Targeting ferroptosis for treatment of Alzheimer' s disease / 中国药理学通报

Alzheimer' s disease (AD) is a progressive neurodegenerative disorder histologically characterized by the presence of senile plaques and neurofibrillary tangles (NFTs) found in and around pyramidal neurons in cortical tissue. Mounting evidence suggests regional increased iron load and dyshomeostasis have been associated with oxidative stress, oxidation of proteins and lipids, and cell death, and appears to be a risk factor for more rapid cognitive decline, thereby involved in multiple aspects of the pathophysiology of AD. Ferroptosis is a newly identified iron-dependent lipid peroxidation-driven cell death and emerging evidences have demonstrated the involvement of ferroptosis in the pathological process of AD. Notably, some novel compounds targeting ferroptosis can relieve AD-related pathological symptoms in AD cells and animal model and exhibit potential clinical benefits in AD patients. This review systematically summarizes the growing molecular and clinical evidence implicating ferroptosis in the pathogenesis of AD, and then reviews the application of ferroptosis inhibitors in mouse/cell models to provide valuable information for future treatment and prevention of AD.

The neuroprotective effects of Herba siegesbeckiae extract on cerebral ischemia/reperfusion in rats / 中国药理学通报

Aim To study the neuroprotective effects of Herba siegesbeckiae extract on cerebral ischemia/ reperfusion rats and its mechanism. Methods Sixty SD rats were randomly divided into model group, low, middle and high dose groups of Herba siegesbeckiae, and Sham operation group, and the drug was given continuously for seven days. The degree of neurologic impairment was evaluated by mNSS, and the infarct volume was measured by MRI. The number of Nissl-posi- tive cells was detected by Nissl staining, and the apop- tosis was accessed by Tunel staining. Furthermore, the expression of Bax, Bcl-2 and NeuN was observed by Western blot, and the expression of NeuN was detected by immunofluorescence staining. The expression of IL- 1β, TNF-α and IL-6 mRNA was performed by RT- qPCR. Results The mNSS score and the volume of ischemic cerebral infarction in the model group were significantly increased, and Herba siegesbeckiae extract treatment significantly decreased the mNSS score and infarct volume (P<0.05, P<0.01). Herba siegesbeckiae extract could increase the number of Nissl-pos- itive cells and the expression of NeuN (P<0.01), and reduce the number of Tunel-positive cells (P<0.01). Western blot showed that Herba siegesbeckiae extract inhibited the expression of Bax, increased Bcl-2 and NeuN in ischemic brain tissue (P<0.01). RT-qPCR showed that Herba siegesbeckiae extract inhibited the expression of IL-1 β, TNF-α and IL-6 mRNA in the is-chemic brain tissue (P<0.01). Conclusions Herba siegesbeckiae extract can reduce the cerebral infarction volume, improve the neurological function damage, inhibit the apoptosis of nerve cells and the expression of inflammatory factors and promote the expression of NeuN, there by exerting protective effects on MCAO rats.

Effect of alisol A on cerebral ischemia reperfusion injury by protecting blood brain barrier and its mechanism / 中国药理学通报

Aim To investigate whether alisol A (AA) could improve the blood brain barrier (BBB) mediated cortex cerebral ischemia-repeifusion injury (CIRI) by inhibiting matrix metalloproteinase 9 (MMP-9). Methods The global cerebral ischemia- reperfusion (GCI/R) model in mice was established, and the AA was intragastric injected subsequently for seven days. The modified neurological severity scores (mNSS), open field test and Y-maze test were applied to detect neurological function. Magnetic resonance spectroscopy (MRS) was used to detect relevant neu- rosubstance metabolism in cortex of mice. Transmission electron microscope (TEM) was employed to observe the ultrastructure of BBB in cortex. Western blot and immunohistochemistry were used to detect the MMP-9 level in cortex. The binding possibility of A A and MMP-9 was determined by molecular docking. Results Compared with Sham group, mice in GCI/R group have an increased mNSS score but decreased at total distance and center distance to total distance ratio in open field test as well as alternation rate in Y-maze test (P<0.01). While mice in GCI/R + AA group have a decreased mNSS score but increased at total distance and center distance to total distance ratio in open field test as well as alternation rate in Y-maze test (P<0.01) compared with GCI/R group. MRS results found that in cortex of GCI/R group mice, the level of GABA and NAA significantly decreased while the Cho, mI and Tau level increased (P<0.01). Whereas in GCI/R + AA group mice, the GABA and NAA level increased and the Cho, ml and Tau decreased significantly (P<0.01). By TEM we observed that the basilemma of cerebral microvessels collapsed, the lumen narrowed, the endothelial cells were active and plasma membranes ruffled, gaps between cells were enlarged and tight junctions were damaged and the end feet of astrocytes were swollen in GCI/R group mice. While in GCI/R + AA group mice, the lumen was filled, plasma membranes of endothelial cells were smooth, tight junctions were complete and end feet of astrocytes were in normal condition. Western blot and immunohistochemistry both found that the MMP-9 level increased in GCI/R group mice (P < 0.01) and decreased in GCI/R + AA group mice (P < 0.05). Molecular docking proved the binding between aliso A and MMP9 through TYR-50 and ARG-106, and the binding energy was calculated as -6.24 kcal · mol

Effects of local and systemic treatment with human natural killer-1 mimetic peptide (HNK-1) after ventral root avulsion and reimplantation in mice

Abstract Background: Spinal ventral root injuries generate significant motoneuron degeneration, which hinders full functional recovery. The poor prognosis of functional recovery can be attributed to the use or combination of different therapeutic approaches. Several molecules have been screened as potential treatments in combination with surgical reimplantation of the avulsed roots, the gold standard approach for such injuries. Among the studied molecules, human natural killer-1 (HNK-1) stands out as it is related to the stimulation of motor axon outgrowth. Therefore, we aimed to comparatively investigate the effects of local administration of an HNK-1 mimetic peptide (mp-HNK-1) and systemic treatment with ursolic acid (UA), another HNK-1 mimetic, after ventral root avulsion and reimplantation with heterologous fibrin biopolymer (HFB). Methods: Female mice of the isogenic strain C57BL/6JUnib were divided into five experimental groups: Avulsion, Reimplantation, mp-HNK-1 (in situ), and UA (systemic treatment). Mice were evaluated 2 and 12 weeks after surgery. Functional assessment was performed every four days using the Catwalk platform. Neuronal survival was analyzed by cytochemistry, and glial reactions and synaptic coverage were evaluated by immunofluorescence. Results: Treatment with UA elicited long-term neuroprotection, accompanied by a decrease in microglial reactions, and reactive astrogliosis. The neuroprotective effects of UA were preceded by increased glutamatergic and GABAergic inputs in the ventral spinal cord two weeks after injury. However, a single application of mp-HNK-1 had no significant effects. Functional analysis showed that UA treatment led to an improvement in motor and sensory recovery. Conclusion: Overall, the results indicate that UA is neuroprotective, acting on glial cells and synaptic maintenance, and the combination of these findings led to a better functional recovery.

Fraction of C. d. collilineatus venom containing crotapotin protects PC12 cells against MPP + toxicity by activating the NGF-signaling pathway

Abstract Background: Parkinson's disease (PD) is the second most prevalent neurodegenerative disease. There is no effective treatment for neurodegenerative diseases. Snake venoms are a cocktail of proteins and peptides with great therapeutic potential and might be useful in the treatment of neurodegenerative diseases. Crotapotin is the acid chain of crotoxin, the major component of Crotalus durissus collilineatus venom. PD is characterized by low levels of neurotrophins, and synaptic and axonal degeneration; therefore, neurotrophic compounds might delay the progression of PD. The neurotrophic potential of crotapotin has not been studied yet. Methods: We evaluated the neurotrophic potential of crotapotin in untreated PC12 cells, by assessing the induction of neurite outgrowth. The activation of the NGF signaling pathway was investigated through pharmacological inhibition of its main modulators. Additionally, its neuroprotective and neurorestorative effects were evaluated by assessing neurite outgrowth and cell viability in PC12 cells treated with the dopaminergic neurotoxin MPP+ (1-methyl-4-phenylpyridinium), known to induce Parkinsonism in humans and animal models. Results: Crotapotin induced neuritogenesis in PC12 cells through the NGF-signaling pathway, more specifically, by activating the NGF-selective receptor trkA, and the PI3K/Akt and the MAPK/ERK cascades, which are involved in neuronal survival and differentiation. In addition, crotapotin had no cytotoxic effect and protected PC12 cells against the inhibitory effects of MPP+ on cell viability and differentiation. Conclusion: These findings show, for the first time, that crotapotin has neurotrophic/neuroprotective/neurorestorative potential and might be beneficial in Parkinson's disease. Additional studies are necessary to evaluate the toxicity of crotapotin in other cell models.

Is Deep Hypothermic Cardiac Arrest Mandatory in Aortic Arch Surgeries?

ABSTRACT Cannulation strategies in aortic arch surgeries are a matter of immense discussion. Majority of time deep hypothermic circulatory arrest (DHCA) is the way out, but it does come with its set of demerits. Here we demonstrate a case with aortic arch dissection dealt with dual cannulation strategy in axillary and femoral artery without need for DHCA and ensuring complete neuroprotection of brain and spinal cord without hinderance of time factor. Inception of new ideas like this may decrease the need for DHCA and hence its drawbacks, thus decreasing the morbidity and mortality associated.

Activation of M1 muscarinic acetylcholine receptors by proline-rich oligopeptide 7a (

Background: The bioactive peptides derived from snake venoms of the Viperidae family species have been promising as therapeutic candidates for neuroprotection due to their ability to prevent neuronal cell loss, injury, and death. Therefore, this study aimed to evaluate the cytoprotective effects of a synthetic proline-rich oligopeptide 7a (PRO-7a; <EDGPIPP) from Bothrops jararaca snake, on oxidative stress-induced toxicity in neuronal PC12 cells and astrocyte-like C6 cells. Methods: Both cells were pre-treated for four hours with different concentrations of PRO-7a, submitted to H2O2-induced damage for 20 h, and then the oxidative stress markers were analyzed. Also, two independent neuroprotective mechanisms were investigated: a) L-arginine metabolite generation via argininosuccinate synthetase (AsS) activity regulation to produce agmatine or polyamines with neuroprotective properties; b) M1 mAChR receptor subtype activation pathway to reduce oxidative stress and neuron injury. Results: PRO-7a was not cytoprotective in C6 cells, but potentiated the H2O2-induced damage to cell integrity at a concentration lower than 0.38 μM. However, PRO-7a at 1.56 µM, on the other hand, modified H2O2-induced toxicity in PC12 cells by restoring cell integrity, mitochondrial metabolism, ROS generation, and arginase indirect activity. The α-Methyl-DL-aspartic acid (MDLA) and L-NΩ-Nitroarginine methyl ester (L-Name), specific inhibitors of AsS and nitric oxide synthase (NOS), which catalyzes the synthesis of polyamines and NO from L-arginine, did not suppress PRO-7a-mediated cytoprotection against oxidative stress. It suggested that its mechanism is independent of the production of L-arginine metabolites with neuroprotective properties by increased AsS activity. On the other hand, the neuroprotective effect of PRO-7a was blocked in the presence of dicyclomine hydrochloride (DCH), an M1 mAChR antagonist. Conclusions: For the first time, this work provides evidence that PRO-7a-induced neuroprotection seems to be mediated through M1 mAChR activation in PC12 cells, which reduces oxidative stress independently of AsS activity and L-arginine bioavailability.(AU)

Anti-inflammatory strategies for hepatic encephalopathy: preclinical studies / Estratégias anti-inflamatórias para encefalopatia hepática: estudos pré-clínicos

Abstract Hepatic encephalopathy (HE) is a potentially reversible neuropsychiatric syndrome. Often, HE causes cognitive and motor dysfunctions due to an acute or chronic insufficiency of the liver or a shunting between the hepatic portal vein and systemic vasculature. Liver damage induces peripheral changes, such as in the metabolism and peripheral inflammatory responses that trigger exacerbated neuroinflammation. In experimental models, anti-inflammatory strategies have demonstrated neuroprotective effects, leading to a reduction in HE-related cognitive and motor impairments. In this scenario, a growing body of evidence has shown that peripheral and central nervous system inflammation are promising preclinical targets. In this review, we performed an overview of FDA-approved drugs and natural compounds which are used in the treatment of other neurological and nonneurological diseases that have played a neuroprotective role in experimental HE, at least in part, through anti-inflammatory mechanisms. Despite the exciting results from animal models, the available data should be critically interpreted, highlighting the importance of translating the findings for clinical essays.

Resumo A encefalopatia hepática (EH) é uma síndrome neuropsiquiátrica potencialmente reversível. Muitas vezes a EH causa disfunções cognitivas e motoras devido à insuficiência do fígado ou por um desvio entre a veia porta hepática e a vasculatura sistêmica. O dano no fígado provoca alterações periféricas, como no metabolismo e nas respostas inflamatórias periféricas, que desencadeiam uma neuroinflamação exacerbada. Em modelos experimentais, estratégias anti-inflamatórias têm demonstrado efeitos neuroprotetores, levando a uma redução dos prejuízos cognitivos e motores relacionados à EH. Neste cenário, evidências crescentes têm mostrado a inflamação periférica e no sistema nervoso central como um promissor alvo pré-clínico. Nesta revisão, abordamos uma visão geral de drogas e compostos naturais aprovados pelo FDA para o uso no tratamento de outras doenças neurológicas e não neurológicas, que tiveram papel neuroprotetor na EH experimental, pelo menos em parte, através de mecanismos anti-inflamatórios. Apesar dos resultados empolgantes em modelos animais, os dados avaliados devem ser criticamente interpretados, destacando a importância da tradução dos achados para ensaios clínicos.

Cuidado desenvolvimental para recém-nascidos pré-termos: revisão de escopo / Atención del desarrollo de los recién nacidos pretérmino: revisión del alcance / Developmental care for preterm newborns: a scoping review

Objetivo: mapear como o cuidado desenvolvimental prestado aos recém nascidos pré-termos tem sido desenvolvido nas unidades de terapia intensiva neonatal com a finalidade de sintetizar as evidências científicas atuais. Métodos: revisão de escopo com busca realizada em novembro de 2022 nas bases MEDLINE, Biblioteca Virtual em Saúde, CINAHL, Embase e Web of Science. Foram incluídos estudos que retratavam o cuidado desenvolvimental nas unidades neonatais, nos últimos cinco anos, sem restrição de idioma. Resultados: incluíram-se sete artigos e os principais temas foram: contato pele a pele, controle do ruído e luminosidade, participação da família e sensibilização e treinamento da equipe. Conclusão: esses cuidados contribuem para o desenvolvimento neuropsicomotor do prematuro, melhoram a assistência e reduzem a morbimortalidade e o tempo de internação.

Objective: To map the evolution of developmental care provided to preterm newborns in Neonatal Intensive Care Units to synthesize current scientific evidence. Methods: Bibliographic search for a scoping review was conducted in November 2022 on the MEDLINE, Virtual Health Library, CINAHL, Embase and Web of Science databases. Studies discussing developmental care in neonatal units in the past five years, without language restriction, were included. Results: The scoping review included articles, whose main topics were skin-to-skin contact, noise and light control, family participation, and team awareness and training. Conclusion: Developmental care practices contribute to the neuropsychomotor development of preterm infants, improve care, reduce morbidity and mortality, and the length of hospitalization.

Objetivo: mapear cómo se ha desarrollado la atención del desarrollo brindada a los recién nacidos pretérmino en las unidades de cuidados intensivos neonatales para sintetizar la evidencia científica actual. Métodos: revisión de alcance realizada en noviembre de 2022 mediante búsquedas en las bases de datos MEDLINE, Biblioteca Virtual en Salud, CINAHL, Embase y Web of Science. Se incluyeron estudios que trataron la atención del desarrollo en unidades neonatales, en los últimos cinco años, sin restricción de idioma. Resultados: se incluyeron siete artículos y los temas principales fueron contacto piel con piel, control de luz y ruido, participación familiar y sensibilización y entrenamiento del equipo. Conclusión: estos cuidados contribuyen al desarrollo neuropsicomotor de los prematuros, mejoran la asistencia y reducen la morbimortalidad y la estancia hospitalaria.

The Neuroprotective Effects of Ginsenoside Rd Pretreatment in a Rat Model of Spinal Cord Ischemia-Reperfusion Injury

ABSTRACT Introduction: Paraplegia may develop as a result of spinal cord ischemia-reperfusion injury in patients who underwent thoracoabdominal aortic surgery. The objective of this research is to determine the neuroprotective effects of ginsenoside Rd pretreatment in a rat model of spinal cord ischemia-reperfusion injury. Methods: Sprague-Dawley rats (n=36) were randomly assigned to three groups. The sham (n=12) and control (n=12) groups received normal saline orally. The Rd group (n=12) received ginsenoside Rd (100 mg/kg) orally 48 hours before the induction of spinal cord ischemia. Spinal cord ischemia was induced by aortic occlusion using a Fogarty balloon catheter in the Rd and control groups. A neurological assessment according to the motor deficit index and a histological evaluation of the spinal cord were performed. To evaluate the antioxidant activity of ginsenoside Rd, malondialdehyde levels and superoxide dismutase activity were determined. Further, the tissue levels of tumor necrosis factor-alpha and interleukin-1 beta were measured. Results: The Rd group showed significantly lower motor deficit index scores than did the control group throughout the entire experimental period (P<0.001). The Rd group demonstrated significantly greater numbers of normal motor neurons than did the control group (P=0.039). The Rd group exhibited decreased malondialdehyde levels (P<0.001) and increased superoxide dismutase activity (P=0.029) compared to the control group. Tumor necrosis factor-alpha and interleukin-1 beta tissue levels were significantly decreased in the Rd group (P<0.001). Conclusion: Ginsenoside Rd pretreatment may be a promising treatment to prevent ischemia-reperfusion injury in patients who undergo thoracoabdominal aortic surgery.

Research progress in the intervention of Chinese herb monomers on diabetic retinal neurodegeneration / 国际眼科杂志(Guoji Yanke Zazhi)

Diabetic retinopathy(DR)has been traditionally considered a purely microvascular disease in the retina. Currently, mainstream therapies focus only on advanced vascular complications and a single molecular target-vascular endothelial growth factor(VEGF). However, the research is shifting towards a more comprehensive view that DR is a neurovascular disease caused by neurovascular unit(NVU)injury. In the early stage of DR, diabetic retinal neurodegeneration(DRN)dominates and may precede the retinal microvascular abnormalities. Moreover, neuronal apoptosis can further lead to microvascular injury and blood-retinal barrier(BRB)disruption. Therefore, it makes sense to develop new therapeutic strategies to prevent or reverse DRN. However, no drug targeting DRN has been approved for clinical use. In recent years, it has become a trend to study the protective effect of traditional Chinese medicine on the retina. The primary research focuses on Chinese herb monomers. This article reviews the research status of representative monomers in DRN to provide references for the early treatment of DR and development of new drugs.

Progress on the neuroprotective effects of ginsenoside Rg1 / 药学学报

Ginsenoside Rg1 is one of the most important saponins in ginseng. It has a wide range of pharmacological activities. It is considered to be a powerful neuroprotective agent. It has neuroprotective effects such as anti-neuroinflammation, anti-oxidative stress, anti-neuronal apoptosis, and enhancing memory. Rg1 shows a good application prospect in the prevention and treatment of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, stroke, and mental diseases such as depression. This paper reviews the research on the neuroprotective mechanism of Rg1 at home and abroad in recent years, in order to provide new research ideas for the clinical treatment of nervous system diseases.

Theoretical Exploration of Luobing Theory Guides Study on Alzheimer's Disease Based on Neurovascular Protection / 中国实验方剂学杂志

Based on the correlation between Qi and blood in traditional Chinese medicine， the collateral disease theory puts forward that the Qi-collateral go hand in hand with the vessel-collateral of the brain， and to be as close as lips to teeth in structure and function， which is an important basis for the function of brain governing mind. And this theory proposes that deficiency/stagnancy of collateral-Qi， stagnation of collaterals and loss of consciousness are the main pathogenesis of Alzheimer's disease（AD）， which is different from the research strategy of modern medicine focusing on neurons. It is suggested that it is necessary to treat AD from two aspects， including neuronal protection（elimination of pathological products such as β-amyloid and phosphorylated tau protein） and cerebral microvascular protection（protection of cerebral microvascular structure and function， promotion of therapeutic angiogenesis and increase of cerebral blood flow. Tongxinluo capsules is a representative drug for dredging collaterals developed under the guidance of the therapeutic principle of collaterals need circulation， it can protect microvessels and play a neuroprotective role mediated by vascular protection. Clinical studies have confirmed that Tongxinluo capsules can effectively treat AD， vascular dementia and cognitive impairment related diseases， which can provide new ideas and effective treatment ways to prevent and treat AD from neurovascular protection in a comprehensive manner.

Two new sesquiterpenes in Qi-nan Aquilariae Lignum Resinatum / 中国中药杂志

This study aimed to investigate the chemical constituents of supercritical extract from Qi-nan Aquilariae Lignum Resinatum by silica gel column chromatography, thin-layer chromatography, and semi-preparative high-performance liquid chromatography. One new elemane-type and one new eudesmane-type sesquiterpene compounds were isolated from the extract, and their structures were identified by MS, UV, IR, NMR, and ECD spectroscopic techniques, and named aquqinanol C(1) and aquqinanol D(2). Both compounds are novel compounds. The neuroprotective effect of the compounds on CORT-induced PC12 cell damage was determined in vitro. The results showed that compounds 1 and 2 exhibited a certain protective effect against CORT-induced damage in PC12 cells.

Neuroprotective effect of tetramethylpyrazine on mice after spinal cord injury / 中国中药杂志

This study aims to investigate the neuroprotective effect of tetramethylpyrazine on mice after spinal cord injury and its mechanism. Seventy-five female C57BL/6 mice were randomly divided into 5 groups, namely, a sham operation group, a model group, a tetramethylpyrazine low-dose group(25 mg·kg~(-1)), a tetramethylpyrazine medium-dose group(50 mg·kg~(-1)), and a tetramethylpyrazine high-dose group(100 mg·kg~(-1)), with 15 mice in each group. Modified Rivlin method was used to establish the mouse model of acute spinal cord injury. After 14 d of tetramethylpyrazine intervention, the motor function of hind limbs of mice was evaluated by basso mouse scale(BMS) and inclined plate test. The levels of inflammatory cytokines tumor necrosis factor-α(TNF-α), interleukin-6(IL-6), and interleukin-1β(IL-1β) in the spinal cord homogenate were determined by enzyme-linked immunosorbent assay(ELISA). Hematoxylin-eosin(HE) staining was used to observe the histology of the spinal cord, and Nissl's staining was used to observe the changes in the number of neurons. Western blot and immunofluorescence method were used to detect the expression of glial fibrillary acidic protein(GFAP) and C3 protein. Tetramethylpyrazine significantly improved the motor function of the hind limbs of mice after spinal cord injury, and the BMS score and inclined plate test score of the tetramethylpyrazine high-dose group were significantly higher than those of the model group(P<0.01). The levels of TNF-α, IL-6, and IL-1β in spinal cord homogenate of the tetramethylpyrazine high-dose group were significantly decreased(P<0.01). After tetramethylpyrazine treatment, the spinal cord morphology recovered, the number of Nissl bodies increased obviously with regular shape, and the loss of neurons decreased. As compared with the model group, the expression of GFAP and C3 protein was significantly decreased(P<0.05,P<0.01) in tetramethylpyrazine high-dose group. In conclusion, tetramethylpyrazine can promote the improvement of motor function and play a neuroprotective role in mice after spinal cord injury, and its mechanism may be related to inhibiting inflammatory response and improving the hyperplasia of glial scar.

Research progress on intra-arterial thrombolysis for the treatment of central retinal artery occlusion / 国际眼科杂志(Guoji Yanke Zazhi)

Central retinal artery occlusion(CRAO), also known as eye stroke, always results in acute and painless visual loss. At present, conservative treatments, such as eye massage, lowering intraocular pressure and vasodilators have little effect on reducing visual loss. Intra-arterial thrombolysis(IAT)has significantly improved prognosis in patients with acute ischemic stroke, thus IAT has been gradually applied in the treatment of CRAO. IAT injects fibrinolytic drugs directly into the ophthalmic artery by a microcatheter, and dissolves the emboli that block the central retinal artery to restore the blood flow of the retina. Theoretically, IAT may be effective for CRAO as what has been found for stroke, but existing clinical studies exhibited inconsistent results. This paper summarizes the feasibility, efficacy, and safety of IAT treatment in CRAO. It will also analyze related factors that affect the prognosis, putting forward potential development directions and providing insights for the further clinical application of IAT.

Short-chain fatty acids ameliorate spinal cord injury recovery by regulating the balance of regulatory T cells and effector IL-17+ γδ T cells / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Spinal cord injury (SCI) causes motor, sensory, and autonomic dysfunctions. The gut microbiome has an important role in SCI, while short-chain fatty acids (SCFAs) are one of the main bioactive mediators of microbiota. In the present study, we explored the effects of oral administration of exogenous SCFAs on the recovery of locomotor function and tissue repair in SCI. Allen's method was utilized to establish an SCI model in Sprague-Dawley (SD) rats. The animals received water containing a mixture of 150 mmol/L SCFAs after SCI. After 21 d of treatment, the Basso, Beattie, and Bresnahan (BBB) score increased, the regularity index improved, and the base of support (BOS) value declined. Spinal cord tissue inflammatory infiltration was alleviated, the spinal cord necrosis cavity was reduced, and the numbers of motor neurons and Nissl bodies were elevated. Enzyme-linked immunosorbent assay (ELISA), real-time quantitative polymerase chain reaction (qPCR), and immunohistochemistry assay revealed that the expression of interleukin (IL)‍-10 increased and that of IL-17 decreased in the spinal cord. SCFAs promoted gut homeostasis, induced intestinal T cells to shift toward an anti-inflammatory phenotype, and promoted regulatory T (Treg) cells to secrete IL-10, affecting Treg cells and IL-17+ γδ T cells in the spinal cord. Furthermore, we observed that Treg cells migrated from the gut to the spinal cord region after SCI. The above findings confirm that SCFAs can regulate Treg cells in the gut and affect the balance of Treg and IL-17+ γδ T cells in the spinal cord, which inhibits the inflammatory response and promotes the motor function in SCI rats. Our findings suggest that there is a relationship among gut, spinal cord, and immune cells, and the "gut-spinal cord-immune" axis may be one of the mechanisms regulating neural repair after SCI.

Schisandrin B Protects against Ischemic Brain Damage by Regulating PI3K/AKT Signaling in Rats / 中国结合医学杂志

OBJECTIVE@#To explore the effect and mechanism of schisandrin B (Sch B) in the treatment of cerebral ischemia in rats.@*METHODS@#The cerebral ischemia models were induced by middle cerebral artery occlusion (MCAO) and reperfusion. Sprague-Dawley rats were divided into 6 groups using a random number table, including sham, MCAO, MCAO+Sch B (50 mg/kg), MCAO+Sch B (100 mg/kg), MCAO+Sch B (100 mg/kg)+LY294002, and MCAO+Sch B (100 mg/kg)+wortmannin groups. The effects of Sch B on pathological indicators, including neurological deficit scores, cerebral infarct volume, and brain edema, were subsequently studied. Tissue apoptosis was identified by terminal transferase-mediated dUTP nick end-labeling (TUNEL) staining. The protein expressions involved in apoptosis, inflammation response and oxidative stress were examined by immunofluorescent staining, biochemical analysis and Western blot analysis, respectively. The effect of Sch B on phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling was also explored.@*RESULTS@#Sch B treatment decreased neurological deficit scores, cerebral water content, and infarct volume in MCAO rats (P<0.05 or P<0.01). Neuronal nuclei and TUNEL staining indicated that Sch B also reduced apoptosis in brain tissues, as well as the Bax/Bcl-2 ratio and caspase-3 expression (P<0.01). Sch B regulated the production of myeloperoxidase, malondialdehyde, nitric oxide and superoxide dismutase, as well as the release of cytokine interleukin (IL)-1 β and IL-18, in MCAO rats (P<0.05 or P<0.01). Sch B promoted the phosphorylation of PI3K and AKT. Blocking the PI3K/AKT signaling pathway with LY294002 or wortmannin reduced the protective effect of Sch B against cerebral ischemia (P<0.05 or P<0.01).@*CONCLUSIONS@#Sch B reduced apoptosis, inflammatory response, and oxidative stress of MCAO rats by modulating the PI3K/AKT pathway. Sch B had a potential for treating cerebral ischemia.

Three new anthraquinones from Prismatomeris tetrandra (Roxb.) K. Schum and their protective effects in neuroblastoma cells / 药学学报

Three new anthraquinones were isolated from the 80% ethanol extract of Prismatomeris tetrandra by silica gel, MCI, ODS column chromatography and high performance preparative liquid chromatography (HPLC). The structures of the new compounds were identified by mass spectrometry, nuclear magnetic resonance and other spectroscopic methods as 6-hydroxy-1,2,3-trimethoxy-7-methylanthracene-9,10-dione (1), 6-(hydroxymethyl)-1,2,3-trimethoxyanthracene-9,10-dione (2) and 7-hydroxy-6-(hydroxymethyl)-1,2-dimethoxyanthracene-9,10-dione (3). Compounds 1, 2 and 3 showed protective effects against monosodium glutamate-induced damage in SH-SY5Y neuroblastoma cells, with the cell survival rates elevated 18.45%, 4.31%, and 7.65%, respectively.

The potential targets and mechanisms of modified Baihe dihuang decoction applied in post-stroke depression / 中国药房

OBJECTIVE To explore the potential targets and mechanisms of the modified Baihe dihuang decoction （MBD/ BDD） applied in post-stroke depression （PSD）. METHODS Network pharmacology was used to mine the potential targets and key pathways of MBD/BDD in the treatment of PSD. PSD model rats were induced by focal cerebral ischemia surgery combined with chronic unforeseen mild stress， and then were randomly divided into PSD model group， MBD/BDD group （12.6 g/kg， by raw drug）， and fluoxetine hydrochloride （FLX） group （positive control， 2.3 mg/kg）； a blank control group was also set up， with 8 rats in each group. Each administration group was given a corresponding medication solution by gavage once a day for 21 consecutive days. The intervention effect of MBD/BDD on depression-like symptoms in model rats was evaluated by open field and forced swimming tests. The brain tissues of rats in each group were dissected and total RNA was extracted for transcriptome sequencing and bioinformatics analysis. The mRNA and protein expressions of genes with significant changes and common neurotrophic factors were verified based on the above results. RESULTS A total of 131 MBD/BDD antidepressant-related target genes were obtained （such as IL1B and AKT1， etc.）， which were closely related to neural active ligand-receptor interactions and cyclic adenosine monophosphate signaling pathway. MBD/BDD could significantly prolong or increase the total time spent and distance traveled in the central grid of qiangzhe@cqtcm.edu.cn PSD model rats， and significantly shorten the cumulative immobility time （P＜0.05）. After treatment with MBD/BDD， the number of genes that changed in rat brain tissue was much higher than that in the FLX group， and there were significant differences in gene profiles among the PSD model group， MBD/BDD group， and FLX group. There were 1 351 differentially expressed genes （DEGs） between the MBD/BDD group and the PSD model group， of which 178 were significantly down-regulated and 1 173 were significantly up-regulated （P＜0.05）. Above 1 351 DEGs were involved in neuronal differentiation， chemical synaptic transmission regulation. They were significantly enriched in axonal guidance， cholinergic synapses and neuroactive ligand-receptor interactions. The top 30 genes in terms of up-regulation in the brain tissue of rats of MBD/BDD group were all associated with neuronal proliferation， development， differentiation， and migration. After MBD/BDD intervention， the expressions of Fezf2， Arx， Ostn， Nrgn genes， brain-derived neurotrophic factor and tyrosine kinase receptor B protein in brain tissue of rats were significantly increased （P＜0.05）. CONCLUSIONS The anti-PSD effect of MBD/BDD may be related to the up-regulation of the expression of genes related to neuronal proliferation， development， differentiation and migration， as well as the promotion of neural structural and functional repair.