-Gruber syndrome, is a severe pleiotropic autosomal recessive developmental disorder caused by dysfunction of the primary cilia during early embryogenesis. The diagnostic criteria are based on clinical variability and genetic heterogeneity. Mutations in the MKS1 gene constitute approximately 7% of all MKS cases. Herein, we present a non-consanguineous couple with three abnormal pregnancies as the fetuses showed MKS-related phenotypes of the central nervous system malformation and postaxial polydactyly. Whole-exome sequencing identified two novel heterozygous mutations of MKS1: c.350C>A and c.1408-14A>G. The nonsense mutation c.350C>A produced a premature stop codon and induced the truncation of the MKS1 protein (p.S117*). Reverse-transcription polymerase chain reaction (RT-PCR) showed that c.1408-14A>G skipped exon 16 and encoded the mutant MKS1 p.E471Lfs*92. Functional studies showed that these two mutations disrupted the B9-C2 domain of the MKS1 protein and attenuated the interactions with B9D2, the essential component of the ciliary transition zone. The couple finally got a healthy baby through preimplantation genetic testing for monogenic disorder (PGT-M) with haplotype linkage analysis. Thus, this study expanded the mutation spectrum of MKS1 and elucidated the genetic heterogeneity of MKS1 in clinical cases.

RESUMEN

Patients with type 2 diabetes mellitus (T2DM) have a very high risk of cardiovascular related events, and reducing complications is an important evaluation criterion of efficacy and safety of hypoglycemic drugs. Previous studies have shown that the dipeptidyl peptidase-4 (DPP-4) inhibitors (DPP4i), such as sitagliptin, might reduce the incidence of major cardiovascular events (MACEs). However, the safety and efficacy of sitagliptin remains controversial, especially the safety for cardiovascular related events. Here, a systematic review was conducted to assess the cardiovascular safety of sitagliptin in T2DM patients. The literature research dating up to October 2018 was performed in the electronic database. The clinical trials about sitagliptin for T2DM patients were included. Two reviewers independently screened literature according to the inclusion and exclusion criteria. The primary outcome was the MACE, and the secondary outcome was all-cause mortality. Finally, 32 clinical trials composed of 16082 T2DM patients were included in this meta-analysis. The results showed that: there was no significant difference between sitagliptin group and the control group on MACE (odds ratio (OR) = 0.85, 95% confidence intervals (CIs) = 0.63-1.15), myocardial infarction (MI) (OR = 0.66, 95% CI = 0.38-1.16), stroke (OR = 0.83, 95% CI = 0.44-1.54) and mortality (OR = 0.52, 95% CI = 0.26-1.07). These results demonstrated that sitagliptin did not increase the risk of cardiovascular events in patients with T2DM.

Asunto(s)

Anomalías Cardiovasculares/epidemiología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Fosfato de Sitagliptina/uso terapéutico , Anomalías Cardiovasculares/inducido químicamente , Anomalías Cardiovasculares/patología , Diabetes Mellitus Tipo 2/patología , Femenino , Humanos , Hipoglucemiantes/efectos adversos , Masculino , Infarto del Miocardio/inducido químicamente , Infarto del Miocardio/epidemiología , Infarto del Miocardio/patología , Factores de Riesgo , Fosfato de Sitagliptina/efectos adversos , Accidente Cerebrovascular/inducido químicamente , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/patología

RESUMEN

The development of diabetes mellitus (DM) and its complications is a chronic inflammatory response process, chemokines and their receptors play an important role in this course of events. The aim of this study is to observe the effects of sodium tanshinone IIa sulfonate (STS) on high glucose-induced fractalkine (FKN) level, and investigate possible mechanisms of STS works. HUVECs cells were employed to explore the effects of STS on FKN protein. TUNEL assay was used to detect the apoptosis rate of HUVECs. Immunohistochemistry was utilized to detect the ß-actin and P-GSK-3ß (Ser9) protein expression. Immunofluorescence was employed to detect FKN protein expression. Real-time RT-PCR was used to examine ß-actin, GSK3ß and FKN mRNA expression. The results indicated that the STS treatment could significantly decrease the apoptosis rate caused by high-glucose (P < 0.05). STS improves ß-catenin and p-GSK-3ß (Ser9) expression, and inhibits FKN levels induced by high glucose. STS inhibited GSK-3ß and FKN mRNA induced by high glucose. In conclusion, STS may play the role of anti- inflammatory by regulate canonical Wnt pathway to inhibit the expression of FKN induced by high glucose.