In the mammalian central nervous system (CNS), astrocytes are the ubiquitous glial cells that have complex morphological and molecular characteristics. These fascinating cells play essential neurosupportive and homeostatic roles in the healthy CNS and undergo morphological, molecular, and functional changes to adopt so-called 'reactive' states in response to CNS injury or disease. In recent years, interest in astrocyte research has increased dramatically and some new biological features and roles of astrocytes in physiological and pathological conditions have been discovered thanks to technological advances. Here, we will review and discuss the well-established and emerging astroglial biology and functions, with emphasis on their potential as therapeutic targets for CNS injury, including traumatic and ischemic injury. This review article will highlight the importance of astrocytes in the neuropathological process and repair of CNS injury.
Astrocytes/drug effects* ; Humans ; Animals ; Central Nervous System/pathology* ; Central Nervous System Diseases/physiopathology*

Objective:To systematically summarize and comparatively analyze the development, establishment and usage of oncology drugs speedy review approaches in China and in the United States between 2012 and 2021.Methods:Based on National Medical Products Administration (NMPA) and Food and Drug Administration (FDA) websites, the development and current status of the speedy review approaches were consulted and summarized. Approved oncology drugs in China and in the United States (87 in China, 118 in the United States) over the past decade were analyzed using chi-square test for group comparison.Results:Five speedy approaches have been established in China and in the United States, three of which are the same, priority review, conditional approval or accelerated approval and breakthrough therapy. The rest two are special review and approval, special examination and approval in China, and fast track and real-time oncology review in the United States. Compared to the United States, speedy review approaches in China set up late (1992 vs. 2005). The overall utilization rates of the oncology drugs speedy review approaches were similar between the China and United States (90.8% vs. 92.4%, P=0.800) in the previous 10 years, and priority review have highest utilization rates in both China and the United States without significant group difference (77.0% vs. 82.2%, P=0.381); relatively low utilization rates of conditional approval (31.0% vs. 44.9%, P=0.041) and breakthrough therapy (2.3% vs. 50.0%, P＜0.001) were seen in China. 52.9% of new drugs applied for special examination and approval in China and 40.7% of new drugs applied for fast track in the United States. Overall, the priority review both in China and the United States are stable, with a similar average annual utilization rate (84.8% vs. 83.7%); accelerated approval and breakthrough therapies in the United States fluctuate wildly, but the situation is tending towards stability in the last 3 years. Conclusions:Both China and the United States have established a relatively complete accelerated review system, with an overall utilization rate over 90%; China's accelerated review started late, although the overall utilization rate is close to that of the United States. The utilization rates of conditional approval and breakthrough therapy are still relatively low. Flexible usage of speedy review approaches, gaining regulatory recognition to use alternative endpoints, achieving real-time review and guidance are keys to accelerate new drug development in China.

Objective:To systematically summarize and comparatively analyze the development, establishment and usage of oncology drugs speedy review approaches in China and in the United States between 2012 and 2021.Methods:Based on National Medical Products Administration (NMPA) and Food and Drug Administration (FDA) websites, the development and current status of the speedy review approaches were consulted and summarized. Approved oncology drugs in China and in the United States (87 in China, 118 in the United States) over the past decade were analyzed using chi-square test for group comparison.Results:Five speedy approaches have been established in China and in the United States, three of which are the same, priority review, conditional approval or accelerated approval and breakthrough therapy. The rest two are special review and approval, special examination and approval in China, and fast track and real-time oncology review in the United States. Compared to the United States, speedy review approaches in China set up late (1992 vs. 2005). The overall utilization rates of the oncology drugs speedy review approaches were similar between the China and United States (90.8% vs. 92.4%, P=0.800) in the previous 10 years, and priority review have highest utilization rates in both China and the United States without significant group difference (77.0% vs. 82.2%, P=0.381); relatively low utilization rates of conditional approval (31.0% vs. 44.9%, P=0.041) and breakthrough therapy (2.3% vs. 50.0%, P＜0.001) were seen in China. 52.9% of new drugs applied for special examination and approval in China and 40.7% of new drugs applied for fast track in the United States. Overall, the priority review both in China and the United States are stable, with a similar average annual utilization rate (84.8% vs. 83.7%); accelerated approval and breakthrough therapies in the United States fluctuate wildly, but the situation is tending towards stability in the last 3 years. Conclusions:Both China and the United States have established a relatively complete accelerated review system, with an overall utilization rate over 90%; China's accelerated review started late, although the overall utilization rate is close to that of the United States. The utilization rates of conditional approval and breakthrough therapy are still relatively low. Flexible usage of speedy review approaches, gaining regulatory recognition to use alternative endpoints, achieving real-time review and guidance are keys to accelerate new drug development in China.

The orbitofrontal cortex (ORB), a region crucial for stimulus-reward association, decision-making, and flexible behaviors, extensively connects with other brain areas. However, brain-wide inputs to projection-defined ORB neurons and the distribution of inhibitory neurons postsynaptic to neurons in specific ORB subregions remain poorly characterized. Here we mapped the inputs of five types of projection-specific ORB neurons and ORB outputs to two types of inhibitory neurons. We found that different projection-defined ORB neurons received inputs from similar cortical and thalamic regions, albeit with quantitative variations, particularly in somatomotor areas and medial groups of the dorsal thalamus. By counting parvalbumin (PV) or somatostatin (SST) interneurons innervated by neurons in specific ORB subregions, we found a higher fraction of PV neurons in sensory cortices and a higher fraction of SST neurons in subcortical regions targeted by medial ORB neurons. These results provide insights into understanding and investigating the function of specific ORB neurons.
Animals ; Neurons/physiology* ; Mice ; Prefrontal Cortex/cytology* ; Parvalbumins/metabolism* ; Brain Mapping/methods* ; Neural Pathways/physiology* ; Somatostatin/metabolism* ; Male ; Interneurons/physiology* ; Mice, Inbred C57BL ; Thalamus/physiology* ; Mice, Transgenic

Objective Apply modified bilateral carotid artery ligation to establish a VD rat model to observe changes in cerebral blood flow and expression of angiogenic proteins.Methods Thirty-six SD male rats were randomly divided into a sham group(n = 18)and model group(n = 18).In the sham group,only the bilateral carotid artery was isolated without ligation,whereas in the model group,the bilateral carotid artery was ligated to establish the VD model.The Morris water maze behavior test was applied before and 14 days after modeling.Variation in cerebral blood flow was detected by laser speckle contrast imaging.Protein expression of HIF-1α,VEGF,and HO-1 was detected by Western Blot.IL-4 and IL-10 contents were measured by ELISA.Results At 14 days after modeling,escape latency was significantly prolonged and the frequency of crossing the platform had significantly decreased in the model group compared with the sham group(P<0.05).At 2 hours,3 days,and 7 days after modeling,cerebral blood flow in the model group was significantly lower than that in the sham group(P<0.05).At 14 and 21 days after modeling,no significant difference was found in cerebral blood flow between sham and model groups(P>0.05).In the model group,cerebral blood flow was decreased to a minimum at 2 hours after modeling(P<0.05)and then began to recover.The peak of recovery occurred at 3～7 days after modeling and returned to the level before modeling on day 14 after modeling.At postoperative day 21,expression of HIF-1α,VEGF,and HO-1 proteins in the hippocampus of the model group was increased remarkably(P<0.05)and the serum contents of IL-4 and IL-10 in the model group were significantly increased compared with those in the sham group(P<0.05).Conclusions The variation in cerebral blood flow in the VD rat model established by the modified bilateral carotid artery ligation was dependent on time.At postoperative day 21,HIF-1α,VEGF,and HO-1 in the hippocampus were increased significantly,which was accompanied by increased levels of IL-4 and IL-10.

OBJECTIVE To investigate the effects and mechanism of luteolin on osteogenic repair of bone defects. METHODS The targets and potential pathways of luteolin in the treatment of bone defects were screened by network pharmacology method， and then the top 2 targets were selected by Hub gene screening for molecular docking verification， with binding energy as the evaluation standard. In vitro experiments were conducted on rat bone mesenchymal stem cells （BMSC） and rat umbilical vein endothelial cells （RUVEC）. Phenotypic validation was performed using alkaline phosphatase staining， alizarin red S staining， and in vitro angiogenesis experiments. Western blot assay was used to detect the protein expressions of phosphatidylinositol 3 kinase （PI3K） and protein kinase 1 （Akt1）， so as to validate the mechanism of luteolin on osteogenic differentiation of BMSC and angiogenesis of RUVEC in vitro. RESULTS The results of network pharmacology showed that the effects of luteolin on vascular formation and bone repair in bone defects were mainly related to Akt1， SRC， estrogen receptor 1， epidermal growth factor receptor， cyclooxygenase 2， matrix metalloproteinase 9 targets， and were closely related to PI3K-Akt signaling pathway. The results of molecular docking showed that luteolin binding to Akt1 and SRC proteins was stable. The results of in vitro experiments showed that luteolin could significantly improve the expressions and activities of alkaline phosphatase in BMSC， increased the number of calcium salt deposits and calcified nodules， and promoted calcification of BMSC. Compared with luteolin 0 μmol/L group， the angiogenesis ability of RUVEC was enhanced significantly in luteolin 1， 10 μmol/L groups， the length of blood vessels and the protein expressions of PI3K and Akt1 were significantly increased （P＜0.05 or P＜0.01）； the higherthe concentration， the better the effect. CONCLUSIONS Luteolin may play a role in promoting angiogenesis and bone repair at the fracture site by activating PI3K/Akt signaling pathway and promoting the protein expressions of PI3K and Akt1.

Objective:To investigate the clinical significance and possible mechanisms of elevated homocysteine(Hcy) levels in peripheral blood of children with sepsis.Methods:The clinical data of 51 children with sepsis (sepsis group) admitted to PICU at Xuzhou Children′s Hospital from January 2019 to December 2019 were analyzed, and the levels of Hcy in plasma were compared with 50 non-septic children (common infection group) and 50 healthy children (healthy control group) during the same period.The possible mechanism of metabolic disorders about Hcy was analyzed by detecting the levels of the key rate-limiting enzymes cystathionine-β-synthase(CBS) and cystathionine-γ-lyase(CSE), which were in the downstream of metabolism in septic mouse model induced by lipopolysaccharide.Results:The level of Hcy in plasma was (12.62±5.46)μmol/L in sepsis group, which was significantly higher than those in common infection group[(9.42±2.28) μmol/L] and healthy control group[(8.14±1.60) μmol/L]( P<0.05). The level of Hcy in plasma of 12 children with acute kidney injury in sepsis group was significantly higher than that of 39 children without acute kidney injury in sepsis group[(16.48±5.87)μmol/L vs.(11.62±4.74) μmol/L, P<0.05]. The level of Hcy in plasma of six children with acute liver failure in sepsis group was significant higher than that of 45 children without acute liver failure in sepsis group[(18.35±7.10) μmol/L vs.(11.84±4.78) μmol/L, P<0.05]. The level of Hcy in serum significantly increased in septic mouse models ( P<0.01). The transcription and protein expression levels of key rate-limiting Hcy transcription enzymes CBS and CSE in liver and kidney tissues of septic mouse were significantly down-regulated ( P<0.05). Conclusion:The level of Hcy in peripheral blood of children with sepsis increases, which is more obviously in children with acute kidney injury or acute liver injury.When patients developed sepsis, the expression of CBS and CSE will be restrained, leading to disorders related to transsulfuration metabolism and elevated level of Hcy in peripheral blood.

Objective:To explore the effect of endoplasmic reticulum stressed (ER) on colorectal cancer (CRC) cell proliferation and invasion via ATG5-mediated autophagy pathway and the underlying mechanism.Methods:We performed bioinformatics analysis to identify the expression level of PERK, ATF6 and ATG5 in CRC tissues and adjacent tissues and the correlation between PERK and ATG5 expression in CRC tissues.The expression level of PERK in CRC cell lines was examined by qRT-PCR assay. Cell proliferation was quantified by CCK-8.The invasion of the cells was detected by Transwell.Western blot assay was performed to verify the levels of protein. The levels of autophagy were examined by electron microscopy.Results:PERK and ATF6 expression in CRC tissues was higher than that in the adjacent tissues and PERK expression was higher in CRC cells than intestinal mucosal cells. Expression level of PERK in CRC cell lines HCT116,SW480,HT29,LoVo and colonic mucosa cell lines FHC was 1.51±0.04,3.12±0.05,2.19±0.04,2.38±0.06 and 0.98±0.04 ( P<0.001) .The increased expression of PERK promoted CRC cell proliferation and invasion. PERK expression levels was positively associated with ATG5 expression levels ( r=0.52, P<0.001) and overexpression of PERK accelerated the protein expression of ATG5 (1.00±0.04,3.53±0.07, t=74.61, P<0.001) . ATG5 was highly expressed in CRC tissues. Overexpression of ATG5 could promote proliferation,invasion and accelerate autophagy of CRC cells (the number of autophagosomes in the blank control group,the negative control group and ATG5-Overexpression group was 4.33±1.53, 4.00±1.00, 9.67±2.52, and t=3.14,3.62, P=0.035,0.022, respectively) .ATG5 promoted colorectal cancer cell proliferation and invasion through autophagy pathway. Conclusion:ER stressed-CRC cells could promote CRC cell proliferation and invasion through ATG5-mediated autophagy pathway.

Objective:To assess the renal-protective effect of Elabela (Ela) on diabetic kidney disease (DKD), and explore its potential mechanism.Methods:db/db mice were randomly divided into diabetic group and Ela intervention group, while db/m mice were taken as normal control group. The mice in the Ela intervention group were intraperitoneally injected with Ela-21 5 mg·kg -1·d -1 for 8 weeks. At the end of the experiment, urinary albumin/creatinine ratio (UACR) was measured. The renal pathological changes were observed by HE and PAS staining. The expression of aquaporin 2(AQP2) examined by immunohistochemistry. The level of collage Ⅳ(Col-Ⅳ) and AQP2 in renal tissue was analyzed by Western blot. The human renal tubular epithelial cells (HK-2) were incubated with high glucose medium and further interfered with apelin receptors (APJ)-siRNA. Western blot analysis was used to detect the effect of Ela intervention on Col-Ⅳ and AQP2 expression. Finally, to clarify the possible mechanism of Ela regulating AQP2, the interaction between Ela-induced APJ activation and arginine vasopressin (AVP)-evoked arginine vasopressin receptor 2 (AVPR2) activation was investigated by NanoBit ? technology. Results:(1) Without affecting blood glucose and body weight, Ela intervention significantly reduced the UACR in db/db mice, and attenuate pathological changes of the kidney, as well as expression of Col-Ⅳ and AQP2. (2) Ela treatment could remarkably inhibit the high glucose-induced the expression of Col-Ⅳ and AQP2, which was reversed by interfering with APJ. (3) AVP-induced downstream β-Arrestin-2 signaling transduction via AVPR2 was obviously antagonized by interaction of Ela and APJ, further suggesting that the inhibitory effect of Ela on AQP2 may be related to antagonizing AVP/AVPR2 signaling.Conclusion:Ela exerts renal protection by inhibiting the expression of AQP2 through APJ.

Objective:To understand the trend of maternal mortality in China from 1992 to 2017, and to evaluate the effects of age, period and cohort of maternal mortality by using the age-period-cohort (APC) model.Methods:The data of maternal mortality in China from 1992 to 2017 were collected from the Global Burden of Disease project. The maternal mortality rate was adopted to describe the trend of death. The APC model and the estimable function algorithm were used to evaluate the impact of age, period and birth cohort factors on maternal mortality risk in China.Results:From1992 to 2017, the maternal mortality rate in China fluctuated slightly and then continued to decline and finally increased slightly. During this period, the net drift was -10.00% per year (95% CI:-10.92% to -9.08% per year), and all the local drifts were lower than zero in all age groups of 10-54 years old ( P<0.05). The results of the APC model analysis showed that the maternal mortality risk of women in their life stage showed a trend of rapid decrease, then a slow climb and finally a rapid increase. The period relative risk and cohort relative risk of maternal mortality both showed a monotonous decreasing trend. Conclusion:From 1992 to 2017, the maternal mortality rate in China generally shows a downward trend, and the risk of maternal mortality has significant age, period and cohort effects.