NLRP3 inflammasome-mediated premature immunosenescence drives diabetic vascular aging dependent on the induction of perivascular adipose tissue dysfunction.

AIMS: The vascular aging process accelerated by type 2 diabetes mellitus (T2DM) is responsible for the elevated risk of associated cardiovascular diseases (CVDs). Metabolic disorder-induced immune senescence has been implicated in multi-organ/tissue damage. Herein, we sought to determine the role of immunosenescence in diabetic vascular aging and to investigate the underlying mechanisms. METHODS AND RESULTS: Aging hallmarks of the immune system appear prior to the vasculature in streptozotocin (STZ)/high-fat diet (HFD)-induced T2DM mice or db/db mice. Transplantation of aged splenocytes or diabetic splenocytes into young mice triggered vascular senescence and injury compared to normal control splenocyte transfer. RNA-seq profile and validation in immune tissues revealed that the Toll-like receptor 4 (TLR4)- Nuclear factor-kappa B (NF-κB) -NLRP3 axis might be the mediator of diabetic premature immunosenescence. The absence of Nlrp3 attenuated immune senescence and vascular aging during T2DM. Importantly, senescent immune cells, particularly T cells, provoked perivascular adipose tissue (PVAT) dysfunction and alternations in its secretome, which in turn impair vascular biology. In addition, senescent immune cells may uniquely affect vasoconstriction via influencing PVAT. Lastly, rapamycin alleviated diabetic immune senescence and vascular aging, which may be partly due to NLRP3 signaling inhibition. CONCLUSION: These results indicated that NLRP3 inflammasome-mediated immunosenescence precedes and drives diabetic vascular aging. The contribution of senescent immune cells to vascular aging is a combined effect of their direct effects and induction of PVAT dysfunction, the latter of which can uniquely affect vasoconstriction. We further demonstrated that infiltration of senescent T cells in PVAT was increased and associated with PVAT secretome alterations. Our findings suggest that blocking the NLRP3 pathway may prevent early immunosenescence and thus mitigate diabetic vascular aging and damage, and targeting senescent T cells or PVAT might also be the potential therapeutic approach.

[AIDS-related knowledge, attitudes and behaviors: a prevalence survey among 309 homosexual men in a Chinese city].

OBJECTIVE: To gain an insight into the demographic characteristics and AIDS-related knowledge, attitudes and behaviors of men who have sex with men (MSM) in a Chinese city, and to offer a base for preventive measures against AIDS. METHODS: We carried out a prevalence survey, using "snowball" methods to set up survey sites in the "comrade" community, the "comrades" looking for the respondents by various means. RESULTS: Among 309 respondents, 265 (85.8%) were younger than 30 years, 187 (60.5%) received college education or above, 187 (60.5%) were government officials or employees, and 91 (29.4%) were students; 299 (96.8%) were willing or very willing to get knowledge about HIV prevention and treatment, 201 (65.1%) considered themselves as MSM, 76 (24.6%) admitted bisexuality, 117 (37.9%) had insertion sex with at least three men in the past six months, 61 (19.7%) had two or more regular male sexual partners, 140 (45.3%) used condoms on >80% occasions and 34 (11.0%) occasionally or never used them during vaginal sex in the past six months. CONCLUSION: MSM in the city showed the characteristics of younger age, higher education, stable employment and income, more than one sexual partner, high frequency of high-risk behavior, and negligence of condom-use, and most (96.8%) of them are willing or very willing to obtain AIDS prevention knowledge, which deserves particular attention from relevant institutions.

[A new mutation in the GJB1 gene of a Chinese family with Charcot-Marie-Tooth disease associated with vocal cord paresis].

OBJECTIVE: To report an X-linked dominant Charcot-Marie-Tooth disease (CMTX) Chinese family with vocal cord paresis and to identify the mutation of gap junction protein beta 1 gene (GJB1). METHODS: Part of the family members with dysphagia, dysphonia and lethal respiratory failure were studied through flexible laryngoscope, clinical, brain MRI and electrophysiological examinations. After excluding large fragment tandem duplication containing peripheral myelin protein 22 gene (PMP22), direct sequencing was performed to analyze the mutation of the GJB1 gene in 5 patients including the proband, 5 unaffected family members and 50 unrelated healthy individuals. RESULTS: Eight members spanning 3 generations in this family were affected with CMTX characterized by progressive atrophy and weakness of the anterior tibial and peroneal muscles, especially in the proband. Vocal cord paresis was observed through flexible laryngoscope in total of 4 affected members with dysarthria and dysphagia, 2 of them died of severe respiratory failure due to complete bilateral vocal cord involvement. Normal brain MRI was observed in the proband. The electrophysiological data showed predominant demyelization involving the motor and sensory nerves in the proband. DNA sequencing revealed a de novo c.186 C>G missense mutation in exon 2 of the GJB1 gene, the mutation cosegregated with phenotype. CONCLUSION: Respiratory failure associated with vocal cord involvement may be a rare and severe symptom in CMTX. The present report provides further evidence for clinical and genetic heterogeneity in the X-linked Charcot-Marie-Tooth disease.