DZ2002 alleviates corneal angiogenesis and inflammation in rodent models of dry eye disease via regulating STAT3-PI3K-Akt-NF-κB pathway.

Dry eye disease (DED) is a prevalent ocular disorder with a multifactorial etiology. The pre-angiogenic and pre-inflammatory milieu of the ocular surface plays a critical role in its pathogenesis. DZ2002 is a reversible type III S-adenosyl-L-homocysteine hydrolase (SAHH) inhibitor, which has shown excellent anti-inflammatory and immunosuppressive activities in vivo and in vitro. In this study, we evaluated the therapeutic potential of DZ2002 in rodent models of DED. SCOP-induced dry eye models were established in female rats and mice, while BAC-induced dry eye model was established in female rats. DZ2002 was administered as eye drops (0.25%, 1%) four times daily (20 µL per eye) for 7 or 14 consecutive days. We showed that topical application of DZ2002 concentration-dependently reduced corneal neovascularization and corneal opacity, as well as alleviated conjunctival irritation in both DED models. Furthermore, we observed that DZ2002 treatment decreased the expression of genes associated with angiogenesis and the levels of inflammation in the cornea and conjunctiva. Moreover, DZ2002 treatment in the BAC-induced DED model abolished the activation of the STAT3-PI3K-Akt-NF-κB pathways in corneal tissues. We also found that DZ2002 significantly inhibited the proliferation, migration, and tube formation of human umbilical endothelial cells (HUVECs) while downregulating the activation of the STAT3-PI3K-Akt-NF-κB pathway. These results suggest that DZ2002 exerts a therapeutic effect on corneal angiogenesis in DED, potentially by preventing the upregulation of the STAT3-PI3K-Akt-NF-κB pathways. Collectively, DZ2002 is a promising candidate for ophthalmic therapy, particularly in treating DED.

Long-lasting and Sex-dependent Effects of Postweaning Swimming Exercise on Social Dominance in Adult Mice.

Increasing evidence has shown that early life events exert long-lasting effects on brain function and mental diseases. Exercise has been proven to have many positive effects on behaviors, such as reducing anxiety- and depression-like behaviors and alleviating cognitive impairment. However, the long-lasting and even short-term effects of regular swimming exercise on social dominance remain unclear. The purpose of this study was to investigate the potential effects of postweaning swimming exercise on social dominance and metabolic adaptation in adult mice. Three-week-old mice performed 1 h of swimming exercise in warm water for 4 weeks. A series of behavioral tests, such as the social dominance test (SDT), open field test (OFT), and forced swim test (FST), were conducted. Behavioral test results showed that both male and female mice in the swimming group had a higher rank than those in the sedentary group in the SDT of early adulthood, while only female mice in the swimming group maintained the social dominance in late adulthood. There was no difference between the swimming and sedentary groups in anxiety- and depression-like behaviors. Metabolomics analysis showed that there were alterations in particular metabolites and signaling pathways after one month of swimming exercise, including sphingolipid metabolism, neuroactive ligand-receptor interaction and caffeine metabolism. In conclusion, our results provide the first evidence that postweaning swimming exercise has long-lasting and sex-dependent effects on social dominance, which may be caused by metabolic adaptation.

Repeated 3,3-Dimethyl-1-butanol exposure alters social dominance in adult mice.

The influence of gut microbiota on brain function and brain disorders has been attracted more and more attention. Trimethylamine N-oxide (TMAO), an indirect metabolite of gut microbiota, has been linked to aging, cognitive impairment, and other brain disorders. However, the relationship between TMAO and social behaviors are still poorly understood. Adult male mice were exposed to drinking water containing 3,3- Dimethyl-1-butanol (DMB), an indirect inhibitors of TMAO, for 21 continuous days followed by a series of behavioral tests to detect the effect of DMB exposure on social behaviors, mainly including social dominance test (SDT), bedding preference test (BP), sexual preference test (SP), social interaction test (SI), open field test (OFT), tail suspension test (TST), forced swim test (FST), novelty suppressed feeding test (NSF), and novel object recognition (NOR) task. In the SDT, compared with the control group, the mice treated with DMB (both 0.2% and 1.0%), both high-ranked and low-ranked mice, showed a reduction in the number of victories. There is no statistical difference on sexual preference, anxiety, depression-like behavior phenotype, and memory formation. In conclusion, the present findings provide direct evidence, for the first time, that repeated DMB exposure produces significant effects on social dominance of adult mice, without any effects on sexual preference, anxiety, depression-like behavior phenotype or memory formation, highlighting the regulatory effects of gut-brain interaction on social behaviors.

Exogenous microbiota-derived metabolite trimethylamine N-oxide treatment alters social behaviors: Involvement of hippocampal metabolic adaptation.

Increasing evidence indicates that gut microbiota and its metabolites can influence the brain function and the related behaviors. Trimethylamine N-oxide (TMAO), an indirect metabolite of gut microbiota, has been linked to aging, cognitive impairment, and many brain disorders. However, the potential effects of TMAO on social behaviors remain elusive. The present study investigated the effects of early life systemic TMAO exposure and intra-hippocampal TMAO infusion during adulthood on social behaviors in mice. We also analyzed the effects of intra-hippocampus infusion of TMAO during adulthood on levels of metabolites. The results showed that both systemic TMAO exposure in the post-weaning period and intra-hippocampal TMAO infusion during adulthood decreased social rank and reduced sexual preference in adult mice. Data from LC-MS metabolomics analysis showed that intra-hippocampal TMAO infusion induced a total 207 differential metabolites, which belongs to several metabolic or signaling pathways, especially FoxO signaling pathway and retrograde endocannabinoid signaling pathway. These data suggest that TMAO may affect social behaviors by regulating metabolites in the hippocampus, which may provide a new insight into the role of gut microbiota in regulating social behaviors.

Long-lasting effects of postweaning sodium butyrate exposure on social behaviors in adult mice.

BACKGROUND: The function of gut microbiota as its role in normal physiology and involvement in brain function has gained a great deal of attention. The potential long-lasting effects of postweaning sodium butyrate (SB) exposure on social behaviors are still unknown; however it acts as one of the metabolites of gut microbiota. METHODS: Male mice (24-day old) were exposed to SB through drinking water for 21 continuous days. A series of behavioral tests, mainly including bedding preference test (BP), sexual preference test (SP), social interaction test (SI), tube dominance test (SDT), forced swimming test (FST), open field test (OFT), novel object recognition task (NOR) were conducted at different time after 21-d SB exposure. Serum Trimethylamine oxide (TMAO) levels were investigated to gain insight into a potential mechanism. RESULTS: Behavioral results indicated that postweaning SB exposure significantly decreased the social dominance status of low-ranked mice and decreased the sexual preference without affecting social interaction. SB exposure also exerted transient anxiolytic-like effects, while having induced a long-lasting depression-like effect without effects on memory formation. Postweaning SB exposure increased serum TMAO levels in mice, especially in lower-ranked mice, but decreased in higher-ranked mice. LIMITATIONS: Lack of understanding of the underlying mechanism. CONCLUSIONS: These findings provide direct evidence, for the first time, that postweaning SB exposure produces long-term effects on social behaviors in adult mice, mainly referring to sexual orientation, social dominance, and depression-like behaviors, which may be related to the serum TMAO levels, highlighting the long-lasting potential effects of gut-brain interaction on social behaviors.

Evidence that HIV-1 CRF01_AE is associated with low CD4+T cell count and CXCR4 co-receptor usage in recently infected young men who have sex with men (MSM) in Shanghai, China.

Men who have sex with men (MSM) have recently accounted for an alarmingly increasing proportion of HIV-1 transmission in China. In order to investigate the immune status as a result of CRF01_AE infection and CXCR4 co-receptor usage in a young Shanghai-based HIV-1-infected MSM population in Shanghai, 364 HIV-1-infected MSM with average age of 22.7 years old, newly diagnosed between Jan 2009 and Jul 2013 were analyzed for CD4+T cell count, subtyping using phylogenetic analysis, and viral co-receptor tropism using Geno2pheno and webPSSM in combination. A total of 276 individuals were identified as recently infected. Subtype assignment were as follows: 176 (63.8%) CRF01_AE, 77 (27.9%) CRF07_BC, and 23 (8.3%) subtype B. Besides, 24 second-generation recombinant strains were identified. A lower CD4+T cell count at baseline survey was observed among CRF01_AE strain-infected individuals, compared to those who were infected with CRF07_BC (P<0.01). The frequency of baseline CD4+T cell count <200 was higher and the frequency of CD4 T counts >500 lower in CRF01_AE infection than CRF07_BC infection. It is worth noting that 32.4%-40.9% of CRF01_AE strain-infected individuals were predicted to carry CXCR4-tropic viruses whereas none of CRF07_BC and subtype B were found to be as CXCR4-tropic viruses (P<0.001). As could be expected CXCR4 tropism was associated with lower CD4 T counts. This study revealed that CRF01_AE strains with high frequency of CXCR4 tropism are prevailing in the young MSM population in China and could potentially cause a severe loss of CD4+T cell count and rapid disease progression. A regular surveillance of HIV-1 subtypes, CD4+T cell count and viral co-receptor usage would be greatly beneficial for effectively monitoring disease progression, improvement of antiretroviral therapy strategy and prompt intervention of transmission.

Analysis of the current situation regarding the aging rural population in China and proposed countermeasures.

China has become a country with an aging population. Compared with the aged in urban areas, the aged in rural areas have low income and are subject to social security deficiencies; the oldest among them are the most vulnerable group. If an effective mechanism for handling health risk is not available, the poor health of the rural elderly will cause an increase in their poverty level, which in turn will cause their health to become worse. Therefore, it is essential to analyze the current situation regarding rural population aging in China and to develop countermeasures. Data from 4 national health services surveys were used to analyze the differences between urban and rural populations. The results of the analysis revealed that the aged population in rural areas has poor health; economic security for the aged population is insufficient; and resources for the aged are lacking in rural areas. The Chinese government should improve medicare for the aged in rural areas, and establish a medical treatment subsidy system and a medical support system for the aged in rural areas.

Disparity and its time trends in stroke mortality between urban and rural populations in China 1987 to 2001: changing patterns and their implications for public health policy.

BACKGROUND AND PURPOSE: The purposes of this study were to describe stroke mortality in urban and rural populations in China and to monitor the transition using the best available surveillance data during the past 2 decades. METHODS: Age- and sex-specific mortality data were obtained from the death registration and classification system covering 100 million population in selected urban and rural areas in China. The age-adjusted stroke mortality and its time trends for population at aged 35 years and over were compared between urban and rural populations during the period of 1987 to 2001. RESULTS: The age-adjusted stroke mortality was higher in urban than in rural populations until the end of 1990 s. The urban:rural ratio was 1:16 for men and 1:21 for women in 1987, but this dropped to 0:77 and 0:79, respectively, in 2001 due to a remarkable decrease in stroke mortality in urban areas (-2.0% for men and -2.5% for women annually, P<0.001), but with little change in rural men (P=0.969) and women (-0.7%, P=0.021) over the period. The decrease is mainly observed in the elderly population. It increased in the population aged 35 to 54 years for all area-gender groups except for urban women. CONCLUSIONS: The heavier burden of stroke shifted from urban to rural areas where a larger population resides and healthcare services are less developed than in urban areas in China. The increasing trend in the younger population will impose a greater burden in the near future. Healthcare policymakers need to focus their attention on this situation and take suitable measures to cope with the challenges it poses.