Ameliorative Role of Mitochondrial Therapy in Cognitive Function of Vascular Dementia Mice.

BACKGROUND: Mitochondrial dysfunction plays a vital role in the progression of vascular dementia (VaD). We hypothesized that transfer of exogenous mitochondria might be a beneficial strategy for VaD treatment. OBJECTIVE: The study was aimed to investigate the role of mitochondrial therapy in cognitive function of VaD. METHODS: The activity and integrity of isolated mitochondria were detected using MitoTracker and Janus Green B staining assays. After VaD mice were intravenously injected with exogenous mitochondria, Morris water maze and passive avoidance tests were used to detect cognitive function of VaD mice. Haematoxylin and eosin, Nissl, TUNEL, and Golgi staining assays were utilized to measure neuronal and synaptic injury in the hippocampus of VaD mice. Detection kits were performed to detect mitochondrial membrane potential (ΔΨ), SOD activity and the levels of ATP, ROS, and MDA in the brains of VaD mice. RESULTS: The results showed that isolated mitochondria were intact and active. Mitochondrial therapy could ameliorate cognitive performance of VaD mice. Additionally, mitochondrial administration could attenuate hippocampal neuronal and synaptic injury, improve mitochondrial ΔΨ, ATP level and SOD activity, and reduce ROS and MDA levels in the brains of VaD mice. CONCLUSIONS: The study reports profitable effect of mitochondrial therapy against cognitive impairment of VaD, making mitochondrial treatment become a promising therapeutic strategy for VaD.

Gliclazide Ameliorates Neuronal Injury by Attenuating Oxidative Stress in D-gal-Induced Senescent Cells and Aging Mice.

Enhancement of oxidative stress and resultant neuronal injury play important roles in initiating cognitive impairment during the aging process. Thus, attenuating oxidative injury is regarded as a profitable therapeutic strategy for age-associated cognitive impairment. Previous studies showed that gliclazide (Gli) had a protective role in neuronal injury from cerebral ischemia/reperfusion (I/R) injury. However, whether Gli has a profitable effect on age-associated cognitive impairment remains largely unclear. The present study showed that Gli held the potential to attenuate neuronal apoptosis in D-gal-induced senescent cells and aging mice. Additionally, Gli could alleviate synaptic injury and cognitive function in D-gal-induced aging mice. Further study showed that Gli could attenuate oxidative stress in D-gal-induced senescent cells and aging mice. The p38 MAPK pathway was predicted as the downstream target of Gli retarding oxidative stress using in silico analysis. Further studies revealed that Gli attenuated D-gal-induced phosphorylation of p38 and facilitated Nrf2 nuclear expression, indicating that the anti-oxidative property of Gli may be associated with the p38 MAPK pathway. The study demonstrates that Gli has a beneficial effect on ameliorating D-gal-induced neuronal injury and cognitive impairment, making this compound a promising agent for the prevention and treatment of age-associated cognitive impairment.

Circular RNAs: emerging players in brain aging and neurodegenerative diseases.

Brain aging is closely related to neurodegenerative diseases. Circular RNAs (circRNAs) are a type of conserved RNAs with covalently closed continuous loops. Emerging evidence has shown that circRNAs are implicated in the biology of brain aging and the pathology of age-related neurodegenerative diseases. Here, we summarize current studies on circRNAs associated with brain aging and neurodegenerative diseases by discussing their expression features, pathophysiological roles, and mechanisms of action. We also discuss the potential challenges of circRNA-based therapy against brain aging and neurodegenerative diseases, as well as their potential as diagnostic biomarkers of neurodegenerative diseases. The review provides insights into current progress in the functions of circRNAs in the process of brain aging and neurodegenerative diseases. © 2022 The Pathological Society of Great Britain and Ireland.

Erratum: Cx43 deficiency confers EMT-mediated tamoxifen resistance to breast cancer via c-Src/PI3K/Akt pathway: Erratum.

[This corrects the article DOI: 10.7150/ijbs.55453.].

Corrigendum: A Novel Role of Connexin 40-Formed Channels in the Enhanced Efficacy of Photodynamic Therapy.

[This corrects the article DOI: 10.3389/fonc.2019.00595.].

MeCP2 prevents age-associated cognitive decline via restoring synaptic plasticity in a senescence-accelerated mouse model.

Age-related cognitive decline in neurodegenerative diseases, such as Alzheimer's disease (AD), is associated with the deficits of synaptic plasticity. Therefore, exploring promising targets to enhance synaptic plasticity in neurodegenerative disorders is crucial. It has been demonstrated that methyl-CpG binding protein 2 (MeCP2) plays a vital role in neuronal development and MeCP2 malfunction causes various neurodevelopmental disorders. However, the role of MeCP2 in neurodegenerative diseases has been less reported. In the study, we found that MeCP2 expression in the hippocampus was reduced in the hippocampus of senescence-accelerated mice P8 (SAMP8) mice. Overexpression of hippocampal MeCP2 could elevate synaptic plasticity and cognitive function in SAMP8 mice, while knockdown of MeCP2 impaired synaptic plasticity and cognitive function in senescence accelerated-resistant 1 (SAMR1) mice. MeCP2-mediated regulation of synaptic plasticity may be associated with CREB1 pathway. These results suggest that MeCP2 plays a vital role in age-related cognitive decline by regulating synaptic plasticity and indicate that MeCP2 may be promising targets for the treatment of age-related cognitive decline in neurodegenerative diseases.

Cx43 deficiency confers EMT-mediated tamoxifen resistance to breast cancer via c-Src/PI3K/Akt pathway.

Tamoxifen (TAM) resistance has indicated a significant challenge during endocrine therapy for hormone-sensitive breast cancer. Thus, it is significant to elucidate the molecular events endowing TAM resistance to endocrine therapy. In this study, we found that epithelial-mesenchymal transition (EMT) was an important event to confer TAM resistance, and attenuating EMT by elevating connexin (Cx) 43 expression could reverse TAM resistance. Specifically, Cx43 overexpression improved TAM sensitivity, while Cx43 depletion facilitated TAM insensitivity by modulating EMT in T47D TAM-resistant and -sensitive cells, and transplanted xenografts. Importantly, we found a novel reciprocal regulation between Cx43 and c-Src/PI3K/Akt pathway contributing to EMT and TAM resistance in breast cancer. Moreover, we identified that Cx43 deficiency was significantly correlated with poor relapse-free survival in patients undergoing TAM treatment. Therefore, Cx43 represents a prognostic marker and an attractive target for breast cancer treatments. Therapeutic strategies designed to increase or maintain Cx43 function may be beneficial to overcome TAM resistance.

Functional roles of circular RNAs in Alzheimer's disease.

Although efforts have been made to develop therapeutic approaches, the clinical management of AD maintains a major challenge. CircRNAs are highly abundant and evolutionarily conserved in neuronal tissues in mammals. Accumulating data suggest that circRNAs regulate biological and pathological processes by sponging miRNAs, binding to RBPs, modulating mRNA stability, and being translated into peptides in various diseases, serving as biomarkers and potential therapeutic targets. Growing evidence demonstrates that circRNAs have been implicated in the pathogenesis of AD. Here, we summarized current studies on circRNAs involved in AD pathology, providing a theoretical basis for the use of circRNAs in AD treatment and diagnosis.

Identification of Potential Therapeutic Targets of Alzheimer's Disease By Weighted Gene Co-Expression Network Analysis.

Objective Alzheimer's disease (AD) is the most common cause of dementia. The pathophysiology of the disease mostly remains unearthed, thereby challenging drug development for AD. This study aims to screen high throughput gene expression data using weighted co-expression network analysis (WGCNA) to explore the potential therapeutic targets.Methods The dataset of GSE36980 was obtained from the Gene Expression Omnibus (GEO) database. Normalization, quality control, filtration, and soft-threshold calculation were carried out before clustering the co-expressed genes into different modules. Furthermore, the correlation coefficients between the modules and clinical traits were computed to identify the key modules. Gene ontology and pathway enrichment analyses were performed on the key module genes. The STRING database was used to construct the protein-protein interaction (PPI) networks, which were further analyzed by Cytoscape app (MCODE). Finally, validation of hub genes was conducted by external GEO datasets of GSE 1297 and GSE 28146.Results Co-expressed genes were clustered into 27 modules, among which 6 modules were identified as the key module relating to AD occurrence. These key modules are primarily involved in chemical synaptic transmission (GO:0007268), the tricarboxylic acid (TCA) cycle and respiratory electron transport (R-HSA-1428517). WDR47, OXCT1, C3orf14, ATP6V1A, SLC25A14, NAPB were found as the hub genes and their expression were validated by external datasets.Conclusions Through modules co-expression network analyses and PPI network analyses, we identified the hub genes of AD, including WDR47, OXCT1, C3orf14, ATP6V1A, SLC25A14 and NAPB. Among them, three hub genes (ATP6V1A, SLC25A14, OXCT1) might contribute to AD pathogenesis through pathway of TCA cycle.

Probucol, a "non-statin" cholesterol-lowering drug, ameliorates D-galactose induced cognitive deficits by alleviating oxidative stress via Keap1/Nrf2 signaling pathway in mice.

Oxidative stress plays a vital role in the initiation and progression of age-related neurodegenerative diseases. Ameliorating oxidative damage is therefore considered as a beneficial strategy for the treatment of age-related neurodegenerative disorders. Probucol (Prob), a lipid-lowering prototype agent, was reported to treat cardiovascular diseases, chronic kidney disease and diabetes mellitus. However, whether Prob has an effect on age-related neurodegenerative diseases remains unknown. In the study, it was found that Prob ameliorated D-galactose (D-gal) induced cognitive deficits and neuronal loss in the hippocampal CA1 region. Moreover, Prob alleviated ROS and MDA levels by elevating SOD, GSH-PX and HO-1 mRNA and protein expressions, and improving plasmic and cerebral SOD and GSH-PX activities in D-gal treated mice. Furthermore, Prob promoted the dissociation of Keap1/Nrf2 complex leading to the accumulation of Nrf2 in nucleus, implying that the improved anti-oxidant property of Prob is mediated by Keap1/Nrf2 pathway. The study firstly demonstrates the favorable effects of Prob against cognitive impairments in a senescent mouse model, rendering this compound a promising agent for the treatment or prevention of age-related neurodegenerative disease.

A Novel Role of Connexin 40-Formed Channels in the Enhanced Efficacy of Photodynamic Therapy.

Despite responses to initial treatment of photodynamic therapy (PDT) being promising, a recurrence rate exists. Thus, finding novel therapeutic targets to enhance PDT efficacy is an urgent need. Reports indicate that connexin (Cx) 40 plays an important role in tumor angiogenesis and growth. However, it is unknown whether Cx40-composed channels have effects on PDT efficacy. The study uniquely demonstrated that Cx40-formed channels could enhance the phototoxicity of PDT to malignant cells in vitro and in vivo. Specifically, Cx40-formed channels at high cell density could increase PDT photocytotoxicity. This action was substantially restricted when Cx40 expression was not induced or Cx40 channels were restrained. Additionally, the presence of Cx40-composed channels enhanced the phototoxicity of PDT in the tumor xenografts. The above results indicate that enhancing the function of Cx40-formed channels increases PDT efficacy. The enhancement of PDT efficacy mediated by Cx40 channels was related with intracellular pathways mediated by ROS and calcium pathways, but not the lipid peroxide-mediated pathway. This work demonstrates the capacity of Cx40-mediated channels to increase PDT efficacy and suggests that therapeutic strategies designed to maintain or enhance Cx40 expression and/or channels composed by Cx40 may increase the therapeutic efficacy of PDT.

A novel role of Cx43-composed GJIC in PDT phototoxicity: an implication of Cx43 for the enhancement of PDT efficacy.

In spite of initially promising responses, 5-year recurrence after photodynamic therapy (PDT) sustains high level and an increase in PDT effectiveness is needed. It has been demonstrated that gap junctional intercellular communication (GJIC) formed by Connexin (Cx)43 could improve the transfer of "death signal" between cells, thereby causing the enhancement of cytotoxicity of chemotherapeutics and suicide gene therapy. Nevertheless, whether Cx43-composed GJIC has an effect on PDT phototoxicity remains unknown. This study showed that Cx43-formed GJIC could improve PDT phototoxicity to tumor cells in vitro and in vivo. Specifically, Cx43-formed GJIC under the condition of high cellular density could improve PDT phototoxicity in Cx43-transfected HeLa cells and Cx43-expressing U87 glioma cells. This effect was remarkably inhibited when Cx43 was not expressed or Cx43-formed GJ channels were prohibited. Additionally, the presence of Cx43-mediated GJIC could decrease the mean RTV and tumor weights of xenografts after Photofrin-PDT. The improved PDT efficacy by Cx43-composed GJIC was correlated with stress signaling pathways mediated by ROS, calcium and lipid peroxide. The present study demonstrates the presence of Cx43-composed GJIC improves PDT phototoxicity and suggests that therapeutic strategies designed to upregulate the expression of Cx43 or enhance Cx43-mediated GJIC function may increase the sensitivity of malignant cell to PDT, leading to the increment of PDT efficacy. Oppositely, factors that retard Cx43 expression or prohibit the function of Cx43-mediated GJIC may cause insensitivity of malignant cells to PDT, leading to PDT resistance.

Decreased phototoxicity of photodynamic therapy by Cx32/Cx26-composed GJIC: A "Good Samaritan" effect.

BACKGROUND AND OBJECTIVE: Photodynamic therapy (PDT) has been widely used to treat malignant tumors. Our previous studies indicated that connexin (Cx) 32- and Cx26-composed gap junctional intercellular communication (GJIC) could improve the phototoxicity of PDT. However, the role of heterotypic Cx32/Cx26-formed GJIC in PDT phototoxicity is still unknown. Thus, the present study was aimed to investigate the effect of Cx32/Cx26-formed GJIC on PDT efficacy. METHODS: CCK8 assay was used to detect cell survival after PDT. Western blot assay was utilized to detect Cx32/Cx26 expression. "Parachute" dye-coupling assay was performed to measure the function of GJ channels. The intracellular Ca2+ concentrations were determined using flow cytometer. ELISA assay was performed to detect the intracellular levels of PGE2 and cAMP. RESULTS: The present study demonstrates there is a Cx32/Cx26-formed GJIC-dependent reduction of phototoxicity when cells were exposure to low concentration of Photofrin. Such a protective action is missing at low cell density due to the lack of GJ coupling. Under high-cell density condition, where there is opportunity for the cells to contact each other and form GJ, suppressing Cx32/Cx26-formed GJIC by either inhibiting the expression of Cx32/Cx26 or pretreating with GJ channel inhibitor augments PDT phototoxicity after cells were treated with at 2.5 µg/ml Photofrin. The above results suggest that at low Photofrin concentration, the presence of Cx32/Cx26-formed GJIC may decrease the phototoxicity of PDT, leading to the insensitivity of malignant cells to PDT treatment. The GJIC-mediated PDT insensitivity was associated with Ca2+ and prostaglandin E2 (PGE2 ) signaling pathways. CONCLUSION: The present study provides a cautionary note that for tumors expressing Cx32/Cx26, the presence of Cx32/Cx26-composed GJIC may cause the resistance of tumor cells to PDT. Oppositely, treatment strategies designed to downregulate the expression of Cx32/Cx26 or restrain the function of Cx32/Cx26-mediated GJIC may increase the sensitivity of malignant cell to PDT. Lasers Surg. Med. 51:301-308, 2019. © 2019 Wiley Periodicals, Inc.

Identification of Differentially Expressed Profiles of Alzheimer's Disease Associated Circular RNAs in a Panax Notoginseng Saponins-Treated Alzheimer's Disease Mouse Model.

Circular RNAs (circRNAs) play vital roles in AD pathogenesis. Thus, developing therapeutic candidates targeting circRNA may provide a novel therapeutic strategy for AD treatment. Our previous studies showed that Panax notoginseng saponins (PNS) could significantly prohibit the pathological progress of AD. However, the mechanisms by which PNS attenuates AD progression is still unclear. The present study shows that PNS may exhibit an ability to modulate the expression of AD-associated circRNAs. Specifically, PNS treatment leads to five circRNAs upregulation and two circRNAs downregulation, indicating that the therapeutic effect of PNS against AD may be associated with its role in the regulation of circRNA expression. Next, mmu_circRNA_013636 and mmu_circRNA_012180 were selected and GO and KEGG analyses were performed to further investigate the biological functions and potential mechanisms of these circRNAs. The results showed that the selected circRNAs were involved in AD-associated biological process and pathways, suggesting that these circRNAs may participate in AD pathogenesis. Collectively, our study indicates that the therapeutic effects of PNS on AD may be through modulating the expression of AD associated circRNAs and suggests that PNS is a potential circRNA-targeted agent against AD, which may provide useful resources for developing potential candidates targeting circRNAs against AD.

Comprehensive analysis of differentially expressed profiles of Alzheimer's disease associated circular RNAs in an Alzheimer's disease mouse model.

Circular RNAs (circRNAs), a novel kind of non-coding RNA, have received increasing attention for their involvement in pathogenesis of Alzheimer's disease (AD); however, few studies have reported in the characterization and function of AD associated circRNAs. Here the expression profiles of circRNAs in 5- and 10-month-old SAMP8 mice were identified using circRNA microarray and found that 85 dysregulated circRNAs were observed in 10-month-old SAMP8 versus control mice and 231 circRNAs exhibited differential expression in 10-month-old SAMP8 versus 5-month-old SAMP8. One most significantly dysregulated circRNA, mmu_circRNA_017963, was select for Gene Oncology (GO) and pathway analysis. The results showed that mmu_circRNA_017963 was strongly related with autophagosome assembly, exocytosis, apoptotic process, transport and RNA splicing and highly associated with synaptic vesicle cycle, spliceosome, glycosaminoglycan and SNARE interactions in vesicular transport pathways. Collectively, this study was the first to describe circRNAs expression in different ages of SAMP8 and will contribute to the understanding of the regulatory roles of circRNAs in AD pathogenesis and provide a valuable resource for the diagnosis and therapy of AD.

Fraction n-Butanol of Radix Notoginseng Protects PC12 Cells from Aß25-35-Induced Cytotoxicity and Alleviates Cognitive Deficits in SAMP8 Mice by Attenuating Oxidative Stress and Aß Accumulation.

Chinese medicine has been used for Alzheimer's disease (AD) treatment for thousands of years with more effective and fewer side effects. Therefore, developing effective potential candidates from Chinese medicine against AD would be considered as critical and efficient therapy for AD treatment. This study was designed to evaluate the neuronal protective effect of fraction n-butanol (NB) of Radix Notoginseng on Aß25-35-induced PC12 cells, explore the effect of the tested fraction on spatial learning and memory, and characterize the impacts of fraction NB on antioxidant enzymes, Aß production, and APP and BACE1 expressions. The results revealed that fraction NB could promote proliferation of PC12 cells and protect and rescue PC12 cells from Aß25-35-induced cell death. Moreover, fraction NB could improve spatial learning and memory impairments of senescence-accelerated prone8 (SAMP8) mice and attenuate oxidative stress and reduce the production of Aß by inhibiting the expressions of APP and BACE1 in the brains of SAMP8 mice. The result of single dose acute toxicity assay showed that fraction NB had a mild toxicity in vivo. The pronounced actions against AD and in vivo low toxicity of fraction NB suggest that fraction NB may be a useful alternative to the current AD treatment.

[Preliminary establishment of integration of Alzheimer's disease and blood stasis syndrome tree shrew model and evaluation of intervention of Panax notoginseng saponins].

To establish the integration of Alzheimer's disease(AD) and blood stasis syndrome tree shrew model. Panax notoginseng saponins (PNS) was used to intervene the model to testify the stability of the model. The level of blood stasis of each group in the tree shrew model was evaluated by analyzing five traditional Chinese medicine(TCM) characterizations, four blood coagulation indexes, plasma nitric oxide (NO) level, plasma superoxide dismutase (SOD) level in each group. Hematoxylin and eosin(HE) staining was used to observe the morphological changes of brain hippocampal neuron cell of each group. Immunohistochemical staining was used to assay the ChAT and SYP levels in brain hippocampus of each group.The blood stasis characterization of the integration of disease and syndrome group was more obvious than the AD group, and that of the drug administration group was lower than that of the integration of disease and syndrome group. Aß1-42, APP, P-Tau, ChAT and SYP level of AD group were lower than those in the blank group, which were further reduced in the model of integration of disease and syndrome. However, the administration of PNS relieved the reduction, indicating that the AD and blood stasis integration syndrome tree shrew model is stable.

Enhanced phototoxicity of photodynamic treatment by Cx26-composed GJIC via ROS-, calcium- and lipid peroxide-mediated pathways.

In spite of the promising initial treatment responses presented by photodynamic therapy (PDT), 5-year recurrence rates remain high level. Therefore, improvement in the efficacy of PDT is needed. There are reports showing that connexin(Cx) 26-composed gap junctional intercellular communication (GJIC) enhances the intercellular propagation of "death signal", thereby increasing chemotherapeutic cytotoxicity. However, it is unclear whether Cx26-formed GJIC has an effect on PDT phototoxicity. The results in the present study showed that Cx26-composed GJ formation at high density enhances the phototoxicity of Photofrin-PDT. When the Cx26 is not expressed or Cx26 channels are blocked, the phototoxicity in high-density cultures substantially reduces, indicating that the enhanced PDT phototoxicity at high density is mediated by Cx26-composed GJIC. The GJIC-mediated increase in PDT phototoxicity was associated with ROS, calcium and lipid peroxide-mediated stress signaling pathways. The work presents the ability of Cx26-composed GJIC to enhance the sensitivity of malignant cells to PDT, and indicates that maintenance or increase of Cx26-formed GJIC may be a profitable strategy towards the enhancement of PDT therapeutic efficiency. Picture: The survival response of Photofrin-PDT in Dox-treated (Cx26 expressing, GJ-formed) and Dox-untreated cells (Cx26 non-expressing, GJ-unformed) at high-cell density condition.

Cestrum nocturnum Flower Extracts Attenuate Proliferation and Induce Apoptosis in Malignant Cells through Inducing DNA Damage and Inhibiting Topoisomerase II Activity.

Most of the existing chemotherapeutic drugs have plenty of side effects. Chinese herbal medicine has been used for pharmaceutical and dietary therapy for thousands of years with more effective and fewer side effects. Cestrum nocturnum (CN) has long been used to treat digestive diseases for centuries in China. Our previous study first proved that the n-butanol part isolated from the flowers of CN produced an inhibitory effect on the proliferation of malignant cells. However, the fractions responsible for the antiproliferation effect of n-butanol part from CN flowers and related mechanisms remain unknown. Thus, in this study, we extracted fractions C4 and C5 from n-butanol part of CN flowers and investigated their immune toxicity and antitumor activities. It was found that fractions C4 and C5 exhibited great cytotoxicity to cancer cell lines but had low immune toxicity towards T and B lymphocytes in vitro. The tested fractions also attenuated proliferation and induced apoptosis at G0/G1 and G2/M phases in Bel-7404 cells through inducing DNA damage and inhibiting topoisomerase II relaxation activity. These results suggest that fractions C4 and C5 may represent important sources of potential antitumor agents due to their pronounced antitumor effects and low immune toxicity.

Neuroprotective Properties of Panax notoginseng Saponins via Preventing Oxidative Stress Injury in SAMP8 Mice.

Inhibiting oxidative damage in early stage of Alzheimer's disease (AD) is considered as a strategy for AD treatment. Our previous study has shown that Panax notoginseng saponins (PNS) have an antiaging action by increasing the levels of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-PX) in the serum of aged rats. In this study, we aimed to investigate the effects of PNS on antioxidant enzymes and uncoupling proteins (UCPs) involved in oxidative stress in AD mice. The results showed that PNS prevented neuronal loss in hippocampal CA1 region and alleviated pathomorphological change of neurons in CA1 region. Moreover, PNS inhibited the production of 8-hydroxydeoxyguanosine (8-OHdG), enhanced the expressions and activities of SOD, CAT, and GSH-PX, and improved the mRNA and protein levels of UCP4 and UCP5 in the brains of SAMP8 mice. Together, our study shows that PNS has the ability to protect neurons in AD brain from oxidative stress damage through attenuating the production of 8-OHdG, enhancing the activities of antioxidant enzymes and the expressions levels of UCP4 and UCP5. Accordingly, PNS may be a promising agent for AD treatment.