The Potential of NLRP3 Inflammasome as a Therapeutic Target in Neurological Diseases.

NLRP3 (NLRP3: NOD-, LRR-, and pyrin domain-containing protein 3) inflammasome is the best-described inflammasome that plays a crucial role in the innate immune system and a wide range of diseases. The intimate association of NLRP3 with neurological disorders, including neurodegenerative diseases and strokes, further emphasizes its prominence as a clinical target for pharmacological intervention. However, after decades of exploration, the mechanism of NLRP3 activation remains indefinite. This review highlights recent advances and gaps in our insights into the regulation of NLRP3 inflammasome. Furthermore, we present several emerging pharmacological approaches of clinical translational potential targeting the NLRP3 inflammasome in neurological diseases. More importantly, despite small-molecule inhibitors of the NLRP3 inflammasome, we have focused explicitly on Chinese herbal medicine and botanical ingredients, which may be splendid therapeutics by inhibiting NLRP3 inflammasome for central nervous system disorders. We expect that we can contribute new perspectives to the treatment of neurological diseases.

Medication Regularity of Traditional Chinese Medicine in the Treatment of Aplastic Anemia Based on Data Mining.

Objective: Aplastic anemia (AA) is an uncommon disease, characterized by pancytopenia and hypocellular bone marrow, but it is common in the blood system. The medication rules of traditional Chinese medicine (TCM) in the treatment of AA are not clear, for which it is worth exploring the medication rules by data mining methods. Methods: This study used SPSS Modeler 18.0 and SPSS statistics to analyze the cases of AA from Zhejiang Provincial Hospital of Chinese Medicine (ZJHCM) from March 1, 2019, to March 1, 2022. Data mining methods, including frequency analysis, cluster analysis, and association rule learning, were performed in order to explore the medication rules for AA. Results: (1) A total of 859 prescriptions, which met the inclusion criteria, consisted of 255 herbs. In descending order of the frequency of herbal medicine, we have Danggui, Huangqi, Shudihuang, Fuling, Gancao, Shanyao, Shanzhuyu, Baizhu, Dangshen, and Xianhecao. (2) Frequency analysis of herb properties: the Four Qi of 255 kinds of TCMs are mainly warm and neutral medicines. The Five Flavors are mainly sweet medicines, followed by bitter medicines. The main meridians are the liver, spleen, and kidney. (3) Clustering of medications: TCMs with the top 20 frequencies are classified into 9 groups by cluster analysis. (4) Association rule analysis of high-frequency herbs: using the Apriori algorithm, the results showed that there were 3 herb pairs with support of over 0.3 and 12 herb pairs with confidence above 0.85. Conclusion: The basic pathogenesis of AA (Sui Lao) is spleen and kidney essence deficiency, Qi deficiency, and blood stasis. The main herbs have warm and neutral properties, sweet tastes, and liver, spleen, and kidney meridian tropisms, whose purpose is to tonify the kidney and invigorate the spleen, tonify Qi, and promote blood circulation.

Efficacy of Melatonin in Animal Models of Subarachnoid Hemorrhage: A Systematic Review and Stratified Meta-Analysis.

Background and Purpose: Subarachnoid hemorrhage (SAH) is a severe disease characterized by sudden headache, loss of consciousness, or focal neurological deficits. Melatonin has been reported as a potential neuroprotective agent of SAH. It provides protective effects through the anti-inflammatory effects or the autophagy pathway. Our systematic review aims to evaluate the efficacy of melatonin administration on experimental SAH animals and offer support for the future clinical trial design of the melatonin treatment following SAH. Methods: The following online databases were searched for experimentally controlled studies of the effect of melatonin on SAH models: PubMed, Web of Knowledge, Embase, and China National Knowledge Infrastructure (all until March 2021). The melatonin effect on the brain water content (BWC) and neurological score (NS) were compared between the treatment and control groups using the standardized mean difference (SMD). Results: Our literature identified 160 possible articles, and most of them were excluded due to duplication (n = 69) and failure to meet the inclusion criteria (n = 56). After screening the remaining 35 articles in detail, we excluded half of them because of no relevant outcome measures (n = 16), no relevant interventions (n = 3), review articles (n = 1), duplicated publications (n = 1), and studies on humans or cells (n = 2). Finally, this systematic review contained 12 studies between 2008 and 2018. All studies were written in English except for one study in Chinese, and all of them showed the effect of melatonin on BWC and NS in SAH models. Conclusion: Our research shows that melatonin can significantly improve the behavior and pathological results of SAH animal models. However, due to the small number of studies included in this meta-analysis, the experimental design and experimental method limitations should be considered when interpreting the results. Significant clinical and animal studies are still required to evaluate whether melatonin can be used in the adjuvant treatment of clinical SAH patients.

Effect Evaluation of Strychnos nux-vomica L. with Integrative Methods for Bortezomib-Induced Peripheral Neuropathy in Multiple Myeloma Patients: A Self-Controlled Clinical Trial.

OBJECTIVE: To explore the clinical effect and adverse reactions of Strychnos nux-vomica in bortezomib-induced peripheral neuropathy (BIPN) of patients with multiple myeloma (MM). METHODS: A total of 19 MM patients with BIPN were enrolled and Nux Vomica Capsule (NVC, 0.4 g, thrice daily) were orally administrated for 30 days. Comparative analysis on parameters between pre- and post-therapy, including peripheral neuropathy (PN) grade, neurotoxicity score, Chinese medicine (CM) syndrome score, total neuropathy score (TNS), coagulation function, and serum nerve growth factor (NGF) levels were conducted. The adverse events were monitored. RESULTS: In BIPN of MM patients who received NVC, PN grade was lowered, neurotoxicity score was obviously decreased (P⩽0.01), and both CM syndrome score and TNS were remarkably decreased (P<0.01). After the therapy, activated partial thromboplastin time was prolonged (P<0.01) and fibrinogen was declined (P<0.05), showing improvement in the hypercoagulable state of patients. No significant difference of NGF recovery degrees was detected between pre- and post-therapy (P>0.05). No evident adverse reactions were observed during the course of treatment. CONCLUSION: Strychnos nux-vomica L. has significantly effect with a good safety in treatment of BIPN in MM patients.

Electroacupuncture regulates the DREAM/NF-κB signalling pathway and ameliorates cyclophosphamide-induced immunosuppression in mice.

BACKGROUND: Immune responses inhibit invasion by pathogens and antigens. Thus, it is important to promote the immune response in immunosuppressed patients. OBJECTIVE: To examine whether electroacupuncture (EA) promotes the immune response by regulating the downstream regulatory element antagonist modulator / nuclear factor kappa B (DREAM/NF-κB) signalling pathway in a mouse model of cyclophosphamide (CP)-induced immunosuppression, and determine the most effective frequency. METHODS: Twenty-four Kunming mice were intraperitoneally injected with CP to establish an immunosuppression model and six mice were injected with the same volume of normal saline as a control. The 24 mice were randomly divided into four groups: manual acupuncture, 2 Hz EA treatment, 100 Hz EA treatment and alternating 2/100 Hz EA treatment. After EA treatment for 3 days, immune response, natural killer (NK) cell toxicity and the expression of cytokines and DREAM/NF-κB were assessed. RESULTS: EA treatment, especially at alternating 2/100 Hz frequency, improved spleen and thymus indices, increased lactate dehydrogenase and acid phosphatase levels, promoted concanavalin A- and lipopolysaccharide-induced splenocyte proliferation, increased NK cell toxicity and ameliorated CP-induced immunosuppression in mice. Additionally, 2/100 Hz EA treatment increased interleukin (IL)-2, IL-6, IL-12, tumour necrosis factor-α and interferon-γ levels and decreased IL-10 levels in CP-induced immunosuppressed mice. Finally, it was found that 2/100 Hz EA treatment increased p-IκBα and NF-κB expression and decreased DREAM and IκBα expression, suggesting that this treatment activates the NF-κB signalling pathway. CONCLUSION: 2/100 Hz EA treatment might be an effective way to enhance immune responses in CP-induced immunosuppressed mice.

[Effect of high frequency electrotherapy on caspase-3 and ultra microstructure of hippocampus in rats following cerebral ischemia/reperfusion].

OBJECTIVE: To investigate the effect of high frequency electrotherapy (HFE) on rat hippocampus after cerebral ischemia/reperfusion (I/R).
 Methods: A rat model of cerebral I/R injury was established. The rats were randomly divided into a sham group, an I/R group and an HFE group. The HFE group received thearapy daily for different sessions for 1, 3, 7 d. Neuronal deficit score,neuron ultra microstructure in the hippocampus and caspase-3 protein expression were measured on 1 st, 3 th and 7th d.
 Results: Compared with the I/R group, the HFE group showed the decreased neurological deficit scores, with significant differences between the 2 groups (P<0.05). The injury in HFE group was reduced compared with that in the I/R group based on the electron microscope test, with significant difference. Caspase-3 protein in brain tissue in the HFE group also downregulated compared with that in the I/R group (P<0.05).
 Conclusion: High frequency electrotherapy can improve neural function, suppress caspase-3 expression and apoptosis in nerve cells and improve the ultra microstructure of neurons, displaying a protective effect on cerebral I/R injury in rats.

Effect of various levels of dietary curcumin on meat quality and antioxidant profile of breast muscle in broilers.

The aim of this study was to determine the effects of curcumin on meat quality and antioxidant profile of breast muscle in broilers. In experiment 1, birds were fed basal diet with an additional 0, 50, 100, or 200 mg/kg curcumin, respectively. The results showed that dietary curcumin significantly increased the redness values of meat, catalase activity, and ABTS radical scavenging activity and decreased drip loss at 48 h. In experiment 2, birds reared under heat stress were assigned to similar treatments as experiment 1. Significant differences in the redox status of breast muscle were observed between the control and heat stress groups. The various levels of curcumin significantly prevented reactive oxygen species overproduction, enhanced the antioxidant defense system, and alleviated the abnormal change of antioxidant-related gene expression of muscle in heat-stressed birds. It was concluded that curcumin, as a potential antioxidant, improved meat quality and oxidant stability of muscle in broilers, whereas the inclusion of 50 and 100 mg/kg would be more efficient.

Elevated homocysteine levels contribute to larger hematoma volume in patients with intracerebral hemorrhage.

BACKGROUND: We investigate whether plasma homocysteine (HCY) levels are associated with hematoma volume and outcome in patients with intracerebral hemorrhage (ICH). METHODS: A total of 69 patients admitted within 24 hours after ICH onset was divided into 2 groups based on admission plasma HCY levels (low homocysteinemia [LHCY] group, plasma HCY concentrations ≤14.62 µmol/L, versus high homocysteinemia [HHCY] group, >14.62 µmol/L). RESULTS: Mean hematoma volumes for 2 groups (LHCY and HHCY) were 13.18 and 23.09 mL (P = .012), respectively, in patients with thalamoganglionic ICH, but hematoma volumes between 2 groups had no significant difference among patients with lobar or infratentorial ICH. On multivariate linear regression analysis, elevated HCY levels significantly correlated with larger hematoma volume in patients with thalamoganglionic ICH (B = .604, P = .004) after adjustment for confounding factors. Poor outcomes (6-month modified Rankin Scale scores ≥3) were not significantly different between 2 groups (low homocysteinemia group, 31.4%, versus high homocysteinemia group, 41.2%, P = .400). CONCLUSIONS: Elevated plasma HCY levels were associated with larger hematoma volume only in patients with thalamoganglionic ICH. HCY levels might not be predictors of the 6-month clinical outcome in patients with ICH.

Bone marrow angiogenesis in patients presenting with differential Chinese medicine syndrome: correlation with the clinico-pathological features of aplastic anemia.

OBJECTIVE: To explore differences in bone marrow angiogenesis seen in aplastic anemia (AA) patients presenting with differential Chinese medicine (CM) syndrome, and to correlate these differences with clinical pathology. METHODS: Thirty-five patients were enrolled, including 18 with "yang deficiency syndrome" and 17 with "yin deficiency syndrome." Bone marrow biopsies and serum were collected. Microvessel density (MVD) and positive expression of vascular endothelial-derived growth factor (VEGF) were detected by immunohistochemisty. Hypoxia inducible factor -1α (HIF-1α), and VEGF expression were assayed by enzyme-linked immunoabsorbent assay (ELISA), serum lactate dehydrogenase (LDH) was tested by enzyme method and liquid chip technology was used to detected the expression of interleukin (IL)-2, IL-4, IL-6, IL-10, interferon (IFN)-γ and tumor necrosis factor (TNF)-α. RESULTS: Counts for leukocytes, absolute neutrophils and platelets in "yin deficiency syndrome" were lower than those found in "yang deficiency syndrome" (P<0.05). MVD and VEGF expression, and the positive rate of CD34 and VEGF in bone marrow were lower in AA, especially in "yin deficiency syndrome" (P<0.01 or P<0.05). "Yin deficiency syndrome" displayed decreased VEGF and LDH expression, and enhanced expression of HIF-1α as compared to "yang deficiency syndrome" (P<0.05). Levels of IL-4 and IL-6 were higher in AA (P<0.01), but IL-10 was decreased (P<0.05). High TNF-α expression was seen in "yang deficiency syndrome" and IFN-γ expression was decreased in "yin deficiency syndrome" as compared with normals (P <0.01 and P<0.05, respectively). CONCLUSION: AA patients have lower MVD than normals, especially in "yin deficiency syndrome." MVD might differentially correlate to disease severity, and could be dependent on bone marrow or serum VEGF expression and LDH. Additionally, IL-2, IL-10, IL-4 and IFN-γ were negatively associated while IL-6 and TNF-α were positively associated with MVD.

Danhong injection: A modulator for Golgi structural stability after cerebral ischemia-reperfusion injury.

The cerebral ischemia-reperfusion model was established using the suture occlusion method, and rats were intraperitoneally given 8 mL/kg Danhong injection once a day prior to model establishment. Rat brain tissues were harvested at 6, 24, 48, 72 hours after reperfusion. Immunohistochemical staining showed that transforming growth factor-ß1 expression increased, while Golgi matrix protein GM130 expression decreased after cerebral ischemia-reperfusion. Danhong injection was shown to significantly up-regulate the expression of transforming growth factor-ß1 and GM130, and expression levels peaked at 7 days after reperfusion. At 7 days after cerebral ischemia-reperfusion, Golgi morphology was damaged in untreated rats, while Golgi morphology breakage was not observed after intervention with Danhong injection. These experimental findings indicate that Danhong injection can up-regulate the expression of transforming growth factor-ß1 and GM130, and maintain Golgi stability, thus playing a neuroprotective role in rats after cerebral ischemia-reperfusion.

[Effect of zengjing no. 1 capsule on morphology and motility of sperm in patients with oligospermia].

OBJECTIVE: To explore the effect of Zengjing Capsule No. 1 (ZJC1) on morphology and motility of sperm in patients with oligospermia (OSM). METHODS: Seventy-two OSM patients were assigned to 2 groups by a randomizing digital table, the treated group and the control group, they were treated respectively by ZJC1 and Wuzi Yanzong Pill (WYP). The changes of density, motility and morphology of sperm in patients before and after 3-month treatment were examined using computerized WLJY-9000 colour semen analysis system with refined Papanicolaou's stain. RESULTS: The density, motility and morphology of sperm were improved and sperm deformity rate was significantly decreased after treatment in both groups (P < 0.01), but the effects in the treated group were better than those in the control group (P < 0.01). CONCLUSION: ZJC1 can enhance the density and motility of sperm and reduce the sperm deformity rate in patients with OSM.

Use of 31P magnetic resonance spectroscopy to study the effect of cortical magnesium and energy metabolism after subarachnoid hemorrhage.

BACKGROUND: Flow metabolism coupling ensures adequate cerebral oxygenation. When subarachnoid hemorrhage (SAH) occurs, the flow metabolism coupling lost its balance and results in cerebral ischemia and infarction second to cortical magnesium and energy metabolism alternation. During chronic vasospasm, change in cortical energy metabolism is coupled with change in cerebral blood flow after SAH. METHODS: What kind of noninvasive technique can be used to directly investigate the biochemical environment in the SAH brain? Studies showed that (31)P magnetic resonance spectroscopy ((31)P MRS) is ideally suited to evaluate the pathophysiology of SAH, especially for cortical magnesium and energy metabolism. RESULTS: The results showed that cortical magnesium and energy metabolism were significantly decreased in both animal models and human beings after SAH by using (31)P MRS, which is associated with the severity and outcome of SAH, especially after aneurysmal SAH. CONCLUSION: (31)P MRS data, combined with other MRI sequences, provide a comprehensive assessment of both structural and functional deficits and a guidance on clinical therapy for SAH.

Electroacupuncture effects in a rat model of complete Freund's adjuvant-induced inflammatory pain: antinociceptive effects enhanced and tolerance development accelerated.

We have previously shown that electroacupuncture (EA) produced antinociception through the release of endogenous opioid peptides to activate opioid receptors during acute nociception. EA produced tolerance after its prolonged application. It has reported that 100 Hz EA could reduce mechanical hyperalgesia in complete Freund's adjuvant (CFA)-induced inflammatory nociception rats. The present study aims to investigate the antinociceptive effect of EA and the development of EA tolerance in chronic inflammatory nociception rats with CFA injection into the hind paw plantar. The results showed that the antinociceptive effect of 100 Hz EA was significantly enhanced in CFA-induced inflammatory nociception rats. Naloxone at 20 mg/kg could significantly block this antinociceptive effect. Chronic tolerance to EA was developed faster in CFA-induced inflammatory nociception rats than in normal rats. Therefore, 100 Hz EA could enhance antinociceptive effects and accelerate tolerance development in CFA-induced inflammatory nociception rats. The enhancement of EA antinociceptive effect in CFA-induced inflammatory nociception rats might involve the endogenous opioid peptides such as dynorphin.

CCK(B) receptor antagonist L365,260 potentiates the efficacy to and reverses chronic tolerance to electroacupuncture-induced analgesia in mice.

Cholecystokinin octapeptide (CCK-8) is a physiological antagonist of endogenous opioids in the central nervous system (CNS). Our previous work has shown that CCK-8 plays an important role in the development of tolerance to morphine analgesia and electroacupuncture (EA) analgesia in the rat. The present studies were designed to examine whether the CCK(B) receptor is involved in the modulation of EA analgesia and the development of EA tolerance in mice. The latency to flick the tail in the radiant heat was used as index to assess the efficacy of EA analgesia. Subcutaneous (s.c.) injection of the CCK(B) receptor antagonist L365,260 produced a dose-dependent (0.125-2.0 mg/kg) potentiation of the analgesia induced by 100 Hz EA, with a maximal effect occurred at 0.5 mg/kg. In addition, L365,260 (0.5 mg/kg) significantly reversed chronic tolerance to 100 Hz EA in mice. These results suggest that the CCK(B) receptor might play a role in the tonic inhibition of 100 Hz EA-induced analgesia and in the mediation of chronic tolerance to 100 Hz EA in mice. The results opened a way for further investigation of the function of CCK-8 in pain modulation using inbred strains of mice.

Attenuation of mechanical but not thermal hyperalgesia by electroacupuncture with the involvement of opioids in rat model of chronic inflammatory pain.

Opioid peptides have been proven effective in reducing the sign of hyperalgesia associated with inflammation. Electroacupuncture (EA) produces antinociception via release of endogenous opioid peptides in normal rats. Moreover, intrathecal injection of dynorphin has antinociceptive effect in rats. The present study was designed to examine whether EA has effect on the thermal and mechanical hyperalgesia in rat model of complete Freund's adjuvant (CFA)-induced inflammatory pain. The results are the following: (1) single session of 100Hz EA (0.5-1.0-1.5 mA, 10 min for each intensity) at both Zusanli (ST 36) and Sanyinjiao acupoints (SP 6) significantly increased mechanical withdrawal threshold determined by von Frey filaments but not with thermal withdrawal latency that is determined by hot plate (52 +/- 0.2 degrees C); (2) 100 Hz EA applied twice a week for 4 weeks and showed a significant decrease in the mechanical hyperalgesia at the third and fourth week, with no effect on thermal hyperalgesia; (3) naloxone (20 mg kg(-1)) had the ability to reverse the inhibition of the mechanical hyperalgesia produced by a single session of EA. In conclusion, the present results indicate that a single or repetitive EA could reduce mechanical hyperalgesia, but not thermal hyperalgesia, in CFA-inflammatory pain rats, and the opioid system might be involved in these effects.

[Experimental research of PDE5 activity in corpora cavernosa of ganyu qizhi rat model].

OBJECTIVES: To study the PDE5 activity in corpora cavernosa of the Ganyu Qizhi model penis and the effect of the Chinese herbal medicine Shugan Liqi Huoxue (SLH) ointment on it. METHODS: Non-injury stress stimulus method similar to human spirit stress was used to extablish the Ganyu Qizhi animal(rat) model, and the PDE5 activity in corpora cavernosa of the rat penis was measured by the method of immunohistochemistry and computer image analysis. RESULTS: The PDE5 activity in corpora cavernosa of the high-dosage SLH group was significantly different from that of the model group (P < 0.01). CONCLUSION: Ganyu Qizhi may increase the PDE5 activity in corpora cavernosa of the penis while SLH can reduce such activity.