A narrative review of potential neural repair poststroke: Decoction of Chinese angelica and peony in regulating microglia polarization through the neurosteroid pathway.

Ischemic stroke is a major global health crisis, characterized by high morbidity and mortality rates. Although there have been significant advancements in treating the acute phase of this condition, there remains a pressing need for effective treatments that can facilitate the recovery of neurological functions. Danggui-Shaoyao-San (DSS), also known as the Decoction of Chinese Angelica and Peony, is a traditional Chinese herbal formula. It has demonstrated promising results in the regulation of microglial polarization and modulation of neurosteroid receptor expression, which may make it a potent strategy for promoting the recovery of neurological functions. Microglia, which plays a crucial role in neuroplasticity and functional reconstruction poststroke, is regulated by neurosteroids. This review posits that DSS could facilitate the recovery of neuronal function poststroke by influencing microglial polarization through the neurosteroid receptor pathway. We will further discuss the potential mechanisms by which DSS could enhance neural function in stroke, including the regulation of microglial activation, neurosteroid regulation, and other potential mechanisms.

Hypoxic Conditioning: A Potential Perioperative Strategy to Reduce Abdominal Aortic Occlusion-Related Injury in Mouse Proximal and Distal Organs.

This study aimed to investigate the impact of abdominal aortic occlusion (AAO)- induced injury on the kidney, lower limb muscles, heart, and brain in mice, and the potential protective effects of hypoxic postconditioning (HyC). The experimental design employed an abdominal aortic occlusion (AAO) model, and involved three groups of mice: sham, AAO, and AAO+HyC. Ten minutes after the AAO model, mice were subjected to hypoxic treatment lowering oxygen concentration to 5% within 45 minutes, and then returned to a normal oxygen environment. Hematoxylin- eosin (HE) stain was used for Histopathological examinations, and Quantibody Mouse Array was used for detecting apoptosis and inflammation-related protein expression. Histopathological examinations showed that HyC mitigated pathological damage to proximal organs (kidneys and lower limb muscles), distal organs (heart and brain), and reduced inflammatory cell infiltration. Expression of apoptosis- and inflammation-related proteins in brain and heart tissues were also evaluated. HyC significantly increased cellular inhibitor of apoptosis 2 (cIAP2) in the brain and Bcl-2 and insulin-like growth factor 2 (IGF-2) in the heart. Additionally, HyC regulated the expression of several inflammation-related factors in both brain and heart tissues. Although further investigation is needed, particularly in human subjects, this study highlights the potential of HyC as a promising therapeutic strategy for reducing AAO-associated organ damage.

Hypoxic postconditioning drives protective microglial responses and ameliorates white matter injury after ischemic stroke.

BACKGROUND: Ischemic stroke (IS) is a cerebrovascular disease with high incidence and mortality. White matter repair plays an important role in the long-term recovery of neurological function after cerebral ischemia. Neuroprotective microglial responses can promote white matter repair and protect ischemic brain tissue. AIMS: The aim of this study was to investigate whether hypoxic postconditioning (HPC) can promote white matter repair after IS, and the role and mechanism of microglial polarization in white matter repair after HPC treatment. MATERIALS & METHODS: Adult male C57/BL6 mice were randomly divided into three groups: Sham group (Sham), MCAO group (MCAO), and hypoxic postconditioning group (HPC). HPC group were subjected to 45 min of transient middle cerebral artery occlusion (MCAO) immediately followed by 40 min of HPC. RESULTS: The results showed that HPC reduced the proinflammatory level of immune cells. Furthermore, HPC promoted the transformation of microglia to anti-inflammatory phenotype on the third day after the procedure. HPC promoted the proliferation of oligodendrocyte progenitors and increased the expression of myelination-related proteins on the 14th day. On the 28th day, HPC increased the expression of mature oligodendrocytes, which enhanced myelination. At the same time, the motor neurological function of mice was restored. DISCUSSION: During the acute phase of cerebral ischemia, the function of proinflammatory immune cells was enhanced, long-term white matter damage was aggravated, and motor sensory function was decreased. CONCLUSION: HPC promotes protective microglial responses and white matter repair after MCAO, which may be related to the proliferation and differentiation of oligodendrocytes.

Abdominal Aortic Occlusion and the Inflammatory Effects in Heart and Brain.

Background: Abdominal aortic occlusion (AAO) occurs frequently and causes ischemia/reperfusion (I/R) injury to distant organs. In this study, we aimed to investigate whether AAO induced I/R injury and subsequent damage in cardiac and neurologic tissue. We also aimed to investigate the how length of ischemic time in AAO influences reactive oxygen species (ROS) production and inflammatory marker levels in the heart, brain, and serum. Methods: Sixty male C57BL/6 mice were used in this study. The mice were randomly divided into either sham group or AAO group. The AAO group was further subdivided into 1-4 hr groups of aortic occlusion times. The infrarenal abdominal aorta was clamped for 1-4 hr depending on the AAO group and was then reperfused for 24 hr after clamp removal. Serum, hippocampus, and left ventricle tissue samples were then subjected to biochemical and histopathological analyses. Results: AAO-induced I/R injury had no effect on cell necrosis, cell apoptosis, or ROS production. However, serum and hippocampus levels of malondialdehyde (MDA) and lactate dehydrogenase (LDH) increased in AAO groups when compared to sham group. Superoxide dismutase and total antioxidant capacity decreased in the serum, hippocampus, and left ventricle. In the serum, AAO increased the level of inducible nitric oxide synthase (iNOS) and decreased the levels of anti-inflammatory factors (such as arginase-1), transforming growth factor- ß1 (TGF-ß1), interleukin 4 (IL-4), and interleukin 10 (IL-10). In the hippocampus, AAO increased the levels of tumor necrosis factor (TNF-α), interleukin 1ß (IL-1ß), interleukin 6 (IL-6), IL-4, and IL-6, and decreased the level of TGF-ß1. In the left ventricle, AAO increased the level of iNOS and decreased the levels of TGF-ß1, IL-4, and IL-10. Conclusions: AAO did not induce cell necrosis or apoptosis in cardiac or neurologic tissue, but it can cause inflammation in the serum, brain, and heart.

Liver cancer cells as the model for developing liver-targeted RNAi therapeutics.

RNAi is a sequence-specific gene regulation mechanism that involves small interfering RNAs (siRNAs). RNAi therapeutic has become a new class of precision medicine and has shown great potential in treating liver-associated diseases, especially metabolic diseases. To facilitate the development of liver-targeted RNAi therapeutics in cell model, we surveyed a panel of liver cancer cell lines for the expression of genes implicated in RNAi therapeutics including the asialoglycoprotein receptor (ASGR) and metabolic disease associated genes PCSK9, ANGPTL3, CIDEB, and LDLR. A high-content screen assay based on lipid droplet staining confirmed the involvement of PCSK9, ANGPTL3, and CIDEB in lipid metabolism in selected liver cancer cell lines. Several liver cancer cell lines have high levels of ASGR1 expression, which is required for liver-specific uptake of GalNAc-conjugated siRNA, a clinically approved siRNA delivery platform. Using an EGFP reporter system, we demonstrated Hep G2 can be used to evaluate gene knockdown efficiency of GalNAc-siRNA. Our findings pave the way for using liver cancer cells as a convenient model system for the identification and testing of siRNA drug candidate genes and for studying ASGR-mediated GalNAc-siRNA delivery in liver.

Docosahexaenoic acid administration improves diabetes-induced cardiac fibrosis through enhancing fatty acid oxidation in cardiac fibroblast.

Diabetes mellitus can lead to various complications, including organ fibrosis. Metabolic remodeling often occurs during the development of organ fibrosis. Docosahexaenoic acid (DHA), an essential ω-3 polyunsaturated fatty acid, shows great benefits in improving cardiovascular disease and organ fibrosis, including regulating cellular metabolism. In this study, we investigated whether DHA can inhibit diabetes-induced cardiac fibrosis by regulating the metabolism of cardiac fibroblasts. Type I diabetic mice were induced by streptozotocin and after supplementation with DHA for 16 weeks, clinical indicators of serum and heart were evaluated. DHA administration significantly improved serum lipid levels, cardiac function and cardiac interstitial fibrosis, but not blood glucose levels. Subsequently, immunofluorescences, western blot and label-free quantitative proteomics methods were used to study the mechanism. The results showed that the anti-fibrotic function of DHA was achieved through regulating extracellular matrix homeostasis including ECM synthesis and degradation. Our research demonstrated DHA regulated the energy metabolism of cardiac fibroblasts, especially fatty acid oxidation, and then affected the balance of ECM synthesis and degradation. It suggested that DHA supplementation could be considered an effective adjuvant therapy for cardiac fibrosis caused by hyperglycemia.

Chlorogenic Acid Alleviates Hyperglycemia-Induced Cardiac Fibrosis through Activation of the NO/cGMP/PKG Pathway in Cardiac Fibroblasts.

SCOPE: Hyperglycemia-induced cardiac fibrosis is one of the main causes of diabetic cardiomyopathy (DM). Chlorogenic acid (CGA) found in many foods has excellent hypoglycemic effectiveness, but it is not known whether CGA can improve DM by inhibiting cardiac fibrosis caused by hyperglycemia. METHODS AND RESULTS: Type I diabetic mice are induced by streptozotocin, and after treatment with CGA for 12 weeks, cardiac functions and fibrosis are determined. CGA significantly attenuates hyperglycemia-induced cardiac fibrosis and improves cardiac functions. The mechanism of CGA on fibrotic inhibition is further studied by immunofluorescence, western blot and RNA interference technology in vivo and in vitro. The results show CGA exerted its anti-fibrotic effects through activating the cyclic GMP/protein kinase G pathway (cGMP/PKG) to block hyperglycemia-induced nuclear translocation of p-Smad2/3, and then inhibiting pro-fibrotic gene expression in cardiac fibroblasts without depending on its hypoglycemic function. Moreover, the data also revealed that CGA increased cGMP level and activated PKG in cardiac fibroblasts by enhancing endothelial nitric oxide synthase (eNOS) activity and NO production. CONCLUSION: Besides lowering blood glucose, CGA also has an independent ability to inhibit cardiac fibrosis. Therefore, long-term consumption of foods rich in CGA for diabetic patients will have great benefits to improve diabetic cardiomyopathy.

Ginsenoside-Rb1 Improved Diabetic Cardiomyopathy through Regulating Calcium Signaling by Alleviating Protein O-GlcNAcylation.

Ginsenoside-Rb1 (Rb1), a major active component of ginseng, has many benefits for cardiovascular disease and diabetes mellitus (DM), but the effect and mechanism on diabetic cardiomyopathy are not clear. In the present study, we found that Rb1-feeding significantly improved cardiac dysfunction and abnormal cardiomyocytes calcium signaling caused by diabetes. This improved calcium signaling was because Rb1 reduced Ca2+ leakage caused by overactivated ryanodine receptor 2 (RyR2) and increased Ca2+ uptake by sarcoplasmic reticulum Ca2+-ATPase 2a (SERCA 2a). Furthermore, we found that Rb1 not only enhanced energy metabolism like metformin and eliminated O-GlcNAcylation of calcium handling proteins to regulate calcium signaling but also directly inhibited RyR2 activity to regulate calcium signaling. The present study indicated that as a health supplement or drug, Rb1 was a relatively effective auxiliary therapeutic substance for diabetic cardiomyopathy.