RIIß-PKA in GABAergic Neurons of Dorsal Median Hypothalamus Governs White Adipose Browning.

The RIIß subunit of  cAMP-dependent protein kinase A (PKA) is expressed in the brain and adipose tissue. RIIß-knockout mice show leanness and increased UCP1 in brown adipose tissue. The authors have previously reported that RIIß reexpression in hypothalamic GABAergic neurons rescues the leanness. However, whether white adipose tissue (WAT) browning contributes to the leanness and whether RIIß-PKA in these neurons governs WAT browning are unknown. Here, this work reports that RIIß-KO mice exhibit a robust WAT browning. RIIß reexpression in dorsal median hypothalamic GABAergic neurons (DMH GABAergic neurons) abrogates WAT browning. Single-cell sequencing, transcriptome sequencing, and electrophysiological studies show increased GABAergic activity in DMH GABAergic neurons of RIIß-KO mice. Activation of DMH GABAergic neurons or inhibition of PKA in these neurons elicits WAT browning and thus lowers body weight. These findings reveal that RIIß-PKA in DMH GABAergic neurons regulates WAT browning. Targeting RIIß-PKA in DMH GABAergic neurons may offer a clinically useful way to promote WAT browning for treating obesity and other metabolic disorders.

Soft Magnetic Microrobot Doped with Porous Silica for Stability-Enhanced Multimodal Locomotion in a Nonideal Environment.

As an emerging field of robotics, magnetic-field-controlled soft microrobot has broad application prospects for its flexibility, locomotion diversity, and remote controllability. Magnetic soft microrobots can perform multimodal locomotion under the control of a magnetic field, which may have potential applications in precision medicine. However, previous research studies mainly focus on new locomotion in a relatively ideal environment, lacking exploration on the ability of magnetic microrobot locomotion to resist external disturbances and proceed in a nonideal environment. Here, a porous silica-doped soft magnetic microrobot is constructed for enhanced stability of multimodal locomotion in the nonideal biological environment. Porous silica spheres are doped into a NdFeB-silicone elastomer base, improving adhesion properties and refining the comprehensive mechanical properties of the microrobot. Multimodal locomotions are achieved, and the influence of porous silica doping on the stability of each locomotion in a nonideal environment is explored in depth. Motions in nonideal circumstances such as climbing, loading, current rushing, wind blowing, and obstacle hindering are conducted successfully with porous silica doping. Such a stability-enhanced multimodal locomotion system can be used in biocatalysis and thrombus removal, and its prospect for precision medicine is highlighted by in vivo demonstration of multimodal locomotion with nonideal disturbance.

Withaferin A Promotes White Adipose Browning and Prevents Obesity Through Sympathetic Nerve-Activated Prdm16-FATP1 Axis.

The increasing prevalence of obesity has resulted in demands for the development of new effective strategies for obesity treatment. Withaferin A (WA) shows a great potential for prevention of obesity by sensitizing leptin signaling in the hypothalamus. However, the mechanism underlying the weight- and adiposity-reducing effects of WA remains to be elucidated. In this study, we report that WA treatment induced white adipose tissue (WAT) browning, elevated energy expenditure, decreased respiratory exchange ratio, and prevented high-fat diet-induced obesity. The sympathetic chemical denervation dampened the WAT browning and also impeded the reduction of adiposity in WA-treated mice. WA markedly upregulated the levels of Prdm16 and FATP1 (Slc27a1) in the inguinal WAT (iWAT), and this was blocked by sympathetic denervation. Prdm16 or FATP1 knockdown in iWAT abrogated the WAT browning-inducing effects of WA and restored the weight gain and adiposity in WA-treated mice. Together, these findings suggest that WA induces WAT browning through the sympathetic nerve-adipose axis, and the adipocytic Prdm16-FATP1 pathway mediates the promotive effects of WA on white adipose browning.

The Nrf2-NLRP3-caspase-1 axis mediates the neuroprotective effects of Celastrol in Parkinson's disease.

Parkinson's disease (PD) is a chronic neurodegenerative disorder that is characterized by motor symptoms as a result of a loss of dopaminergic neurons in the substantia nigra pars compacta (SNc), accompanied by chronic neuroinflammation, oxidative stress, formation of α-synuclein aggregates. Celastrol, a potent anti-inflammatory and anti-oxidative pentacyclic triterpene, has emerged as a neuroprotective agent. However, the mechanisms by which celastrol is neuroprotective in PD remain elusive. Here we show that celastrol protects against dopamine neuron loss, mitigates neuroinflammation, and relieves motor deficits in MPTP-induced PD mouse model and AAV-mediated human α-synuclein overexpression PD model. Whole-genome deep sequencing analysis revealed that Nrf2, NLRP3 and caspase-1 in SNc may be associated with the neuroprotective actions of celastrol in PD. By using multiple genetically modified mice (Nrf2-KO, NLRP3-KO and Caspase-1-KO), we identified that celastrol inhibits NLRP3 inflammasome activation, relieves motor deficits and nigrostriatal dopaminergic degeneration through Nrf2-NLRP3-caspase-1 pathway. Taken together, these findings suggest that Nrf2-NLRP3-caspase-1 axis may serve as a key target of celastrol in PD treatment, and highlight the favorable properties of celastrol for neuroprotection, making celastrol as a promising disease-modifying agent for PD.

High irisin and low BDNF levels in aqueous humor of high myopia.

BACKGROUND: The pathogenesis of myopia remains unclear. Both genetic and environmental factors play a role in the disease progression. Reasons including reduced physical activity (PA) and low-grade intraocular inflammation may be involved in the development of myopia. OBJECTIVES: To analyze the levels of irisin, brain-derived neurotrophic factor (BDNF) and other intraocular cytokines in aqueous humor of high myopia patients, and to evaluate the roles of PA and inflammation in developing myopia. MATERIAL AND METHODS: We collected aqueous humor samples from patients with axial length (AL) over 26 mm (n = 35) or shorter than 25 mm (n = 38) during cataract extraction surgery. Samples were assayed using the enzyme-linked immunosorbent assay (ELISA) kit for irisin and a multiplex immunoassay kit for BDNF, interleukin (IL)-6, IL-8 and IL-10, and tumor necrosis factor alpha (TNF-α). RESULTS: Irisin levels in the aqueous samples of the highly myopic eyes were significantly higher than in the control group (p = 0.027). The BDNF levels of the highly myopic group were significantly lower than in the control group (p = 0.043). Median level of leukemia inhibitory factor (LIF) for highly myopic group (2.035 pg/mL) was statistically significantly higher than in the control group (0.750 pg/mL) (U = 210.5, Z = -4.495, p < 0.001). Interleukin 1 receptor antagonist (IL-1ra) level in the aqueous samples of the highly myopic group was significantly lower than in the shorter AL group (p = 0.049). Interleukin 6, IL-8 and IL-10 levels were not significantly different between the 2 groups (p = 0.501, p = 0.059 and p = 0.192, respectively). Tumor necrosis factor α levels could only be detected in 30 samples and median levels in the 2 groups were not statistically significantly different (U = 99, Z = -0.482, p = 0.650). No correlation was found between IL-6, IL-8, IL-10 and TNF-α, and the AL (p > 0.05). Irisin was positively correlated with AL (p = 0.028, r = 0.287). The BDNF was negatively correlated with AL (p = 0.040, r = -0.246). Interleukin 1ra was negatively correlated with AL (p = 0.038, r = -0.276). There was also a correlation between LIF and AL (p < 0.001, r = 0.486). CONCLUSIONS: Higher irisin level in high myopia group opens a new direction to discover the relationship between PA and myopia. The decreased BDNF in high myopia group probably demonstrates the connection between myopia and neurodegenerative disease.

The DJ1-Nrf2-STING axis mediates the neuroprotective effects of Withaferin A in Parkinson's disease.

The pathogenesis of Parkinson's disease (PD) remains unclear, and there is no disease-modifying agent for PD. Withaferin A (WA), a naturally occurring compound, has emerged as a neuroprotective agent. However, the mechanisms by which WA is neuroprotective in PD are unknown. Here we show that WA protected against loss of dopaminergic neurons, neuroinflammation, and motor deficits in MPTP-induced PD mouse models. Whole-genome deep sequencing analysis combined with Meta-analysis of human PD studies reveal that DJ1, Nrf2, and STING in substantia nigra pars compacta (SNc) are linked to anti-PD effect of WA. We found that WA activated DJ1 and Nrf2, and suppressed STING within SNc; and overexpression of STING in SNc dampened the effect of WA. Using genetically modified mice (DJ1-KO, Nrf2-KO, STINGgt/gt and STING-KO) and immunolabeling technique, we identified that WA targeted DJ1-Nrf2-STING pathway in dopaminergic neurons; and we demonstrate that STING might be an important factor in PD pathogenesis. In addition, WA alleviated accumulation of phosphorylated α-synuclein (p-α-syn) and insoluble α-syn within SNc in adeno-associated virus (AAV)-mediated human α-syn overexpression PD model. Our comparative analysis on whole-genome transcriptome profiles suggests that STING might be a key target of WA and amantadine in PD treatment. This study highlights a multifaceted role for WA in neuroprotection, and suggests that WA can be a potential candidate for treatment of PD.

A longitudinal study reveals the alterations of the Microtus fortis colonic microbiota during the natural resistance to Schistosoma japonicum infection.

The gut microbiota has been demonstrated to associate with protection against helminth infection and mediate via microbial effects on the host humoral immunity. As a non-permissive host of Schistosoma japonicum, the Microtus fortis provides an ideal animal model to be investigated, because of its natural self-healing capability. Although researches on the systemic immunological responses have revealed that the host immune system contributes a lot to the resistance, the role of gut microbiome remains unclear. In this study, we exposed the M. fortis to the S.japonicum infection, carried out a longitudinal research (uninfected control, infected for 7 days, 14 days, 21 days, and 31 days) on their colonic microbiota based on the 16S rRNA gene amplicon sequencing. The bacterial composition disclosed a disturbance-recovery alteration followed by the resistance to S. japonicum. The alpha diversity of colon microbiota was reduced after the infection, but it gradually recovered along with self-healing process. Further LEfSe analysis revealed that phyla shifted from Firmicutes to Bacteroidetes, which were mainly driven by an increase of Ruminococcaceae and a depletion of Muribaculaceae in the family level along the Control-Infection-Recovery (CIR) process. We identified a temporary blooming of Lactobacillaceae and Lactobacillus in the mid infection stage (D14). As a recognized probiotics repository, we speculate the increased abundance of Lactobacillaceae in M. fortis colonic microbiota might relate to the natural resistance to the schistosome. Besides, potential microbial functions were also significantly changed in the resistance process. These results demonstrate the remarkable alterations of reed vole colonic microbiota in both community structure and potential functions along with the resistance to S. japonicum infection. The identified microbial biomarkers might offer new ways for drug development to conquer human schistosomiasis.

The effect of combined ecological remediation (plant microorganism modifier) on rare earth mine wasteland.

Due to the vegetation destruction and soil desertification caused by excessive exploitation at Ganzhou ion-type rare earth mine in the mid-1980s, it is essential to carry out ecological remediation. The symbiotic mycorrhiza formed by the developed perennial ryegrass (Lolium perenne L.) roots infected with arbuscular mycorrhizal fungi (AMF) can significantly improve the growth and resistance of plants. In this study, the combination of symbiotic mycorrhiza and soil modifier was used to construct the ryegrass-AMF-soil modifier combined remediation technology, which achieved effective ecological remediation of soil tailings. The orthogonal experiment of soil modifier showed that the most efficient formula for ryegrass biomass, soil organic matter, soil alkaline hydrolysis, soil available phosphorus, and soil pH was 5 g/kg sepiolite, 3 g/kg chicken manure, 2 g/kg humic acid, and 2 g/kg biochar (A4B3C3D3), and chicken manure (B), humic acid (C), and biochar (D) had significant effects on the improvement of ryegrass biomass, soil organic matter, soil alkaline nitrogen, and soil available phosphorus. Sepiolite (A) had a significant improvement in soil pH. Furthermore, the AMF infection results indicated that Glomus moss (G.m.) had higher affinity with ryegrass. The T4 treatment-combined remediation using G.m. inoculation had the most significant effect on ryegrass growth; plant height increased by 39.19% compared with T1 treatment-inoculation using G.m. Under combined remediation, soil pH, organic matter, alkali nitrogen, and effective phosphorus content also significantly improved after combined treatment. Under G.m. inoculation treatment (T4 treatment), the soil nutrient content reached the three criteria of the soil nutrient grading standard.

Association between Take-Out Food Consumption and Obesity among Chinese University Students: A Cross-Sectional Study.

BACKGROUND: The frequency of take-out food consumption has increased rapidly among Chinese college students, which has contributed to high obesity prevalence. However, the relationships between take-out food consumption, body mass index (BMI), and other individual factors influencing eating behavior among college students are still unclear. This study explored the association of take-out food consumption with gender, BMI, physical activity, preference for high-fat and high-sugar (HFHS) food, major category, and degree level among Chinese college students. METHODS: Cross-sectional data were collected from 1220 college students in Beijing, China, regarding information about take-out food consumption, physical activity, and preference for HFHS food using a self-reported questionnaire. The logistic linear regression model was used to analyze the association between take-out food consumption and personal and lifestyle characteristics. RESULTS: Out of 1220 college students, 11.6% of college students were overweight or obese. Among the personal and lifestyle characteristics, high frequency of take-out food consumption was significantly associated with a non-medical major, high preference for HFHS food, degree level, and higher BMI, but not physical activity. CONCLUSION: Among Chinese college students, consumption of take-out food may be affected by major category, preference for HFHS food, degree level, and BMI. This could provide guidance on restrictions of high take-out food consumption, which contributes to high obesity prevalence and high risk for metabolic diseases.

Geniposide regulates the miR-101/MKP-1/p38 pathway and alleviates atherosclerosis inflammatory injury in ApoE-/- mice.

Atherosclerosis (AS) is the common pathological basis of chronic cardiovascular diseases and is associated with inflammation and lipid metabolism dysfunction. Geniposide, the main active ingredient of Gardenia jasminoides Ellis fruit, exhibits a variety of anti-inflammatory and anti-oxidative functions; however, its role in AS remains unclear. The aim of this study was to investigate the mechanisms of geniposide in alleviating inflammation and thereby attenuating the development of AS. ApoE-/- mice were fed a high fat diet to induce AS and were treated with geniposide (50 mg/kg) for 12 weeks. Blood glucose and lipid levels were measured by biochemical analysis. H&E, Masson and Oil red O staining were performed to observe morphological changes and lipid deposition in the aorta and liver. Serum inflammatory cytokines were detected by ELISA. Dual-luciferase reporter gene assay was used to verify the target relationship between microRNA-101 (miR-101) and mitogen-activated protein kinase phosphatase-1 (MKP-1). The levels of miR-101, p-p38, and MKP-1 in the aorta were detected by qPCR and western blotting. The anti-inflammatory effect of geniposide in vitro was investigated in the RAW264.7 macrophage cell line. A miR-101 mimic and an inhibitor were used to study the effect of miR-101 on regulating the expression of the target MKP-1 and the downstream inflammatory cytokines. Geniposide treatment reduced lipid levels and plaque size in the mouse model of AS. Geniposide downregulated miR-101 to upregulate MKP-1 and suppress the production of inflammatory factors in vitro and in vivo. Geniposide suppressed the levels of inflammatory factors in the presence of the miR-101 mimic, whereas no obvious effect was observed in the miR-101 inhibitor group. We concluded that geniposide reduced the plaque size and alleviated inflammatory injury in ApoE-/- mice and RAW264.7 cells. The specific anti-inflammatory mechanism was related to the miR-101/ MKP-1/p38 signaling pathway.

[Protein Kinase A and Lipid Metabolism].

Protein kinase A(PKA),as a pivotal factor in the cellular signal transduction,plays an es-sential role in the regulation of lipid metabolism.PKA activates the key lipases including hormone sensi-tive lipase (HSL)and adipose triglyceride lipase (ATGL)to promote the fat mobilization.PKA signaling up-regulates the mitochondrial thermogenesis by enhancing the expression of uncoupling protein-1 (UCP-1),which critically contributes to the body heat production.PKA is closely involved in the regulation of lipogenesis in the liver.Notably,the dysregulation of PKA signaling is associated with the pathogenic mechanisms underlying the obesity,cardiovascular diseases and diabetes mellitus.The pharmacological studies show that PKA is linked to the pharmacological effects of the major lipid regulating agents.In this review,the studies on roles of PKA in the regulation of lipid metabolism are summarized with an emphasis on progress made during the last five years for providing insights into the mechanism by which PKA regu-lates the lipid metabolism as well as the novel therapeutic strategy for lipid-metabolic diseases.

Research of micro-prism distribution on the bottom surface of the small-size integrated light guide plate.

The luminance uniformity of the backlight module (BLM) importantly depends on the microstructure distribution on the bottom surface of the light guide plate (LGP). Based on the small-size integrated LGP (ILGP) proposed, we put forward a distribution expression of micro-prisms on the bottom surface of the ILGP, and present the relational expressions between the coefficients of the analytical expression and the structural parameters of the ILGP, such as the light guide length L, width of the ILGP W, thickness of the ILGP H, and space between light emitting diodes (LEDs) d. Then, the research results above are applied to the design of the small-size ILGPs. Not only can the micro-structure distributions on the bottom surface of the ILGPs be directly given, but also the simulation results show that the luminance uniformities of the integrated BLMs are higher than 85%. The research indicates that the expressions proposed in this paper are correct and effective, and have important guiding significances and referential value.

Algorithm research on microstructure distribution on the bottom surface of an integrated micro-optical light guide plate.

Based on the backlight module (BLM) with an integrated micro-optical light guide plate (MOLGP) that we proposed [Opt. Express21, 20159 (2013)], an optical model that maps the relationship between the distribution of microprisms on the bottom surface of the integrated MOLGP and the luminance of the output light is established by a backpropagation neural network in this paper. Then the optimized distribution of the microprisms for high luminance uniformity of the output light is obtained by a genetic algorithm. Finally, the integrated BLM with the optimized distribution of microprisms on the bottom surface of the integrated MOLGP is set up in optical software, and the simulation results show that the luminance uniformity of the output light in this BLM reaches 93%.

Integrated micro-optical light guide plate.

In this paper, we propose an integrated micro-optical light guide plate (MOLGP), of which the top surface is designed as aspheric semi-cylindrical micro-concentrator structure (ASCMCS) arrays and the bottom surface is fused with micro-prism arrays coated with a high-reflective film. And we also present the optimized structural parameters and distribution pattern of the MOLGP. By the simulation of the professional optical software Lighttools, it's verified that the integrated MOLGP we proposed can achieve the functions of five complex-structure films in current typical backlight module (BLM), and the Five Parameters (light energy utilization efficiency, average illuminance and luminance, uniformity of illuminance and uniformity of luminance) in the BLM with integrated MOLGP are respectively 1.49, 1.40, 1.07, 0.91 and 0.97 times than those in the typical BLM. Obviously, the performance parameters of the MOLGP exceed the traditional design. Moreover, we design two sets of four-step masks of the ASCMCS by the graphical user interface (GUI). At last, we fabricate a 1.8 inch integrated MOLGP sample. Comparative experiments show that the Five Parameters of the fabricated MOLGP sample are respectively 1.43, 1.43, 0.97, 0.89 and 0.70 times than those of the typical BLM. The experimental results verify the feasibility of the concept of the integrated MOLGP proposed in this paper.