HIV-associated neurocognitive disorder: key implications of the microbiota-gut-brain axis.

HIV-associated neurocognitive disorder (HAND) is now recognized to be relatively common in people living with HIV (PLWH), and remains a common cause of cognitive impairment. Unfortunately, the fundamental pathogenic processes underlying this specific outcome of HIV infection have not as yet been fully elucidated. With increased interest in research related to the microbiota-gut-brain axis, the gut-brain axis has been shown to play critical roles in regulating central nervous system disorders such as Alzheimer's disease and Parkinson's disease. PLWH are characterized by a particular affliction, referred to as gut-associated dysbiosis syndrome, which provokes an alteration in microbial composition and diversity, and of their associated metabolite composition within the gut. Interestingly, the gut microbiota has also been recognized as a key element, which both positively and negatively influences human brain health, including the functioning and development of the central nervous system (CNS). In this review, based on published evidence, we critically discuss the relevant interactions between the microbiota-gut-brain axis and the pathogenesis of HAND in the context of HIV infection. It is likely that HAND manifestation in PLWH mainly results from (i) gut-associated dysbiosis syndrome and a leaky gut on the one hand and (ii) inflammation on the other hand. In other words, the preceding features of HIV infection negatively alter the composition of the gut microbiota (microbes and their associated metabolites) and promote proinflammatory immune responses which singularly or in tandem damage neurons and/or induce inadequate neuronal signaling. Thus, HAND is fairly prevalent in PLWH. This work aims to demonstrate that in the quest to prevent and possibly treat HAND, the gut microbiota may ultimately represent a therapeutically targetable "host factor."

CircLZIC regulates ox-LDL-induced HUVEC cell proliferation and apoptosis via Micro-330-5p/NOTCH2 axis in atherosclerosis.

Atherosclerosis (AS) is a major chronic non-communicable disease and a primary cause of cardiovascular disease. Recent studies have shown that circRNAs are potential epigenetic factors that regulate vascular endothelial inflammatory responses and AS progression. Therefore, identification of the circRNAs that regulate ox-LDL levels is a critical step to understanding the pathology of AS. Our study is aim to investigate how circLZIC regulates atherosclerosis (AS) via the Micro-330-5p/NOTCH2 regulatory axis. The results showed that CircLZIC and NOTCH2 are highly expressed in human AS clinical samples, while Micro-330-5p is expressed locally. The CCK-8 experiment results showed that circLZIC promotes the proliferation of HUVECS cells. Flow cytometry analysis showed that circLZIC act as an inhibitor of HUVEC cell apoptosis. The expression level of Micro-330-5p can be up-regulated by transfection of small interfering RNA against circLZIC. Further, Starbase predicted that Micro-330-5p could target and regulate NOTCH2. Next, we confirmed that overexpression of Micro-330-5p could significantly reduce the expression of fluorescein using the double Luciferase reporter assay. RIP-qRT-PCR experiment showed that Micro-330-5p and NOTCH2 mRNAs are effectively enriched by ago2 protein. Further, we found that knocking down circLZIC increases the expression of Micro-330-5p and promotes cell apoptosis, while inhibiting the expression of NOTCH2 and cell activity. On the other hand, co-transfection of Micro-330-5p inhibitor decreases Micro-330-5p expression and inhibit cell apoptosis, while increasing NOTCH2 expression and cell activity. In conclusion, CircLZIC regulates HUVEC cell activity by the Micro-330-5p/NOTCH2 signaling pathway, suggesting that circLZIC plays a key role in atherosclerosis development.

Identification and characterization of the metabolites of moscatilin in mouse, rat, dog, monkey and human hepatocytes by LC-Orbitrap-MS/MS combined with diagnostic fragment ions and accurate mass measurements.

Moscatilin, a bibenzyl derivative from the stem of Dendrobium loddigesii, has been shown to have anticancer activity. The aim of this study was to identify and characterize the possible in vitro metabolites of moscatilin generated from hepatocytes. The metabolites generated in the hepatocytes of mouse, rat, dog, monkey and human were identified and characterized employing ultra-high-performance liquid chromatography coupled with quadrupole Orbitrap tandem mass spectrometry (LC-Orbitrap-MS/MS) based on diagnostic fragment ions and accurate mass measurements. A total of 18 metabolites were identified, among which seven were phase I and 11 were phase II metabolites. The plausible structures of the metabolites and the probable biotransformation pathways were proposed based on the diagnostic fragment ions, chemical formula and mass fragmentation pattern, as well as the accurate masses. The majority of phase I metabolites were generated by demethylation and hydroxylation, while phase II metabolites were mainly generated by glucuronidation, glutathione conjugation and sulfation. Our study first expounded the metabolites of moscatilin in mouse, rat, dog, monkey and human hepatocytes and provided a foundation for a further pharmacokinetic and toxicity study. More importantly, LC-Orbitrap-MS/MS combined with diagnostic fragment ions and accurate mass measurements has been proved to be an effective method for the rapid identification of bibenzyl derivatives and their metabolites.

Safety and efficacy of His-bundle pacing/left bundle branch area pacing versus right ventricular pacing: a systematic review and meta-analysis.

BACKGROUND: Recent studies have demonstrated that right ventricular pacing (RVP) has deleterious effects on non-synchronized ventricular contraction, while His-bundle pacing (HBP) or left bundle branch area pacing (LBBaP) contribute to improvements in patients' mid- and long-term outcomes. This meta-analysis aimed to compare the safety and efficacy of physiologic pacing (HBP/LBBaP) versus those of RVP. METHODS: A systematic search of PubMed, Cochrane Library, and Embase was conducted for studies that compared the effects of physiologic pacing and RVP. All eligible studies were published before January 1, 2021 and were conducted in humans. STATA software version 15.0 was used for all the data analyses. RESULTS: Twenty articles (n = 2787 patients) were included in this meta-analysis. Compared to RVP, physiologic pacing was associated with a significantly shorter QRS duration and better cardiac function. Physiologic pacing was also correlated with lower rates of mitral regurgitation, pacing-induced cardiomyopathy, death, heart failure hospitalization, and atrial fibrillation, although the above results were not statistically significant. In addition, RVP led to the achievement of higher success rates than physiologic pacing, a shorter fluoroscopic time and mean procedure duration, a lower pacing threshold: the results were statistically significant. Compared with HBP, LBBaP appeared to have some advantages in R wave amplitudes, pacing threshold, fluoroscopic time, procedure time, and success rate, with statistically significant differences. Whereas HBP was associated with fewer surgical complications and shorter QRS duration, the results were not statistically significant. CONCLUSION: Physiologic pacing (HBP/LBBaP) might be a better strategy than RVP and improve long-term clinical outcomes like cardiac function. Although LBBaP appears to have some advantages over HBP, the long-term benefits are still controversial. More large-scale randomized clinical trials are needed for further verification.

Effects of SGLT2 inhibitors on cardiovascular, renal, and major safety outcomes in heart failure: A meta-analysis of randomized controlled trials.

AIMS: Sodium-glucose co-transporter 2 inhibitor (SGLT2i), initially introduced for the treatment of diabetes mellitus (DM), demonstrates cardiovascular and renal benefits in patients with heart failure (HF). We aimed to conduct a meta-analysis of its effects on cardiovascular, renal, and major safety outcomes in HF. METHODS AND RESULTS: PubMed, Embase, Cochrane Library, and Web of Science were searched using the terms of "SGLT2i and HF" or "SGLT2i *". Seven randomized, placebo-controlled trials comprising 14,113 HF patients (mean age, 66.0 years; female, 27.6%; DM, 58.9%) were included. SGLT2i treatment was associated with lower incidences (compared with placebo) of the composite outcomes of cardiovascular death or hospitalization for HF (HHF) (ratio risk [RR] 0.773; 95% confidence interval [CI], 0.719-0.831; p < 0.001; I2 = 8.1%), cardiovascular death (RR 0.872; 95% CI, 0.788-0.964; p = 0.008; I2 = 0.0%), HHF (RR 0.722; 95% CI, 0.657-0.793; p < 0.001; I2 = 15.4%) and serious decrease in renal function (RR 0.673; 95% CI, 0.549-0.825; p < 0.001; I2 = 17.7%). SGLT2i treatment was associated with a lower incidence of serious adverse events (SAEs) (RR 0.867; 95% CI, 0.808-0.930; p < 0.001; I2 = 60.1%), but a higher incidence of volume depletion (RR 1.177; 95% CI, 1.040-1.333; p = 0.010; I2 = 0.0%). Analysis on patients without DM showed consistent results, except for cardiovascular death. CONCLUSION: SGLT2i treatment contributed to better cardiovascular and renal outcomes in patients with HF, regardless of the presence or absence of DM. SGLT2i also resulted in a lower incidence of SAEs, although a higher incidence of volume depletion was observed.

Microbiota-Meditated Immunity Abnormalities Facilitate Hepatitis B Virus Co-Infection in People Living With HIV: A Review.

Hepatitis B virus (HBV) co-infection is fairly common in people living with HIV (PLWH) and affects millions of people worldwide. Identical transmission routes and HIV-induced immune suppression have been assumed to be the main factors contributing to this phenomenon. Moreover, convergent evidence has shown that people co-infected with HIV and HBV are more likely to have long-term serious medical problems, suffer more from liver-related diseases, and have higher mortality rates, compared to individuals infected exclusively by either HIV or HBV. However, the precise mechanisms underlying the comorbid infection of HIV and HBV have not been fully elucidated. In recent times, the human gastrointestinal microbiome is progressively being recognized as playing a pivotal role in modulating immune function, and is likely to also contribute significantly to critical processes involving systemic inflammation. Both antiretroviral therapy (ART)-naïve HIV-infected subjects and ART-treated individuals are now known to be characterized by having gut microbiomic dysbiosis, which is associated with a damaged intestinal barrier, impaired mucosal immunological functioning, increased microbial translocation, and long-term immune activation. Altered microbiota-related products in PLWH, such as lipopolysaccharide (LPS) and short-chain fatty acids (SCFA), have been associated with the development of leaky gut syndrome, favoring microbial translocation, which in turn has been associated with a chronically activated underlying host immune response and hence the facilitated pathogenesis of HBV infection. Herein, we critically review the interplay among gut microbiota, immunity, and HIV and HBV infection, thus laying down the groundwork with respect to the future development of effective strategies to efficiently restore normally diversified gut microbiota in PLWH with a dysregulated gut microbiome, and thus potentially reduce the prevalence of HBV infection in this population.