Empagliflozin alleviates neuroinflammation by inhibiting astrocyte activation in the brain and regulating gut microbiota of high-fat diet mice.

A high-fat diet can modify the composition of gut microbiota, resulting in dysbiosis. Changes in gut microbiota composition can lead to increased permeability of the gut barrier, allowing bacterial products like lipopolysaccharides (LPS) to enter circulation. This process can initiate systemic inflammation and contribute to neuroinflammation. Empagliflozin (EF), an SGLT2 inhibitor-type hypoglycemic drug, has been reported to treat neuroinflammation. However, there is a lack of evidence showing that EF regulates the gut microbiota axis to control neuroinflammation in HFD models. In this study, we explored whether EF could improve neuroinflammation caused by an HFD via regulation of the gut microbiota and the mechanism underlying this phenomenon. Our data revealed that EF alleviates pathological brain injury, reduces the reactive proliferation of astrocytes, and increases the expression of synaptophysin. In addition, the levels of inflammatory factors in hippocampal tissue were significantly decreased after EF intervention. Subsequently, the results of 16S rRNA gene sequencing showed that EF could change the microbial community structure of mice, indicating that the abundance of Lactococcus, Ligilactobacillus and other microbial populations decreased dramatically. Therefore, EF alleviates neuroinflammation by inhibiting gut microbiota-mediated astrocyte activation in the brains of high-fat diet-fed mice. Our study focused on the gut-brain axis, and broader research on neuroinflammation can provide a more holistic understanding of the mechanisms driving neurodegenerative diseases and inform the development of effective strategies to mitigate their impact on brain health. The results provide strong evidence supporting the larger clinical application of EF.

Determination of the 90% Effective Dose of Dexmedetomidine for Treating Postoperative Catheter­related Bladder Discomfort During Recovery: An Open-label, Single-group Study.

PURPOSE: Catheter-related bladder discomfort (CRBD) is an unpleasant experience for patients during postoperative recovery. Dexmedetomidine is an effective therapy for CRBD; however, little is known about dexmedetomidine administration for treating CRBD during recovery. This study was conducted to determine the 90% effective dose (ED90) of dexmedetomidine to provide adequate treatment for CRBD during recovery. DESIGN: Prospective, single-blind dose-finding study. METHODS: This open-label, single-group trial included severe postoperative CRBD patients aged 18 to 80 years and the American Society of Anesthesiologists' physical status class I or II in the postanesthesia care unit. All patients were assigned to receive intravenous dexmedetomidine. The dose of dexmedetomidine was determined using the modified Dixon's up-and-down method. The first patient was treated with 0.4 mcg/kg dexmedetomidine. An increment or decrement of 0.05 mcg/kg dexmedetomidine was used based on the response of the previous patient. A successful treatment was defined as the transition from severe CRBD to mild CRBD. Probit regression was applied to calculate the ED90 of dexmedetomidine. FINDINGS: A total of 29 patients were recruited, of whom 14 patients (48.3%) underwent successful treatment. The ED90 of dexmedetomidine required for successfully treating postoperative CRBD was 0.55 mcg/kg (95% confidence interval: 0.49-1.54 mcg/kg). CONCLUSIONS: The ED90 of dexmedetomidine for the successful treatment of severe postoperative CRBD during recovery is 0.55 mcg/kg.

Class I histone deacetylase complex: Structure and functional correlates.

The Schizosaccharomyces pombe Clr6S complex, a class I histone deacetylase complex, functions as a zinc-dependent enzyme to remove acetyl groups from lysine residues in histone tails. We report here the cryo-EM structure of Clr6S alone and a cryo-EM map of Clr6S in complex with a nucleosome. The active center, revealed at near-atomic resolution, includes features important for catalysis-A water molecule coordinated by zinc, the likely nucleophile for attack on the acetyl-lysine bond, and a loop that may position the substrate for catalysis. The cryo-EM map in the presence of a nucleosome reveals multiple Clr6S-nucleosome contacts and a high degree of relative motion of Clr6S and the nucleosome. Such flexibility may be attributed to interaction at a site in the flexible histone tail and is likely important for the function of the deacetylase, which acts at multiple sites in other histone tails.

Molecular mechanisms and therapeutic potential of icariin in the treatment of Alzheimer's disease.

BACKGROUND: Icariin (ICA) is the main active component of Epimedium, a traditional Chinese medicine (TCM), known to enhance cognitive function in Alzheimer's disease (AD). This study aims to investigate and summarize the mechanisms through which ICA treats AD. METHODS: The PubMed and CNKI databases were utilized to review the advancements in ICA's role in AD prevention and treatment by analyzing literature published between January 2005 and April 2023. To further illustrate ICA's impact on AD development, tables, and images are included to summarize the relationships between various mechanisms. RESULTS: The study reveals that ICA ameliorates cognitive deficits in AD model mice by modulating Aß via multiple pathways, including BACE-1, NO/cGMP, Wnt/Ca2+, and PI3K/Akt signaling. ICA exhibits neuroprotective properties by inhibiting neuronal apoptosis through the suppression of ER stress in AD mice, potentially linked to NF-κB, MAPK, ERK, and PERK/Eif2α signaling pathways. Moreover, ICA may safeguard neurons by attenuating mitochondrial oxidative stress injury. ICA can also enhance learning, memory, and cognition by improving synaptic structure via regulation of the PSD-95 protein. Furthermore, ICA can mitigate neuroinflammation by inactivating microglial activity through the upregulation of PPARγ, TAK1/IKK/NF-κB, and JNK/p38 MAPK signaling pathways. CONCLUSION: This study indicates that ICA possesses multiple beneficial effects in AD treatment. Through the integration of pharmacological and molecular biological research, ICA may emerge as a promising candidate to expedite the advancement of TCM in the clinical management of AD.

Shen Qi Wan attenuates renal interstitial fibrosis through upregulating AQP1.

Renal interstitial fibrosis (RIF) is the crucial pathway in chronic kidney disease (CKD) leading to the end-stage renal failure. However, the underlying mechanism of Shen Qi Wan (SQW) on RIF is not fully understood. In the current study, we investigated the role of Aquaporin 1 (AQP1) in SQW on tubular epithelial-to-mesenchymal transition (EMT). A RIF mouse model induced by adenine and a TGF-ß1-stimulated HK-2 cell model were etablished to explore the involvement of AQP 1 in the protective effect of SQW on EMT in vitro and in vivo. Subsequently, the molecular mechanism of SQW on EMT was explored in HK-2 cells with AQP1 knockdown. The results indicated that SQW alleviated kidney injury and renal collagen deposition in the kidneys of mice induced by adenine, increased the protein expression of E-cadherin and AQP1 expression, and decreased the expression of vimentin and α-smooth muscle actin (α-SMA). Similarly, treatmement with SQW-containing serum significantly halted EMT process in TGF-ß1 stimulated HK-2 cells. The expression of snail and slug was significantly upregulated in HK-2 cells after knockdown of AQP1. AQP1 knockdown also increased the mRNA expression of vimentin and α-SMA, and decreased the expression of E-cadherin. The protein expression of vimentin increased, while the expression of E-cadherin and CK-18 significantly decreased after AQP1 knockdown in HK-2 cells. These results revealed that AQP1 knockdown promoted EMT. Furthermore, AQP1 knockdown abolished the protective effect of SQW-containing serum on EMT in HK-2 cells. In sum, SQW attentuates EMT process in RIF through upregulation of the expression of AQP1.

Essential oil of Acorus tatarinowii Schott inhibits neuroinflammation by suppressing NLRP3 inflammasome activation in 3 × Tg-AD transgenic mice.

BACKGROUND: Shi chang pu (Acorus tatarinowii Schott) is a herbal used in the treatment of Alzheimer's disease (AD) in China. The essential oil of Shi chang pu (SCP-oil) is the main active component. However, its effects on the neuroinflammation of AD have not been well studied. PURPOSE: Neuroinflammation mediated by the NLRP3 inflammasome plays a crucial role in AD. This study was designed to evaluate the effect of SCP-oil on cognitive impairment of AppSwe/PSEN1M146V/MAPTP301L triple transgenic (3 × Tg-AD) mice model and investigate the mechanism underlying its anti-inflammation effects. METHODS: Thirty-two 3 × Tg-AD mice at 12 months and 8 wild-type B6 mice were used for this experiment. The 3 × Tg-AD mice were administered with SCP-oil or donepezil hydrochloride for 8 weeks. Morris water maze test and step-down test were used to evaluate the cognitive ability of mice. The pathological changes, neuroinflammation, and the NLRP3 inflammasome related-protein of AD mice were detected by histomorphological examination, TUNEL staining, immunofluorescence, immunohistochemistry, qRT-PCR, Elisa, and western blot assays. RESULTS: SCP-oil treatment attenuated cognitive dysfunction of 3 × Tg-AD mice. Moreover, SCP-oil also ameliorated characteristics pathological of AD, such as pathological changes damage, deposition of Aß, phosphorylation of Tau, and neuronal loss. Additionally, SCP-oil treatment alleviated the neuroinflammation and inhibited phosphorylation of IKKß, NF-κB, and NLRP3 inflammasome related-protein NLRP3, ASC, Caspase-1, cleaved-Caspase-1, and GSDMD-N in the hippocampus of 3 × Tg-AD mice. CONCLUSION: Overall, SCP-oil contributed to neuroprotection in 3 × Tg-AD mice by reduced activation of NLRP3 inflammasome by inhibiting the NF-κB signaling pathway.

Curcumin Regulates Gut Microbiota and Exerts a Neuroprotective Effect in the MPTP Model of Parkinson's Disease.

Objectives: The experiment aimed to explore the effects of curcumin on motor impairment, dopamine neurons, and gut microbiota in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mice model. Methods: Mice were randomly assigned to six groups: normal control group, solvent control group, MPTP group, curcumin-low-dose group (40 mg/kg), curcumin-medium-dose group (80 mg/kg), and curcumin-high-dose group (160 mg/kg). After 14 days, each group of mice was subjected to the pole text, the hanging test, and the open-field test. Tyrosine hydroxylase (TH) immunohistochemistry was used to observe the survival of nigrostriatal dopamine neurons. Moreover, ultrastructural changes were observed with a transmission electron microscope in mice striatal tissue cells. Then, 16S rRNA was used to assess changes in the gut microbiota. Results: (1) Each dose of curcumin reduced pole climbing time and increased suspension score and total distance moved dose-dependently. (2) All curcumin groups improved cell wrinkling and vacuolar degeneration, increased the number of TH positives, improved cell survival, and the higher the dose of curcumin, the better the effect. (3) There were differences in microbiota composition and a relative abundance among the groups. The relative abundance of Patescibacteria, Proteobacteria, and Verrucomicrobia was higher in the MPTP group. The relative abundance of Patescibacteria, Enterobacteriaceae, Enterococcaceae all decreased in all curcumin groups. In addition, the Kyoto Encyclopedia of Genes and Genomes pathways showed a reduction in the superpathway of N-acetylneuraminate degradation after medium- and high-dose curcumin administration. Conclusions: Curcumin regulates gut microbiota and exerts a neuroprotective effect in the MPTP mice model. This preliminary study demonstrates the therapeutic potential of curcumin for Parkinson's disease, providing clues for microbially targeted therapies for Parkinson's disease.

Structure of the NuA4 histone acetyltransferase complex.

Nucleosome acetyltransferase of H4 (NuA4), one of two major histone acetyltransferase complexes in Saccharomyces cerevisiae specifically acetylates histone H2A and H4, resulting in increased transcriptional activity. Here we present a 3.8-4.0 Å resolution structure of the NuA4 complex from cryoelectron microscopy and associated biochemical studies. The determined structure comprises six subunits and appropriately 5,000 amino acids, with a backbone formed by subunits Eaf1 and Eaf2 spanning from an Actin-Arp4 module to a platform subunit Tra1. Seven subunits are missing from the cryo-EM map. The locations of missing components, Yaf9, and three subunits of the Piccolo module Esa1, Yng2, and Eaf6 were determined. Biochemical studies showed that the Piccolo module and the complete NuA4 exhibit comparable histone acetyltransferase activities, but the Piccolo module binds to nucleosomes, whereas the complete NuA4 does not. The interaction lifetime of NuA4 and nucleosome is evidently short, possibly because of subunits of the NuA4 complex that diminish the affinity of the Piccolo module for the nucleosome, enabling rapid movement from nucleosome to nucleosome.

Discovery and characterization of novel potent BCR-ABL degraders by conjugating allosteric inhibitor.

The oncogenic fusion protein BCR-ABL is the driving force of leukemogenesis in chronic myeloid leukemia (CML). Despite the great advance in CML treatment through the application of tyrosine kinase inhibitors (TKIs) against BCR-ABL, disease recurrence after TKI discontinuation and clinical resistance mainly due to BCR-ABL mutations continue to be an issue. Herein we report our efforts to synthesize a novel series of CRBN-recruiting proteolysis-targeting chimeras (PROTACs) targeting BCR-ABL based on the allosteric inhibitor asciminib. Our efforts have led to the discovery of compound 30 (SIAIS100) through extensive SAR studies by the optimization of linker parameters as well as linker attachment points of both target-binding warhead and CRBN ligands, which exhibited the most potent degradative activity with a DC50 value of 2.7 nM and Dmax of 91.2% against BCR-ABL and has an IC50 value of 12 nM in BCR-ABL + K562 cells. The binding model and the stability evaluation of 30-induced ternary complex formation were also elucidated through computational simulations. Furthermore, 30 induced sustained and robust BCR-ABL degradation and maintained the efficacy for 96 h post-washout. Moreover, the proteomics analysis showed that 30 degraded BCR-ABL and three CRBN's neo-substrates, including IKZF1, IKZF3, and ZFP91. Additionally, 30 also exerted degradative activity against a panel of clinically relevant resistance-conferring mutations of BCR-ABL, including gatekeeper mutation T315I, several single mutations associated with TKI resistance, and certain highly resistant compound mutations. Our study provided a deeper understanding of the development of PROTACs targeting BCR-ABL and novel potential therapeutic agents for CML treatment.

Analyzing the metabolic fate of oral administration drugs: A review and state-of-the-art roadmap.

The key orally delivered drug metabolism processes are reviewed to aid the assessment of the current in vivo/vitro experimental systems applicability for evaluating drug metabolism and the interaction potential. Orally administration is the most commonly used state-of-the-art road for drug delivery due to its ease of administration, high patient compliance and cost-effectiveness. Roles of gut metabolic enzymes and microbiota in drug metabolism and absorption suggest that the gut is an important site for drug metabolism, while the liver has long been recognized as the principal organ responsible for drugs or other substances metabolism. In this contribution, we explore various experimental models from their development to the application for studying oral drugs metabolism of and summarized advantages and disadvantages. Undoubtedly, understanding the possible metabolic mechanism of drugs in vivo and evaluating the procedure with relevant models is of great significance for screening potential clinical drugs. With the increasing popularity and prevalence of orally delivered drugs, sophisticated experimental models with higher predictive capacity for the metabolism of oral drugs used in current preclinical studies will be needed. Collectively, the review seeks to provide a comprehensive roadmap for researchers in related fields.

The genomic stability regulator PTIP is required for proper chromosome segregation in mitosis.

BACKGROUND: The Pax transcription activation domain-interacting protein (PTIP) is a nuclear protein that is an essential component of H3K4 methylation for gene activation in vascular, kidney, B cell, and adipocyte development. Furthermore, it plays a key role in genomic stability in higher eukaryotic cells. It binds to 53BP1 and antagonizes inappropriate homologous recombination for a proper DNA damage response. Interestingly, an early study reported mitotic defects after PTIP inactivation, but it is not clear whether PTIP directly facilitates mitotic processes. RESULTS: Here, we showed that PTIP is essential for the mitotic integrity of HeLa cells. PTIP inactivation increases cell death during mitotic exit, which appears to result from direct mitotic defects. PTIP inactivation did not affect the G2M DNA damage checkpoint during interphase upon etoposide treatment. However, in mitosis, PTIP inactivation results in prolonged mitotic time, inefficient chromosome alignment, and increased cell death. Furthermore, PTIP localizes to the mitotic centrosome via BRCT domains at the C-terminus. CONCLUSION: This study reveals a novel function of PTIP in maintaining the genomic stability of higher eukaryotes during mitosis. Therefore, its deregulation, which occurs in various tumors, may destabilize the genome by introducing an abnormal DNA damage response, as well as erroneous chromosome segregation.

Naringin suppressed airway inflammation and ameliorated pulmonary endothelial hyperpermeability by upregulating Aquaporin1 in lipopolysaccharide/cigarette smoke-induced mice.

Naringin is one of the natural flavonoids extracted from many Chinese medicines. It ameliorates endothelial dysfunctions in atherosclerosis, diabetes, and cardiovascular diseases through free radical scavenging and antioxidant activities. The aim of the present study was to investigate the protective effects of naringin against pulmonary endothelial permeability in addition to airway inflammation in lipopolysaccharide/cigarette smoke (LPS/CS)-induced chronic obstructive pulmonary disease (COPD) mice.The COPD mice were exposed to LPS twice through intranasal inhalation and then to cigarette smoke daily for 6 weeks. The mice were orally administrated with naringin at doses of 40 or 80 mg/kg one hour before cigarette smoke exposure since the first day of the experiment. Naringin significantly alleviated pulmonary histopathological injury, and suppressed inflammatory cell infiltration and cytokine release in bronchoalveolar lavage fluid. Naringin decreased fluorescence intensity of Evans Blue in the lung tissues, and elevated the expression levels of tight junctional proteins. Meanwhile, naringin decreased neutrophil/lymphocyte/platelet counts and MDA content in blood, and upregulated Aquaporin1 (AQP1) in the lung tissues. However, the effect of naringin on airway inflammation and pulmonary endothelial permeability was inhibited in LPS/CS-treatment AQP1 deficiency mice. These results indicated that naringin attenuated LPS/CS-induced airway inflammatory and pulmonary hyperpermeability via upregulating AQP1 expression.

The Food Additive ß-Caryophyllene Exerts Its Neuroprotective Effects Through the JAK2-STAT3-BACE1 Pathway.

Despite extensive research on Alzheimer's disease (AD), its diagnosis and treatment remain challenging, and no effective therapies are currently available. Amyloid ß (Aß) extracellular plaques and intracellular neurofibrillary tangles are the histological characteristics of AD that have been directly linked to neuropathological events such as synaptic and neuronal cell loss. In this study, we explored whether the "JAK2-STAT3-BACE1" pathway is involved in neuroprotection conferred by the food flavouring agent ß-caryophyllene (BCP). PC-12 cells with overexpressed amyloid-ß protein precursor (APP) were utilised to construct an AD model in vitro, which was then split into four groups, namely control, empty vector, APP overexpression, and BCP (5, 10, and 20 µM). CCK-8 was used to evaluate cell viability, immunofluorescence was utilised to examine synaptic morphology, and quantitative real-time polymerase chain reaction and western blot were used to examine gene and protein expression levels. The relative expression levels of JAK2, STAT3, and BACE1 mRNA in the transfected PC-12 cells were found to be significantly upregulated. The cell morphology altered dramatically 72 h after transfection, becoming rounder, with a decrease in cell number. BCP exhibited the potential to dramatically increase PC-12 cell viability while protecting cell morphology. BCP inhibited APP, JAK2, STAT3, BACE1 mRNA and BACE1 protein overexpression, as well as JAK2 and STAT3 hyperphosphorylation. Molecular docking simulated the docking of BCP with JAK2, STAT3, BACE1, CB2. And JAK2 was found to be the most stable protein. In conclusion, inhibition of the "JAK2-STAT3-BACE1" signalling pathway may be one of the mechanisms through which BCP protects neurons and antagonises Aß's neurotoxicity.

Icariin Ameliorates Alzheimer's Disease Pathology by Alleviating Myelin Injury in 3 × Tg-AD Mice.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by excessive deposition of ß amyloid (Aß), hyperphosphorylation of tau protein, and neuronal cell death. Recent studies have shown that myelin cell damage, which leads to cognitive dysfunction, occurs before AD-related pathological changes. Here, we examine the effect of icariin (ICA), a prenylated flavonol glycoside, in improving cognitive function in AD model mice. ICA has been reported to exhibit cardiovascular protective functions and antiaging effects. In this study, we used 3 × Tg-AD mice as an AD model. The Morris water maze and Y maze tests were performed to assess the learning and memory of the mice. Immunofluorescence analysis of Aß1-42 deposition and myelin basic protein (MBP) expression in the mouse hippocampus was performed. Tau protein phosphorylation and MBP protein expression in the hippocampus were further analyzed by Western blotting. Myelin damage in the mouse optic nerve was evaluated by electron microscopy, and LFB staining was performed to assess myelin morphology in the mouse corpus callosum. MBP, Mpp5, and Egr2 transcript levels were quantified by qPCR. We observed that ICA treatment improved the learning and memory of 3 × Tg-AD mice and reduced Aß deposition and tau protein phosphorylation in the hippocampus. Moreover, this treatment protocol increased myelin-related gene expression and reduced myelin damage.

Guifu Dihuang Pills Ameliorated Mucus Hypersecretion by Suppressing Muc5ac Expression and Inactivating the ERK-SP1 Pathway in Lipopolysaccharide/Cigarette Smoke-Induced Mice.

Mucus hypersecretion is a hallmark of chronic obstructive pulmonary disease (COPD) and is associated with increasing sputum production and declining pulmonary function. Therefore, reducing mucus secretion can be a new therapeutic opportunity for preventing COPD. The Guifu Dihuang pill (GFDHP) is a classical Chinese medicine and has been used as an immunoregulator for treatment of kidney yang deficiency syndrome, including hypothyroidism, adrenocortical hypofunction, chronic bronchitis, and COPD, for more than 2000 years. However, the protective effects and mechanisms of GFDHP against mucus hypersecretion in COPD remain obscure. The aim of the present study was to explore the inhibitory effects of GFDHP on lipopolysaccharide/cigarette smoke- (LPS/CS-) induced Mucin5ac (Muc5ac) overproduction and airway goblet cell hyperplasia in mice. The mice were randomly assigned into 6 groups: control, model, GFDHP-L, GFDHP-M, GFDHP-H, and dexamethasone. The mice were given LPS twice through intranasal inhalation and then exposed to CS daily for 6 weeks. Three doses of GFDHP were orally administered daily during the last 3 weeks of the experiment. Pulmonary function was examined with an EMKA pulmonary system, and pulmonary hyperpermeability and lung damage were evaluated with an in vivo imaging system. Inflammatory cells and cytokines in bronchoalveolar lavage fluid (BALF) were detected with a cell count analyzer and though ELISA analysis, respectively. Lung pathological changes and airway goblet cell hyperplasia were analyzed with hematoxylin and eosin and Alcian blue periodic acid Schiff staining. The protein expression levels of Muc5ac and extracellular signal-regulated kinase (ERK)-specificity protein1 (SP1) signaling pathway were measured with Western blot and immunohistochemistry. The results demonstrated that GFDHP improved pulmonary function and suppressed mouse pulmonary hyperpermeability and edema. GFDHP suppressed inflammatory cell infiltration and cytokine release in BALF, thereby elevating pulmonary function. It ameliorated lung pathological changes and airway goblet cell hyperplasia, and suppressed expression levels of Muc5ac mRNA and protein and phospho-ERK and SP1 levels in the lung tissues of the COPD mice. In conclusion, GFDHP inhibited mucus hypersecretion induced by LPS/CS by suppressing the activation of the ERK-SP1 pathway.

Protective effect of α-asarone and ß-asarone on Aß -induced inflammatory response in PC12 cells and its.

To investigate effects of α-asarone and ß-asarone on induced PC12 cell injury and related mechanisms. Aß toxic injury cell model was induced by Aß in PC12 cells. PC12 cells were divided into blank control group, model control group, α-asarone group (0.5, 1.0, ß-asarone group (6.3, 12.5, vasoactive intestinal peptide (VIP) group, and VIP antagonist control group. Cell survival rate was detected by CCK-8 kit; cell apoptosis rate was detected by flow cytometry. The levels of inflammatory cytokines interleukin (IL)-1, , tumor necrosis factor (TNF)-α, oxidation-related inducible nitric oxide synthase (iNOS), nitric oxide (NO), apoptosis factors caspase-3 and p53 were detected by ELISA method. The expressions of C-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38MAPK) were detected by Western blotting. Compared with model control group, cell survival rates of group, ß-asarone group and VIP group increased; the cell apoptosis rate decreased; levels of apoptosis-related factors caspase-3, p53, inflammatory factors IL-1, TNF-α decreased; IL-10 level increased; levels of oxidization-related factors iNOS and NO decreased; the expression of JNK and p38MAPK protein decreased (all <0.05). After VIP antagonist intervention, the survival rate of ß-asarone group decreased; apoptosis rate increased; apoptosis related factors caspase-3, p53, inflammatory factors IL-1, TNF-α increased; IL-10 decreased; oxidation related factors iNOS and NO increased; the expression of JNK and p38MAPK protein increased (all <0.05); while there were no significant changes in these indicators of α-asarone group (all >0.05). α-asarone and ß-asarone have protective effects on PC12 cell injury induced by Aß. ß-asarone may inhibit inflammatory factors and oxidation-related factors through promoting VIP secretion, regulating JNK/MAPK pathway, and reducing PC12 cell apoptosis; however, the effect of α-asarone may be not related to VIP secretion.

The Protective Effect of Shen Qi Wan on Adenine-Induced Podocyte Injury.

Podocytes are a special type of differentiated epithelial cells that maintain the glomerular filtration barrier in the kidney. Injury or damages in podocytes can cause kidney-related disorders, like CKD. The injury or dysfunction of podocytes can occur by different metabolic disorders. Due to the severity and complexity of podocyte injuries, this state is considered as a serious health issue worldwide. Here, we examined and addressed the efficacy of an alternative Chinese medicine, Shen Qi Wan (SQW), on podocyte-related kidney injury. We evaluated the role and mechanism of action of SQW in podocyte injury. We observed that SQW significantly reduced 24-hour urinary protein and blood urea nitrogen levels and alleviated the pathological damage caused by adenine. Moreover, SQW significantly decreased the expression of nephrin and increased the expression of WT1 and AQP1 in the kidney of mice treated with adenine. We observed that SQW did not effectively reduce the high level of proteinuria in AQP1-/- mice indicating the prominent role of AQP1 in the SQW-ameliorating pathway. Transmission electron microscopy (TEM) images indicated the food processes effacement in AQP1-/- mice were not lessened by SQW. In conclusion, podocyte injury could alter the pathological nature of the kidney, and SQW administration relieves the nature of pathogenesis by activating AQP1.

Acori tatarinowii rhizoma extract ameliorates Alzheimer's pathological syndromes by repairing myelin injury and lowering Tau phosphorylation in mice.

It has been shown that Acori tatarinowii rhizoma (ATR) extract can improve cognitive functions in Alzheimer Diseas (AD) patients or animal models. In this study, we have examined the activity of ATR in 3×Tg-AD model mice with different comprehensive behavioral tests like the Morris water maze and Y-maze test assay for behavior. Moreover, we performed LFB staining for myelin determination in the AD model mouse. By analyzing different pathways, we determined key proteins that are beneficial for ameliorating AD syndrome in the mouse. Periluminally, ATR treatment improved the learning and memory ability that was determined by comprehensive behavioral tests. Moreover, treatment reduces the p-Tau accumulation in the 3×Tg-AD mouse and the level of p-Tau accumulation was at per with the wildtype control mouse and improves the myelin lining in 3×Tg-AD mouse. In conclusion, our results indicate that ATR-treatment can improve the learning ability of AD model mice and the hyperphosphorylation of Tau protein was decreased. ATR can protect myelin lining from damage in AD syndrome.

Anti-Alzheimer's Disease Molecular Mechanism of Acori Tatarinowii Rhizoma Based on Network Pharmacology.

BACKGROUND Acori Tatarinowii Rhizoma (ATR), a traditional Chinese herbal medicine, is used to treat Alzheimer's disease (AD), which is a worldwide degenerative brain disease. The aim of this study was to identify the potential mechanism and molecular targets of ATR in AD by using network pharmacology. MATERIAL AND METHODS The potential targets of the active ingredients of ATR were predicted by PharmMapper, and the targets of Alzheimer's disease were searched by DisGeNET. All screened genes were intersected to obtain potential targets for the active ingredients of ATR. The protein-protein interaction network of possible targets was established by STRING, GO Enrichment, and KEGG pathway enrichment analyses using the Annotation of DAVID database. Next, Cytoscape was used to build the "components-targets-pathways" networks. Additionally, a "disease-component-gene-pathways" network was constructed and verified by molecular docking methods. In addition, the active constituents ß-asarone and ß-caryophyllene were used to detect Aß1₋42-mediated SH-SY5Y cells, and mRNA expression levels of APP, Tau, and core target genes were estimated by qRT-PCR. RESULTS The results showed that the active components of ATR participate in related biological processes such as cancer, inflammation, cellular metabolism, and metabolic pathways and are closely related to the 13 predictive targets: ESR1, PPARG, AR, CASP3, JAK2, MAPK14, MAP2K1, ABL1, PTPN1, NR3C1, MET, INSR, and PRKACA. The ATR active components of ß-caryophyllene significantly reduced the mRNA expression levels of APP, TAU, ESR1, PTPN1, and JAK2. CONCLUSIONS The targets and mechanism corresponding to the active ingredients of ATR were investigated systematically, and novel ideas and directions were provided to further study the mechanism of ATR in AD.

Identification and prevention of heterotopias in mouse neocortical neural cell migration incurred by surgical damages during utero electroporation procedures.

In utero electroporation (IUE) is a useful technique for gene delivery in embryonic mouse brain. IUE technique is used to investigate the mammalian brain development in vivo. However, according to recent studies, IUE methodology has some limitations like the formation of artificial ectopias and heterotopias at the micro-injection site. Thus far, the artificial heterotopias generated by physical trauma during IUE are rarely reported. Here, we reported the artificial heterotopias and ectopias generated from surgical damages of micropipette in detail, and moreover, we described the protocol to avoid these phenotypes. For the experimental purpose, we transferred empty plasmids (pCAGIG-GFP) with green fluorescent-labelled protein into the cortical cortex by IUE and then compared the structure of the cortex region between the injected and un-injected cerebral hemispheres. The coronary section showed that ectopias and heterotopias were appeared on imperfect-injected brains, and layer maker staining, which including Ctip2 and TBR1 and laminin, can differentiate the physical damage, revealing the neurons in artificial ectopic and heterotopic area were not properly arranged. Moreover, premature differentiation of neurons in ectopias and heterotopias were observed. To avoid heterotopias and ectopias, we carefully manipulated the method of IUE application. Thus, this study might be helpful for the in utero electroporator to distinguish the artificial ectopias and heterotopias that caused by the physical injury by microneedle and the ways to avoid those undesirable circumstances.