Donepezil combined with traditional Chinese medicine has promising efficacy on mild cognitive impairment: a systematic review and meta-analysis.

Objective: Prior research has shown mixed results regarding the effectiveness of combining donepezil and traditional Chinese medicine (TCM) to treat mild cognitive impairment (MCI). In light of this, our study aims to examine the efficacy and safety of this treatment approach for patients with MCI. Methods: We conducted a comprehensive search of various databases, including Medline (via PubMed), Cochrane, Embase, Web of Science, Chinese National Knowledge Infrastructure, Chinese Biomedical Literature Database, Chinese Scientific Journal Database, and Wanfang Database from their inception to November 16, 2022. The selection of studies, risk of bias assessment, and data extraction were carried out independently by two authors. The statistical analysis was performed using STATA. Results: Our meta-analysis included a total of 35 studies with 2,833 patients, published between 2008 and 2022, with intervention durations ranging from 4 weeks to 12 months. However, most of the studies had a high risk of detection bias. Our findings indicated that the combination of donepezil and TCM significantly improved the Montreal Cognitive Assessment (MoCA) score (weighted mean difference [WMD] = 2.79, 95% confidence interval [CI]: 1.82 to 3.75) and the Barthel Index score (WMD = 9.20, 95% CI: 5.39 to 13.00) compared to donepezil alone. However, subgroup analyses showed that the MoCA score did not increase significantly in patients with MCI resulting from cerebrovascular disease (WMD = 1.47, 95% CI: -0.02 to 2.96). Conclusion: The combination of donepezil and TCM may have a more positive effect on cognitive function and activities of daily living in patients with MCI compared to the use of donepezil alone. However, due to the limited quality of the studies included in our analysis, these findings should be interpreted with caution.

Extraction and characterization of polysaccharide from fermented mycelia of Coriolus versicolor and its efficacy for treating nonalcoholic fatty liver disease.

Coriolus versicolor, a popular traditional Chinese medicinal herb, is widely used in China to treat spleen and liver diseases; however, the beneficial effects of C. versicolor polysaccharides (CVPs) on nonalcoholic fatty liver disease (NAFLD) remain elusive. Herein we isolated and purified a novel CVP (molecular weight, 17,478 Da) from fermented mycelium powder. This CVP was composed of mannose, galacturonic acid, glucose, galactose, xylose, and fucose at a molar ratio of 22:1:8:15:10:3. Methylation, gas chromatography-mass spectrometry, and nuclear magnetic resonance analyses indicated that the CVP backbone consisted of →1)-ß-D-Man-(6,4→1)-α-D-Gal-(3→1)-α-D-Man-(4→1)-α-D-Gal-(6→, with branches of →1)-α-D-Glc-(6→1)-α-D-Man-(4,3→1)-ß-D-Xyl-(2→1)-ß-D-Glc on the O-6 position of →1)-ß-D-Man-(6,4→ of the main chain. The secondary branches linked to the O-4 position of →1)-α-D-Man-(4,3→ with the chain of →1)-α-D-Fuc-(4→1)-α-D-Man. Further, CVP treatment alleviated the symptoms of NAFLD in an HFD-induced mice model. CVP altered gut microbiota, predominantly suppressing microbes associated with bile acids both in the serum and cecal contents. In vitro data showed that CVP reduced HFD-induced hyperlipidemia via farnesoid X receptor. Our results improve our understanding of the mechanisms underlying the cholesterol- and lipid-lowering effects of CVP and indicate that CVP is a promising candidate for NAFLD therapy.

Processing Mechanism of Massa Medicata Fermentata Based on the Correlation Analysis of Strains, Chemical Compositions and Anti-Inflammatory Activity.

The traditional Chinese medicine of fermented medicine may be under the involvement of multiple strains and the interaction between these microorganisms. Liu Shenqu (Massa Medicata Fermentata, MMF) is one of the most widely used fermented medicines, whose potential processing mechanism is still unclear. In this work, UPLC/MS and GNPS methods were employed to rapidly predict chemical compositions in MMF. Moreover, the dynamic changes of strains, chemical compositions and anti-inflammatory activity of MMF during fermentation process were investigated, and subsequently strains-chemical compositions-efficacy interactions were revealed by Pearson correlation analysis and partial least squares regression (PLSR) analysis. As a result, 24 components were identified, and the potential strains including Bacillus, Burkholderia_Caballeronia_Paraburkholderia, Enterobacter, Aspergillus heterocaryoticus, Rhizopus arrhizus, Kazachstania bulderi, which related to the production of anti-inflammatory active ingredients were exposed. These results demonstrated chemical compositions-strains-efficacy interactions during fermentation of MMF, and provide reference for the exploration of the processing mechanism of MMF.

Bloodletting Puncture at Hand Twelve Jing-Well Points Relieves Brain Edema after Severe Traumatic Brain Injury in Rats via Inhibiting MAPK Signaling Pathway.

OBJECTIVE: To investigate whether blood-brain barrier (BBB) served a key role in the edema-relief effect of bloodletting puncture at hand twelve Jing-well points (HTWP) in traumatic brain injury (TBI) and the potential molecular signaling pathways. METHODS: Adult male Sprague-Dawley rats were assigned to the sham-operated (sham), TBI, and bloodletting puncture (bloodletting) groups (n=24 per group) using a randomized number table. The TBI model rats were induced by cortical contusion and then bloodletting puncture were performed at HTWP twice a day for 2 days. The neurological function and cerebral edema were evaluated by modified neurological severity score (mNSS), cerebral water content, magnetic resonance imaging and hematoxylin and eosin staining. Cerebral blood flow was measured by laser speckles. The protein levels of aquaporin 4 (AQP4), matrix metalloproteinases 9 (MMP9) and mitogen-activated protein kinase pathway (MAPK) signaling were detected by immunofluorescence staining and Western blot. RESULTS: Compared with TBI group, bloodletting puncture improved neurological function at 24 and 48 h, alleviated cerebral edema at 48 h, and reduced the permeability of BBB induced by TBI (all P<0.05). The AQP4 and MMP9 which would disrupt the integrity of BBB were downregulated by bloodletting puncture (P<0.05 or P<0.01). In addition, the extracellular signal-regulated kinase (ERK) and p38 signaling pathways were inhibited by bloodletting puncture (P<0.05). CONCLUSIONS: Bloodletting puncture at HTWP might play a significant role in protecting BBB through regulating the expressions of MMP9 and AQP4 as well as corresponding regulatory upstream ERK and p38 signaling pathways. Therefore, bloodletting puncture at HTWP may be a promising therapeutic strategy for TBI-induced cerebral edema.

Valproate-Induced Epigenetic Upregulation of Hypothalamic Fto Expression Potentially Linked with Weight Gain.

Valproate (VPA), a widely-used antiepileptic drug, is a selective inhibitor of histone deacetylase (HDAC) that play important roles in epigenetic regulation. The patient with different diseases receiving this drug tend to exhibit weight gain and abnormal metabolic phenotypes, but the underlying mechanisms remain largely unknown. Here we show that VPA increases the Fto mRNA and protein expression in mouse hypothalamic GT1-7 cells. Interestingly, VPA promotes histone H3/H4 acetylation and the FTO expression which could be reversed by C646, an inhibitor for histone acetyltransferase. Furthermore, VPA weakens the FTO's binding and enhances the binding of transcription factor TAF1 to the Fto promoter, and C646 leads to reverse effect of the VPA, suggesting an involvement of the dynamic of histone H3/H4 acetylation in the regulation of FTO expression. In addition, the mice exhibit an increase in the food intake and body weight at the beginning of 2-week treatment with VPA. Simultaneously, in the hypothalamus of the VPA-treated mice, the FTO expression is upregulated and the H3/H4 acetylation is increased; further the FTO's binding to the Fto promoter is decreased and the TAF1's binding to the promoter is enhanced, suggesting that VPA promotes the assembly of the basal transcriptional machinery of the Fto gene. Finally, the inhibitor C646 could restore the effects of VPA on FTO expression, H3/H4 acetylation, body weight, and food intake; and loss of FTO could reverse the VPA-induced increase of body weight and food intake. Taken together, this study suggests an involvement of VPA in the epigenetic upregulation of hypothalamic FTO expression that is potentially associated with the VPA-induced weight gain.

Berberine Exerts Anti-cancer Activity by Modulating Adenosine Monophosphate- Activated Protein Kinase (AMPK) and the Phosphatidylinositol 3-Kinase/ Protein Kinase B (PI3K/AKT) Signaling Pathways.

Background: The antagonistic relationship between adenosine monophosphate-activated protein kinase (AMPK) and phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling play a vital role in cancer development. The anti-cancer effects of berberine have been reported as a main component of the traditional Chinese medicine Rhizoma coptidis, although the roles of these signaling pathways in these effects have not been systematically reviewed. METHODS: We searched the PubMed database for studies with keywords including ["berberine"] and ["tumor" or "cancer"] and ["AMPK"] or ["AKT"] published between January 2010 and July 2020, to elucidate the roles of the AMPK and PI3K/AKT pathways and their upstream and downstream targets in the anti-cancer effects of berberine. RESULTS: The anti-cancer effects of berberine include inhibition of cancer cell proliferation, promotion of apoptosis and autophagy in cancer cells, and prevention of metastasis and angiogenesis. The mechanism of these effects involves multiple cell kinases and signaling pathways, including activation of AMPK and forkhead box transcription factor O3a (FOXO3a), accumulation of reactive oxygen species (ROS), and inhibition of the activity of PI3K/AKT, rapamycin (mTOR) and nuclear factor-κB (NF-κB). Most of these mechanisms converge on regulation of the balance of AMPK and PI3K/AKT signaling by berberine. CONCLUSION: This evidence supports the possibility that berberine is a promising anti-cancer natural product, with pharmaceutical potential in inhibiting cancer growth, metastasis and angiogenesis via multiple pathways, particularly by regulating the balance of AMPK and PI3K/AKT signaling. However, systematic preclinical studies are still required to provide scientific evidence for further clinical studies.

Effects and Mechanisms of Acupuncture Combined with Mesenchymal Stem Cell Transplantation on Neural Recovery after Spinal Cord Injury: Progress and Prospects.

Spinal cord injury (SCI) is a structural event with devastating consequences worldwide. Due to the limited intrinsic regenerative capacity of the spinal cord in adults, the neural restoration after SCI is difficult. Acupuncture is effective for SCI-induced neurologic deficits, and the potential mechanisms responsible for its effects involve neural protection by the inhibition of inflammation, oxidation, and apoptosis. Moreover, acupuncture promotes neural regeneration and axon sprouting by activating multiple cellular signal transduction pathways, such as the Wnt, Notch, and Rho/Rho kinase (ROCK) pathways. Several studies have demonstrated that the efficacy of combining acupuncture with mesenchymal stem cells (MSCs) transplantation is superior to either procedure alone. The advantage of the combined treatment is dependent on the ability of acupuncture to enhance the survival of MSCs, promote their differentiation into neurons, and facilitate targeted migration of MSCs to the spinal cord. Additionally, the differentiation of MSCs into neurons overcomes the problem of the shortage of endogenous neural stem cells (NSCs) in the acupuncture-treated SCI patients. Therefore, the combination of acupuncture and MSCs transplantation could become a novel and effective strategy for the treatment of SCI. Such a possibility needs to be verified by basic and clinical research.

[Progress of research on acupuncture treatment of nonspecific low back pain].

Nonspecific low back pain (NLBP) is a heterogeneous disease with no definite pathological anatomical causes. Although acupuncture treatment of NLBP has been included in the international clinical guidelines for low back pain in many countries, the grade strength is still low, and the Results of clinical efficacy evaluation are controversial. Moderate evidence from international studies indicates that acupuncture treatment of NLBP has a clear short-term analgesic effect and can improve pain related depression symptoms to a certain extent, but the exploration of efficacy rules is relatively insufficient, and there is no specific operational scheme to guide the acupuncture treatment of NLBP. Domestic clinical studies are quite distinctive in the aspects of dose-effect acupoint selection, characteristic needling Methods, and acupuncture apparatuses, but lack of systematic research, and have low quality and weak evidence. In terms of the underlying mechanisms, acupuncture may achieve analgesic effect through anti-inflammation, relieving central sensitization, and improving the damage of local multifidus muscles and bones. However, due to the heterogeneity of NLBP disease, the current elaboration on the mechanism of acupuncture treatment of NLBP may not reach a consensus, and it is still worth further exploration.

[Research advances in the mechanism of acupuncture in regulating tumor immunosuppression].

As a characteristic therapy in traditional Chinese medicine, acupuncture has shown potential advantages in anti-tumor therapy, and one of the therapeutic effects of acupuncture is to improve the immunosuppressive conditions in patients with tumor. Based on the immunoregulatory effect of acupuncture, this article summarized the mechanism of acupuncture in regulating tumor immune status from the following aspects: stimulating the activation of natural killer cells, increasing the number of CD8+ T cells, and adjusting the balance between T helper 1 cells and T helper 2 cells and between regulatory T cells and T helper 17 cells. With reference to existing evidence, we believe that acupuncture can regulate the body's immunosuppressive conditions through a variety of targets, but further clinical and basic studies are needed to clarify its regulatory effect on tumor immune microenvironment and related mechanism of action.

AMPK and its Activator Berberine in the Treatment of Neurodegenerative Diseases.

Neurodegenerative disorders are heterogeneous diseases associated with either acute or progressive neurodegeneration, causing the loss of neurons and axons in the central nervous system (CNS), showing high morbidity and mortality, and there are only a few effective therapies. Here, we summarized that the energy sensor adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK), and its agonist berberine can combat the common underlying pathological events of neurodegeneration, including oxidative stress, neuroinflammation, mitochondrial disorder, glutamate excitotoxicity, apoptosis, autophagy disorder, and disruption of neurovascular units. The abovementioned effects of berberine may primarily depend on activating AMPK and its downstream targets, such as the mammalian target of rapamycin (mTOR), sirtuin1 (SIRT1), nuclear factor erythroid-2 related factor-2 (Nrf2), nuclear factor-κB (NF-κB), phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), nicotinamide adenine dinucleotide (NAD+), and p38 mitogen-activated protein kinase (p38 MAPK). It is hoped that this review will provide a strong basis for further scientific exploration and development of berberine's therapeutic potential against neurodegeneration.

Hypothalamic proteome changes in response to nicotine and its withdrawal are potentially associated with alteration in body weight.

Nicotine, a major addictive component in tobacco, plays an important role in the changes of body weight upon smoking and its cessation. Here we showed that nicotine-treated mice exhibited weight loss and nicotine withdrawal led to weight gain. Using TMT-based proteomic analysis, we obtained the different hypothalamic protein profiles in response to nicotine and its withdrawal. A total of ~5000 proteins were identified from the hypothalamus with 50 altered proteins upon 28-day nicotine treatment and 28 altered proteins upon 15-day nicotine withdrawal. Of the altered proteins, CASP3, LCMT2, GRIN2D, CCNT2, FADS3 and MRPS18B were inversely changed in response to nicotine and withdrawal, coincidence with the change of body weight. Of them, CASP3, LCMT2, GRIN2D and CCNT2 were found to be associated with several GO terms and KEGG pathways linking with cell apoptosis, neurotransmission and metabolism. Further Western blot and RT-qPCR analyses confirmed that the levels of the 4 proteins CASP3, LCMT2, GRIN2D and CCNT2, instead of their mRNA transcripts, altered in response to nicotine and withdrawal. Thus this study provides nicotine- and withdrawal-induced hypothalamic protein profiles and suggests potential roles of these altered proteins in the change of body weight. SIGNIFICANCE: Cigarette smoking is one of important factors harming human health. Most smokers tend to have lower body weights and smoking cessation often lead to overweight or obesity, which is an important reason for smokers to insist on smoking. It is known that nicotine, a critical component in tobacco, is associated with the alteration in body weight by affecting hypothalamic function. Through TMT-based proteomic analysis, this study identified differential hypothalamic protein profiles in response to nicotine treatment and its withdrawal, and 4 nicotine- and withdrawal-induced contrary proteins CASP3, LCMT2, GRIN2D and CCNT2 are involved in several enriched GO terms and KEGG pathways, which are associated with cell apoptosis, neurotransmission and metabolism. Our study may provide novel targets for further investigation of the molecular mechanisms of nicotine- and withdrawal-induced alteration in body weight.

P2RX7 in Dopaminergic Neurons of Ventral Periaqueductal Gray Mediates HTWP Acupuncture-Induced Consciousness in Traumatic Brain Injury.

The induction of a coma by traumatic brain injury (TBI) is a crucial factor for poor clinical prognoses. We report that acupuncture at the hand 12 Jing-Well points (HTWP) improved consciousness and neurologic function in TBI rats. Gene chip analyses showed that HTWP acupuncture mostly activated genes modulating neuronal projections (P2rx7, P2rx3, Trpv1, Tacr1, and Cacna1d), protein secretion (Exoc1, Exoc3l1, Fgb, and Fgr), and dopamine (DA) receptor D3 (Drd3) in the ventral periaqueductal gray (vPAG), among which the expression rate of P2rx7 was the most obviously increased. Acupuncture also increased the expression and excitability of DA and P2RX7 neurons, and the DA neurons expressed P2RX7, P2RX3, and TRPV1 in the vPAG. Intracerebroventricular administration of P2RX7, P2RX3, or TRPV1 antagonists blocked acupuncture-induced consciousness, and the subsequent injection of a P2RX7 antagonist into the vPAG nucleus also inhibited this effect. Our findings provide evidence that acupuncture alleviates TBI-induced comas via DA neurons expressing P2RX7 in the vPAG, so as to reveal the cellular and molecular mechanisms of the improvement of TBI clinical outcomes by HTWP acupuncture.

[Research advances in the clinical effect of bloodletting puncture at well-points in treatment of acute central nervous injury].

Bloodletting puncture at twelve well-points is a characteristic emergency therapy in traditional Chinese medicine. This article reviewed the research advances in the clinical effect of this therapy in the treatment of acute central nervous injury and its mechanism of action over the past 30 years, and it is found that this therapy can effectively improve disturbance of consciousness, neurological defects, and cerebral edema caused by stroke, traumatic brain injury, and carbon monoxide poisoning. The mechanism involves the improvement of cerebral blood flow and tissue oxygen supply, repair of the blood-brain barrier, and regulation of local ion balance. Well-designed clinical trials and in-depth research on biological mechanisms should be performed in future to promote and guide its clinical application.

Neurophysiology and Treatment of Disorders of Consciousness Induced by Traumatic Brain Injury: Orexin Signaling as a Potential Therapeutic Target.

BACKGROUND: Traumatic brain injury (TBI) can cause disorders of consciousness (DOC) by impairing the neuronal circuits of the ascending reticular activating system (ARAS) structures, including the hypothalamus, which are responsible for the maintenance of the wakefulness and awareness. However, the effectiveness of drugs targeting ARAS activation is still inadequate, and novel therapeutic modalities are urgently needed. METHODS: The goal of this work is to describe the neural loops of wakefulness, and explain how these elements participate in DOC, with emphasis on the identification of potential new therapeutic options for DOC induced by TBI. RESULTS: Hypothalamus has been identified as a sleep/wake center, and its anterior and posterior regions have diverse roles in the regulation of the sleep/wake function. In particular, the posterior hypothalamus (PH) possesses several types of neurons, including the orexin neurons in the lateral hypothalamus (LH) with widespread projections to other wakefulness-related regions of the brain. Orexins have been known to affect feeding and appetite, and recently their profound effect on sleep disorders and DOC has been identified. Orexin antagonists are used for the treatment of insomnia, and orexin agonists can be used for narcolepsy. Additionally, several studies demonstrated that the agonists of orexin might be effective in the treatment of DOC, providing novel therapeutic opportunities in this field. CONCLUSION: The hypothalamic-centered orexin has been adopted as the point of entry into the system of consciousness control, and modulators of orexin signaling opened several therapeutic opportunities for the treatment of DOC.

FTO is a transcriptional repressor to auto-regulate its own gene and potentially associated with homeostasis of body weight.

Fat mass and obesity-associated (FTO) protein is a ferrous ion (Fe2+)/2-oxoglutarate (2-OG)-dependent demethylase preferentially catalyzing m6A sites in RNA. The FTO gene is highly expressed in the hypothalamus with fluctuation in response to various nutritional conditions, which is believed to be involved in the control of whole body metabolism. However, the underlying mechanism in response to different nutritional cues remains poorly understood. Here we show that ketogenic diet-derived ketone body ß-hydroxybutyrate (BHB) transiently increases FTO expression in both mouse hypothalamus and cultured cells. Interestingly, the FTO protein represses Fto promoter activity, which can be offset by BHB. We then demonstrate that FTO binds to its own gene promoter, and Fe2+, but not 2-OG, impedes this binding and increases FTO expression. The BHB-induced occupancy of the promoter by FTO influences the assembly of the basal transcriptional machinery. Importantly, a loss-of-function FTO mutant (I367F), which induces a lean phenotype in FTOI367F mice, exhibits augmented binding and elevated potency to repress the promoter. Furthermore, FTO fails to bind to its own promoter that promotes FTO expression in the hypothalamus of high-fat diet-induced obese and 48-h fasting mice, suggesting a disruption of the stable expression of this gene. Taken together, this study uncovers a new function of FTO as a Fe2+-sensitive transcriptional repressor dictating its own gene switch to form an auto-regulatory loop that may link with the hypothalamic control of body weight.

Bletilla striata polysaccharide inhibits angiotensin II-induced ROS and inflammation via NOX4 and TLR2 pathways.

In the current study, we analyzed the functions and mechanisms of Bletilla striata polysaccharide b (BSPb) against Angiotensin II (Ang II)-induced oxidative stress and inflammation in human mesangial cells (HMCs). It was found that BSPb could inhibit generation of Ang II-induced reactive oxygen species (ROS) and activation of proinflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) in a dose-dependent manner. Further studies revealed that BSPb effectively blocked upregulation of NADPH oxidase 4 (NOX4). Moreover, knockdown of NOX4 significantly impaired the anti-oxidative function of BSPb. In addition, BSPb decreased overexpression of Toll-like receptor 2 (TLR2) induced by Ang II. Blocking TLR2 expression impaired the anti-inflammatory effects of BSPb. In conclusion, BSPb was found to possess anti-oxidative stress and anti-inflammatory functions against Ang II-induced ROS generation and proinflammatory cytokines activation. The NOX4 and TLR2 pathways played important roles in the biological effects mediated by BSPb.

Chinese herbal formula Tongluo Jiunao injection protects against cerebral ischemia by activating neurotrophin 3/tropomyosin-related kinase C pathway.

The Chinese herbal formula Tongluo Jiunao, containing the active components Panax notoginseng and Gardenia jasminoides, has recently been patented and is in use clinically. It is known to be neuroprotective in cerebral ischemia, but the underlying pathway remains poorly understood. In the present study, we established a rat model of cerebral ischemia by occlusion of the middle cerebral artery, and administered Tongluo Jiunao, a positive control (Xuesai Tong, containing Panax notoginseng) or saline intraperitoneally to investigate the pathway involved in the action of Tongluo Jiunao injection. 2,3,5-Triphenyltetrazolium chloride (TTC) staining showed that the cerebral infarct area was significantly smaller in model rats that received Tongluo Jiunao than in those that received saline. Enzyme-linked immunosorbent assay revealed significantly greater expression of neurotrophin 3 and growth-associated protein 43 in ischemic cerebral tissue, and serum levels of neurotrophin 3, in the Tongluo Jiunao group than in the saline group. The reverse transcription polymerase chain reaction and immunohistochemical staining showed that after treatment with Tongluo Jiunao or Xuesai Tong, tropomyosin-related kinase C gene expression and immunoreactivity were significantly elevated compared with saline, with the greatest expression observed after Tongluo Jiunao treatment. These findings suggest that Tongluo Jiunao injection exerts a neuroprotective effect in rats with cerebral ischemia by activating the neurotrophin 3/tropomyosin-related kinase C pathway.

Progesterone and vitamin D: Improvement after traumatic brain injury in middle-aged rats.

Progesterone (PROG) and vitamin D hormone (VDH) have both shown promise in treating traumatic brain injury (TBI). Both modulate apoptosis, inflammation, oxidative stress, and excitotoxicity. We investigated whether 21 days of VDH deficiency would alter cognitive behavior after TBI and whether combined PROG and VDH would improve behavioral and morphological outcomes more than either hormone alone in VDH-deficient middle-aged rats given bilateral contusions of the medial frontal cortex. PROG (16 mg/kg) and VDH (5 µg/kg) were injected intraperitoneally 1 h post-injury. Eight additional doses of PROG were injected subcutaneously over 7 days post-injury. VDH deficiency itself did not significantly reduce baseline behavioral functions or aggravate impaired cognitive outcomes. Combination therapy showed moderate improvement in preserving spatial and reference memory but was not significantly better than PROG monotherapy. However, combination therapy significantly reduced neuronal loss and the proliferation of reactive astrocytes, and showed better efficacy compared to VDH or PROG alone in preventing MAP-2 degradation. VDH+PROG combination therapy may attenuate some of the potential long-term, subtle, pathophysiological consequences of brain injury in older subjects.

Progesterone and low-dose vitamin D hormone treatment enhances sparing of memory following traumatic brain injury.

Progesterone (PROG) has been shown to protect the brain from traumatic injury and is now in Phase III clinical trials. Our work shows that PROG's beneficial effects can be reduced in vitamin D hormone (VDH)-deficient subjects. VDH can modulate neuronal apoptosis, trophic factors, inflammation, oxidative stress, excitotoxicity, and myelin and axon repair. We investigated whether VDH combined with PROG could improve behavioral outcomes more than PROG alone in VDH-sufficient rats given bilateral contusions of the medial frontal cortex. PROG and different doses of VDH (1 µg/kg, VDH1; 2.5 µg/kg, VDH2; 5 µg/kg, VDH3) were injected intraperitoneally 1 h post-injury. Eight additional doses of PROG were given subcutaneously over 8 days with tapering over the last 2 days. Neurobehavioral tests, necrotic cavity, neuronal death and activation of astrocytes were evaluated 21 days post-injury. We found that PROG and PROG + VDH preserve spatial memory processing. VDH1 + PROG improved performance in acquisition more effectively than PROG alone, indicating that the low VDH dose is optimal for combination therapy. There were no significant differences in necrotic cavity size among the groups. The density of positive staining for reactive astrocytes (glial fibrillary acidic protein (GFAP)) increased and the cell bodies and processes of GFAP-positive cells were enlarged in the PROG + VDH1 group. Our data indicate that the combination of PROG and VDH is more effective than PROG alone in preserving spatial and reference memory, and that PROG plus low-dose VDH can activateGFAP reactions up to 21 days after injury. This effect may be one of the mechanisms underlying PROG's neuroprotective effects in combination with VDH.

Protective effect of extract of Cordyceps sinensis in middle cerebral artery occlusion-induced focal cerebral ischemia in rats.

BACKGROUND: Ischemic hypoxic brain injury often causes irreversible brain damage. The lack of effective and widely applicable pharmacological treatments for ischemic stroke patients may explain a growing interest in traditional medicines. From the point of view of "self-medication" or "preventive medicine," Cordyceps sinensis was used in the prevention of cerebral ischemia in this paper. METHODS: The right middle cerebral artery occlusion model was used in the study. The effects of Cordyceps sinensis (Caterpillar fungus) extract on mortality rate, neurobehavior, grip strength, lactate dehydrogenase, glutathione content, Lipid Peroxidation, glutathione peroxidase activity, glutathione reductase activity, catalase activity, Na+K+ATPase activity and glutathione S transferase activity in a rat model were studied respectively. RESULTS: Cordyceps sinensis extract significantly improved the outcome in rats after cerebral ischemia and reperfusion in terms of neurobehavioral function. At the same time, supplementation of Cordyceps sinensis extract significantly boosted the defense mechanism against cerebral ischemia by increasing antioxidants activity related to lesion pathogenesis. Restoration of the antioxidant homeostasis in the brain after reperfusion may have helped the brain recover from ischemic injury. CONCLUSIONS: These experimental results suggest that complement Cordyceps sinensis extract is protective after cerebral ischemia in specific way. The administration of Cordyceps sinensis extract significantly reduced focal cerebral ischemic/reperfusion injury. The defense mechanism against cerebral ischemia was by increasing antioxidants activity related to lesion pathogenesis.