Notes

The autopsy case study of lymphocytic hypophysitis brought on by simply nivolumab strategy to esophageal malignant cancer.
TXL reversed the high expression of class I histone deacetylases (HDACs) induced by ox-LDL (p less then 0.05). Compared with the TXL + ox-LDL group, TXL failed to promote intracellular lipid droplet decomposition after the addition of the histone deacetylase agonist. We found that TXL attenuates the accumulation of lipids in macrophage by enhancing Beclin-1-induced autophagy, and additionally, it inhibits the inhibitory effect of class I HDAC on the expression of Beclin-1.The uncontrolled proliferation and migration of vascular smooth muscle cells is a critical step in the pathological process of restenosis caused by vascular intimal hyperplasia. Jujuboside B (JB) is one of the main biologically active ingredients extracted from the seeds of Zizyphus jujuba (SZJ), which has the properties of anti-platelet aggregation and reducing vascular tension. However, its effects on restenosis after vascular intervention caused by VSMCs proliferation and migration remain still unknown. Herein, we present novel data showing that JB treatment could significantly reduce the neointimal hyperplasia of balloon-damaged blood vessels in Sprague-Dawley (SD) rats. In cultured VSMCs, JB pretreatment significantly reduced cell dedifferentiation, proliferation, and migration induced by platelet-derived growth factor-BB (PDGF-BB). JB attenuated autophagy and reactive oxygen species (ROS) production stimulated by PDGF-BB. Besides, JB promoted the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and the expression of peroxisome proliferator-activated receptor-γ (PPAR-γ). Notably, inhibition of AMPK and PPAR-γ partially reversed the ability of JB to resist the proliferation and migration of VSMCs. Taken as a whole, our findings reveal for the first time the anti-restenosis properties of JB in vivo and in vitro after the endovascular intervention. JB antagonizes PDGF-BB-induced phenotypic switch, proliferation, and migration of vascular smooth muscle cells partly through AMPK/PPAR-γ pathway. These results indicate that JB might be a promising clinical candidate drug against in-stent restenosis, which provides a reference for further research on the prevention and treatment of vascular-related diseases.Systems biology unravels the black box of signaling pathway of cells; but which has not been extensively applied to reveal the mechanistic synergy of a herbal formula. The therapeutic efficacies of a herbal formula having multi-target, multi-function and multi-pathway are the niches of traditional Chinese medicine (TCM). Here, we reported an integrated omics approach, coupled with the knockout of an active compound, to measure the regulation of cellular signaling, as to reveal the landscape in cultured rat osteoblasts having synergistic pharmacological efficacy of Danggui Buxue Tang (DBT), a Chinese herbal formula containing Angelicae Sinensis Radix and Astragali Radix. The changes in signaling pathways responsible for energy metabolism, RNA metabolism and protein metabolism showed distinct features between DBT and calycosin-depleted DBT. Here, our results show that calycosin within DBT can orchestrate the osteoblastic functions and signaling pathways of the entire herbal formula. This finding reveals the harmony of herbal medicine in pharmacological functions, as well as the design of drug/herbal medicine formulation. The integration of systems biology can provide novel and essential insights into the synergistic property of a herbal formula, which is a key in modernizing TCM.Introduction Mirabegron is available for treatment of storage symptoms in overactive bladder, which may be improved by β3-adrenoceptor-induced bladder smooth muscle relaxation. In addition to storage symptoms, lower urinary tract symptoms in men include obstructive symptoms attributed to benign prostatic hyperplasia, caused by increased prostate smooth muscle tone and prostate enlargement. In contrast to the bladder and storage symptoms, effects of mirabegron on prostate smooth muscle contraction and obstructive symptoms are poorly understood. Evidence from non-human smooth muscle suggested antagonism of α1-adrenoceptors as an important off-target effect of mirabegron. As α1-adrenergic contraction is crucial in pathophysiology and medical treatment of obstructive symptoms, we here examined effects of mirabegron on contractions of human prostate tissues and on proliferation of prostate stromal cells. Methods Contractions were induced in an organ bath. Effects of mirabegron on proliferation, viability, and cAMPs of 8% in proliferation assays and 17% in viability assays. Mirabegron did not induce detectable increases of cAMP levels in cultured stromal cells. Conclusion Mirabegron inhibits neurogenic and α1-adrenergic human prostate smooth muscle contractions. This inhibition may be based on antagonism of α1-adrenoceptors by mirabegron, and does not include activation of β3-adrenoceptors and requires concentrations ranging 50-100fold higher than plasma concentrations reported from normal dosing. Non-adrenergic contractions and proliferation of prostate stromal cells are not inhibited by mirabegron.Chimeric antigen receptor T cells (CAR-T) therapy is a prospective therapeutic strategy for blood cancers tumor, especially leukemia, but it is not effective for solid tumors. Glioblastoma (GBM) is a highly immunosuppressive and deadly malignant tumor with poor responses to immunotherapies. Although CAR-T therapeutic strategies were used for glioma in preclinical trials, the current proliferation activity of CAR-T is not sufficient, and malignant glioma usually recruit immunosuppressive cells to form a tumor microenvironment that hinders CAR-T infiltration, depletes CAR-T, and impairs their efficacy. Moreover, specific environments such as hypoxia and nutritional deficiency can hinder the killing effect of CAR-T, limiting their therapeutic effect. The normal brain lack lymphocytes, but CAR-T usually can recognize specific antigens and regulate the tumor immune microenvironment to increase and decrease pro- and anti-inflammatory factors, respectively. This increases the number of T cells and ultimately enhances anti-tumor effects. CAR-T therapy has become an indispensable modality for glioma due to the specific tumor-associated antigens (TAAs). This review describes the characteristics of CAR-T specific antigen recognition and changing tumor immune microenvironment, as well as ongoing research into CAR-T therapy targeting TAAs in GBM and their potential clinical application.Bazi Bushen capsule (BZBS), as a Chinese medicine used to relieve fatigue, has been proven effective for the treatment of atherogenesis through antilipid effects. To investigate the potential mechanism of BZBS in the anti-atherosclerotic effect, Ovx/ApoE-/- mice were applied to investigate the anti-atherosclerotic efficiency and potential mechanism of BZBS. Therapeutic effect was evaluated based on the number of CD68+ and CD3+ cells, the level of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), and the ratio of cleaved caspase-3/caspase-3, as well as increasing ratio of Bcl2/Bax. Human umbilical vein endothelial cells (HUVECs) were chosen to evaluate the role of GPER1. Treatment with BZBS reduced lipid deposition by reducing the numbers of CD68+ and CD3+ cells, the level of ICAM-1 and VCAM-1, and the ratio of cleaved caspase-3/caspase-3, and increasing the ratio of Bcl2/Bax as compared with the control group. In si-GPER1-treated HUVECs, the anti-apoptotic effect of BZBS was decreased. This study revealed that BZBS exhibited a clear effect against atherogenesis via GPER1-dependent anti-inflammatory and anti-apoptotic mechanisms. We believe that this manuscript is informative and useful for researchers pursuing the related alleviation of post-menopausal AS via anti-inflammatory and anti-apoptotic mechanisms.The effect of cream and gel vehicles containing clove water on skin permeability was compared for a new eugenol derivative (eugenyl dichloroacetate-EDChA) with antioxidant activity. In vitro permeation experiments were conducted in a Franz cell with porcine skin. The cumulative mass and skin accumulation of EDChA were investigated and compared. The antioxidative capacity of the studied vehicles was determined by using the diphenylpicrylhydrazyl (DPPH) free radical reduction method. The antioxidant activity (evaluated with DPPH, ABTS, and the Folin-Ciocalteu methods) of the fluid that penetrated through the pig skin and of the fluid obtained after the skin extraction, were also determined. For comparison, eugenol was also tested. The results of this work could contribute to the development of vehicles with antioxidant potential estimated after 24 h of conducting the experiment, which indicates long-term protection against reactive oxygen species (ROS) in the deeper layers of the skin. The waste water from the clove buds steam distillation -contains several valuable biologically active compounds, and its use is environmentally friendly. We observed that gel vehicles were the best enhancer of skin permeation for both eugenol and its derivative. In most cases, -similar cumulative masses of eugenol and its ester were found in the acceptor fluid. The accumulation of EDChA was higher for cream vehicles in relation to the parent eugenol when applied onto the skin. The greatest amounts of eugenol were accumulated in the skin when these compounds were used in gel vehicles.Coronavirus disease 2019 (COVID-19) spread to Japan in 2020, where the number of infected patients exceeded 250,000 and COVID-related deaths exceeded 3,500 in one year. Basic guidelines for infection control were implemented in Japan, and research and development of effective drugs and vaccines were promoted. This included considering Kampo medicine, which has a long history of treating recurring emerging viral infections. Considering the characteristics of the disease (inflammation of the upper and lower respiratory tract as well as potential neural damage and vasculitis), Kampo medicine could be considered as a treatment strategy due to its antiviral and anti-inflammatory effects induced by multiple active substances that could aid in disease prevention and recovery. In this study, case reports on the management of COVID-19 with Kampo medicine, which were published until March 31, 2021, were reviewed. The search strategy involved the use of Medline and hand-searching. Twenty two patients were treated using Kampo medicines with or without Western medicine, based on individual conditions. On the other hand, the effects of Kampo medicines as a potential preventive treatment (pre-infection), active treatment (especially in the acute and subacute stage), or treatment of sequelae to aid recovery (after infection) in the different stages of COVID-19 are being studied as research projects in the Japan Society for Oriental Medicine (JSOM). JSOM has also organized a pioneering project of clinical trials for COVID-19, some of which are now in progress.Background Hand-foot-and-mouth disease (HFMD) is a common childhood illness caused by enteroviruses. Oseltamivir (OS), a neuraminidase inhibitor, has been frequently used as an adjunctive therapy for the treatment of HFMD. Solid evidence, however, is lacking regarding the efficacy of such adjunctive therapy. This work is to conduct a meta-analysis of randomized clinical trials (RCTs) to assess the efficacy of oseltamivir for HFMD in children. Methods Eligible studies from inception to October 10, 2020 were identified by searching six databases (PubMed, Embase, CENTRAL, CNKI, Wanfang, and VIP database). Quality of evidence was assessed using the Cochrane Collaboration tool. Results Of a total of 91 entries, 11 RCTs involving 977 HFMD children were included in the final analysis. The results showed that the therapy combined with oseltamivir was more effective, with higher effective rate (RR, 0.84; 95% CI, 0.80 to 0.87; p less then 0.01), shorter fever clearance time (days) (SMD, -0.74; 95% CI, -1.12 to -0.35; p less then 0.01), shorter rash regression time (days) (MD, -0.89; 95% CI, -1.05 to -0.72; p less then 0.01) and shorter clinical cure time (SMD, -1.08; 95% CI, -1.55 to -0.61; p less then 0.01). No significant difference was observed in the risk of adverse reactions between the groups with and without oseltamivir. Conclusion The use of oseltamivir as adjunctive therapy shows effectiveness and no increased risk of adverse reactions for the treatment of HFMD in children.Grona styracifolia (Osbeck) Merr. (GS), a popular folk medicine, is clinically applied to treat nephrolithiasis. In this study, a urinary metabolic analysis was performed in a mouse model of renal calcium oxalate (CaOx) crystal deposition to identify the differentially altered metabolites in mice with oxalate-induced renal injury and explore the therapeutic mechanisms of GS against nephrolithiasis. Twenty-four mice were randomly divided into the control, oxalate and GS-treated groups. A metabolomics approach based on ultra-high-performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry (UHPLC-Q-TOF/MS) was used to analyze the metabolic profiles of the urine samples. In addition, network pharmacology analysis was performed with different databases. As a result, the protective effects of GS were verified by measuring biochemical parameters and detecting crystal deposition. Fifteen metabolites were identified as the differentially altered metabolites in mice with crystal-induced renal injury. Most were involved in amino acid and fatty acid metabolism. Thirteen of these metabolites showed a reversal trend following GS treatment. A component-target-metabolite network was further constructed and nine overlapping target proteins of GS and the differentially altered metabolites were discovered. Among these proteins, the expression of estrogen receptor 2 (ESR2) in renal tissues was significantly down-regulated while androgen receptor (AR) expression was obviously increased in the oxalate group compared with the control group. These changes were reversed by the GS treatment. In conclusion, GS exerts its therapeutic effect by regulating multiple metabolic pathways and the expression of ESR and AR in mice with oxalate-induced renal injury.Background Most guidelines advise that women taking lithium should not breastfeed. The variation in transfer is just one reason behind this advice. Objectives To present clinical and pharmacokinetic data of nine mother-infant pairs exposed to lithium monotherapy during late pregnancy and exclusive breastfeeding at the Perinatal Psychiatric Unit (2006-2018). Methods We obtained sociodemographic data, medical risk factors, obstetric variables, and family and personal psychiatric history by semi-structured interview, and assessed maternal psychopathology with the Hamilton Depression Rating Scale and Young Mania Rating Scale. A senior neonatologist reviewed neonatal outcomes at birth using the Peripartum Events Scale. Paired maternal and cord blood and infant venous blood samples were collected. During the breastfeeding period, we monitored serum lithium and creatinine concentrations in mother-infant pairs at delivery, and at days 1-5, 7-11, 30, and 60 postpartum, and monthly until 6-months. Results Lithium equilibrated completely across the placenta [1.13 (0.10), range (1.02-1.30)]. No women presented symptoms of postpartum lithium intoxication, two of the neonates presented transient hypotonia (22%). Lithium exposure was significantly less during breastfeeding than during late pregnancy, and serum lithium concentrations decreased up to 44% overtime from delivery to the first-month, and up to 60% to the third-month postpartum. There was no growth or developmental delay in the follow-up period. One woman had a manic episode with psychotic features at 45 days postpartum. Conclusions In carefully selected women with bipolar disorder, lithium therapy when breastfeeding can be an appropriate option if coupled with close monitoring of the mother-infant pair.Objective The aim of the study was to observe the clinical efficacy and safety of intravenous and oral sequential treatment with voriconazole for Candida central nervous system (CNS) infection in premature infants. Methods The study included retrospective analysis of the clinical data of six premature infants with Candida CNS infection admitted to the neonatology department in Shanghai Children's Hospital between November 2016 and November 2019. By reviewing the characteristics of voriconazole based on the literature, it showed that infants without gastrointestinal dysfunction could be effectively treated by intravenous and oral sequential therapy with voriconazole (both 7 mg/kg/dose, every 12 h). Clinical manifestations, the time required for the cerebrospinal fluid (CSF), blood culture, nonspecific infection markers such as platelets and C-reactive protein (CRP) to turn normal, and drug-related side effects were observed and recorded in the process of treatment. All data were statistically analyzed by T tesre found. The white blood cells, CSF glucose/plasma glucose ratio, and protein in CSF were significantly improved after the treatment (p 0.05). Conclusion Voriconazole is a relatively safe and effective alternative treatment for Candida CNS infection in preterm infants. No severe drug-related side effects were detected.Introduction Biosimilar medicines are considered promising alternatives to new biologicals with high price tags. The extent of savings resulting from biosimilar use depends on their price and uptake, which are largely shaped by pricing, reimbursement, and demand-side policies. This article informs about different policy measures employed by European countries to design the biologicals market and explores potential savings from the increased use of biosimilar medicines in Germany. Methods Policy measures that target the price and uptake of biosimilar medicines were identified based on a prefilled questionnaire survey with public authorities in 16 European countries, who were the members of the Pharmaceutical Pricing and Reimbursement Information network (July 2020). Potential savings that could have been generated in Germany if different measures identified in the surveyed countries had been implemented were calculated for six publicly funded biological molecules. Price data of the Pharma Price Information sergeting the price and uptake of biosimilar medicines. The potential for savings of some of these policies was clearly demonstrated. Monitoring and evaluation of these rather recent measures is key for obtaining a more comprehensive picture of their impact.Background Chronic kidney disease (CKD) is a leading cause of morbidity and mortality. Mitochondrial dysfunction has been implicated as a key factor in the development of CKD. According to traditional Chinese medicine (TCM) theory, many Chinese Yang/Qi-invigorating botanical drugs/herbal formulations have been shown to produce promising outcomes in the clinical management of CKD. Experimental studies have indicated that the health-promoting action of Yang/Qi invigoration in TCM is related to the up-regulation of mitochondrial energy generation and antioxidant status. Objective In this review, we aim to test whether Chinese Yang/Qi-invigorating tonic botanical drugs/herbal formulations can provide medical benefits in CKD and its complications. And we also explore the possible involvement of mitochondrial-associated signaling pathway underlying the beneficial effects of Yang/Qi invigoration in TCM. Methods A systematic search of "PubMed", "China National Knowledge Infrastructure (CNKI)" and "Google Scholar" wasng renal functional integrity, the enhancement of mitochondrial energy metabolism and antioxidant status in kidney tissue is likely involved in renal protection. Future studies on the biochemical and chemical basis underlying the effects of Chinese Yang/Qi-invigorating tonic botanical drugs/herbal formulations from a mitochondrial perspective will hopefully provide novel insights into the rational development of new drugs for the prevention and/or treatment of CKD.The therapeutic indices (TIs) and efficacy of the non-steroidal mineralocorticoid receptor antagonist (MRA) KBP-5074 and steroidal MRA eplerenone were evaluated in a uninephrectomized Sprague Dawley rat model of aldosterone-mediated renal disease. In two parallel studies, rats were placed on a high-salt diet and received aldosterone by osmotic mini-pump infusion over the course of 27 days. The urinary albumin-to-creatinine ratio (UACR) was evaluated after 7, 14, and 26 days of treatment. Serum K+ was evaluated after 14 and 27 days of treatment. Urinary Na+, urinary K+, and urinary Na+/K+ ratio were evaluated after 7, 14, and 26 days of treatment. The TI was calculated for each drug as the ratio of the concentration of drug producing 50% of maximum effect (EC50) for increasing serum K+ to the EC50 for lowering UACR. The TIs were 24.5 for KBP-5074 and 0.620 for eplerenone, resulting in a 39-fold improved TI for KBP-5074 compared with eplerenone. Aldosterone treatment increased UACR, decreased serum K+, and decreased urinary Na+ relative to sham-operated controls that did not receive aldosterone infusion in both studies, validating the aldosterone/salt renal injury model. KBP-5074 prevented the increase in UACR at 0.5, 1.5, and 5 mg/kg BID while eplerenone did so only at the two highest doses of 50 and 450 mg/kg BID. Both KBP-5074 and eplerenone blunted the reduction in serum K+ seen in the aldosterone treatment group, with significant increases in serum K+ at the high doses only (5 mg/kg and 450 mg/kg BID, respectively). Additionally, the urinary Na+ and Na+/K+ ratio significantly increased at the middle and high doses of KBP-5074, but only at the highest dose of eplerenone. These results showed increased TI and efficacy for KBP-5074 compared with eplerenone over a wider therapeutic window.Background Clinical research found that Hedysarum Multijugum Maxim.-Chuanxiong Rhizoma Compound (HCC) has definite curative effect on cerebral ischemic diseases, such as ischemic stroke and cerebral ischemia-reperfusion injury (CIR). However, its mechanism for treating cerebral ischemia is still not fully explained. Methods The traditional Chinese medicine related database were utilized to obtain the components of HCC. The Pharmmapper were used to predict HCC's potential targets. The CIR genes were obtained from Genecards and OMIM and the protein-protein interaction (PPI) data of HCC's targets and IS genes were obtained from String database. After that, the DAVID platform was applied for Gene Ontology (GO) enrichment analysis and pathway enrichment analysis. Finally, a series of animal experiments were carried out to further explore the mechanism of HCC intervention in CIR. Results The prediction results of systematic pharmacology showed that HCC can regulate CIR-related targets (such as AKT1, MAPK1, CASP3, EGFR), biological processes (such as angiogenesis, neuronal axonal injury, blood coagulation, calcium homeostasis) and signaling pathways (such as HIF-1, VEGF, Ras, FoxO signaling). The experiments showed that HCC can improve the neurological deficit score, decrease the volume of cerebral infarction and up-regulate the expression of HIF-1α/VEGF and VEGFR protein and mRNA (p less then 0.05). Conclusion HCC may play a therapeutic role by regulating CIR-related targets, biological processes and signaling pathways found on this study.The correlation among olfactory dysfunction, spinal cord injury (SCI), subjective cognitive decline, and neurodegenerative dementia has been established. Impaired olfaction is considered a marker for neurodegeneration. Hence, there is a need to examine if SCI leads to olfactory dysfunction. In this study, the brain tissue of mice with spinal cord hemisection injury was subjected to microarray analysis. The mRNA expression levels of olfactory receptors in the brain began to decline at 8 h post-SCI. SCI promoted neuroinflammation, downregulated the expression of olfactory receptors, decreased the number of neural stem cells (NSCs), and inhibited the production of neurotrophic factors in the olfactory bulbs at 8 h post-SCI. In particular, the SCI group had upregulated mRNA and protein expression levels of glial fibrillary acidic protein (GFAP; a marker of astrocyte reactivation) and pro-inflammatory mediators [IL-1β, IL-6, and Nestin (marker of NSCs)] in the olfactory bulb compared to levels in the sham control group. The mRNA expression levels of olfactory receptors (Olfr1494, Olfr1324, Olfr1241, and Olfr979) and neurotrophic factors [brain-derived neurotrophic factor (BDNF), glial cell-derived neurotrophic factor (GDNF), and nerve growth factor (NGF)] were downregulated in the olfactory bulb of the SCI group mice at 8 h post-SCI. The administration of granulocyte colony-stimulating factor (G-CSF) mitigated these SCI-induced pathological changes in the olfactory bulb at 8 h post-SCI. These results indicate that the olfactory bulb is vulnerable to environmental damage even if the lesion is located at sites distant from the brain, such as the spinal cord. Additionally, SCI initiated pathological processes, including inflammatory response, and impaired neurogenesis, at an early stage. The findings of this study will provide a basis for future studies on pathological mechanisms of early neurodegenerative diseases involving the olfactory bulb and enable early clinical drug intervention.
Despite emerging evidence suggesting that visceral fat may play a major role in obesity-induced neurodegeneration, little evidence exists on the association between visceral fat and brain cortical thickness in the elderly.

We aimed to examine the association between abdominal fat and brain cortical thickness in a Korean elderly population.

This cross-sectional study included elderly individuals without dementia (
= 316). Areas of visceral fat and subcutaneous fat (cm
) were estimated from computed tomography scans. Regional cortical thicknesses (mm) were obtained by analyzing brain magnetic resonance images. Given the inverted U-shaped relationship between visceral fat area and global cortical thickness (examined using a generalized additive model), visceral fat area was categorized into quintiles, with the middle quintile being the reference group. A generalized linear model was built to explore brain regions associated with visceral fat. The same approach was used for subcutaneous fat.

The mean (standard deviation) age was 67.6 (5.0) years. The highest quintile (vs. the middle quintile) group of visceral fat area had reduced cortical thicknesses in the global [β = -0.04 mm, standard error (SE) = 0.02 mm,
= 0.004], parietal (β = -0.04 mm,
= 0.02 mm,
= 0.01), temporal (β = -0.05 mm,
= 0.02 mm,
= 0.002), cingulate (β = -0.06 mm,
= 0.02 mm,
= 0.01), and insula lobes (β = -0.06 mm,
= 0.03 mm,
= 0.02). None of the regional cortical thicknesses significantly differed between the highest and the middle quintile groups of subcutaneous fat area.

The findings suggest that a high level of visceral fat, but not subcutaneous fat, is associated with a reduced cortical thickness in the elderly.
The findings suggest that a high level of visceral fat, but not subcutaneous fat, is associated with a reduced cortical thickness in the elderly.Apathy predicts poor outcomes in older adults, and its underlying neural mechanism needs further investigation. We examined the association between symptoms of apathy and functional connectivity (FC) in older adults without stroke or dementia. Participants included 48 individuals (mean age = 70.90) living independently in the community, who underwent resting-state fMRI and completed the Apathy Evaluation Scale (AES). Seed-to-voxel analysis (cluster-level p-FDR less then 0.05, voxel threshold p less then 0.001) tested the association between AES scores and the whole-brain FC of brain regions involved in reward- and salience-related processing. We found that AES scores were negatively associated with FC of the right insula cortex and right anterior temporal regions (124 voxels, t = -5.10) and FC of the left orbitofrontal cortex and anterior cingulate regions (160 voxels, t = -5.45), and were positively associated with FC of the left orbitofrontal cortex and left lateral prefrontal (282 voxels, t = 4.99) and anterior prefrontal (123 voxels, t = 4.52) regions. These findings suggest that apathy in older adults may reflect disruptions in neural connectivity involved in reward- and salience-related processing.While the central nervous system compromises 2% of our body weight, it harbors up to 25% of the body's cholesterol. Cholesterol levels in the brain are tightly regulated for physiological brain function, but mounting evidence indicates that excessive cholesterol accumulates in Alzheimer's disease (AD), where it may drive AD-associated pathological changes. This seems especially relevant for late-onset AD, as several of the major genetic risk factors are functionally associated with cholesterol metabolism. In this review we discuss the different systems that maintain brain cholesterol metabolism in the healthy brain, and how dysregulation of these processes can lead, or contribute to, Alzheimer's disease. We will also discuss how AD-risk genes might impact cholesterol metabolism and downstream AD pathology. Finally, we will address the major outstanding questions in the field and how recent technical advances in CRISPR/Cas9-gene editing and induced pluripotent stem cell (iPSC)-technology can aid to study these problems.Lewy Body Disorders (LBDs) lie within the spectrum of age-related neurodegenerative diseases now frequently categorized as the synucleinopathies. LBDs are considered to be among the second most common form of neurodegenerative dementias after Alzheimer's disease. They are progressive conditions with variable clinical symptoms embodied within specific cognitive and behavioral disorders. There are currently no effective treatments for LBDs. LBDs are histopathologically characterized by the presence of abnormal neuronal inclusions commonly known as Lewy Bodies (LBs) and extracellular Lewy Neurites (LNs). The inclusions predominantly comprise aggregates of alpha-synuclein (aSyn). It has been proposed that post-translational modifications (PTMs) such as aSyn phosphorylation, ubiquitination SUMOylation, Nitration, o-GlcNacylation, and Truncation play important roles in the formation of toxic forms of the protein, which consequently facilitates the formation of these inclusions. This review focuses on the role of different PTMs in aSyn in the pathogenesis of LBDs. We highlight how these PTMs interact with aSyn to promote misfolding and aggregation and interplay with cell membranes leading to the potential functional and pathogenic consequences detected so far, and their involvement in the development of LBDs.Background Increased aortic stiffness has been found to be associated with cognitive function decline, but the evidence is still under debate. It is of great significance to elucidate the evidence in this debate to help make primary prevention decisions to slow cognitive decline in our routine clinical practice. Methods Electronic databases of PubMed, EMBASE, and Cochrane Library were systematically searched to identify peer-reviewed articles published in English from January 1, 1986, to March 16, 2020, that reported the association between aortic stiffness and cognitive function. Studies that reported the association between aortic pulse wave velocity (PWV) and cognitive function, cognitive impairment, and dementia were included in the analysis. Results Thirty-nine studies were included in the qualitative analysis, and 29 studies were included in the quantitative analysis. The aortic PWV was inversely associated with memory and processing speed in the cross-sectional analysis. In the longitudinal analysis, the high category of aortic PWV was 44% increased risk of cognitive impairment (OR 1.44; 95% CI 1.24-1.85) compared with low PWV, and the risk of cognitive impairment increased 3.9% (OR 1.039; 95% CI 1.005-1.073) per 1 m/s increase in aortic PWV. Besides, meta-regression analysis showed that age significantly increased the association between high aortic PWV and cognitive impairment risk. Conclusion Aortic stiffness measured by aortic PWV was inversely associated with memory and processing speed and could be an independent predictor for cognitive impairment, especially for older individuals.Hydrogen sulfide (H2S), originally considered a toxic gas, is now a recognized gasotransmitter. Numerous studies have revealed the role of H2S as a redox signaling molecule that controls important physiological/pathophysiological functions. The underlying mechanism postulated to serve as an explanation of these effects is protein persulfidation (P-SSH, also known as S-sulfhydration), an oxidative posttranslational modification of cysteine thiols. Protein persulfidation has remained understudied due to its instability and chemical reactivity similar to other cysteine modifications, making it very difficult to selectively label. Recent developments of persulfide labeling techniques have started unraveling the role of this modification in (patho)physiology. PSSH levels are important for the cellular defense against oxidative injury, albeit they decrease with aging, leaving proteins vulnerable to oxidative damage. Aging is one of the main risk factors for many neurodegenerative diseases. Persulfidation has been shown to be dysregulated in Parkinson's, Alzheimer's, Huntington's disease, and Spinocerebellar ataxia 3. This article reviews the latest discoveries that link protein persulfidation, aging and neurodegeneration, and provides future directions for this research field that could result in development of targeted drug design.Background The spectrum of early Alzheimer's disease (AD) is thought to include subjective cognitive impairment, early mild cognitive impairment (eMCI), and late mild cognitive impairment (lMCI). Choline dysfunction affects the early progression of AD, in which the basal nucleus of Meynert (BNM) is primarily responsible for cortical cholinergic innervation. The aims of this study were to determine the abnormal patterns of BNM-functional connectivity (BNM-FC) in the preclinical AD spectrum (SCD, eMCI, and lMCI) and further explore the relationships between these alterations and neuropsychological measures. Methods Resting-state functional magnetic resonance imaging (rs-fMRI) was used to investigate FC based on a seed mask (BNM mask) in 28 healthy controls (HC), 30 SCD, 24 eMCI, and 25 lMCI patients. Furthermore, the relationship between altered FC and neurocognitive performance was examined by a correlation analysis. The receiver operating characteristic (ROC) curve of abnormal BNM-FC was used to specifically BNM-FC of SFG in distinguishing eMCI from SCD; BNM-FC of MTG in distinguishing lMCI from SCD; BNM-FC of the MTG, hippocampus, and cerebellum in distinguishing SCD from HC; and BNM-FC of the hippocampus and MFG in distinguishing eMCI from lMCI have high sensitivity and specificity. Conclusions The abnormal BNM-FC patterns can characterize the early disease spectrum of AD (SCD, eMCI, and lMCI) and are closely related to the cognitive domains. These new and reliable findings will provide a new perspective in identifying the early disease spectrum of AD and further strengthen the role of cholinergic theory in AD.The current trend for the rapid growth of the global aging population poses substantial challenges for society. The human aging process has been demonstrated to be closely associated with changes in gut microbiota composition, diversity, and functional features. During the first 2 years of life, the gut microbiota undergoes dramatic changes in composition and metabolic functions as it colonizes and develops in the body. Although the gut microbiota is nearly established by the age of three, it continues to mature until adulthood, when it comprises more stable and diverse microbial species. Meanwhile, as the physiological functions of the human body deteriorated with age, which may be a result of immunosenescence and "inflammaging," the guts of elderly people are generally characterized by an enrichment of pro-inflammatory microbes and a reduced abundance of beneficial species. The gut microbiota affects the development of the brain through a bidirectional communication system, called the brain-gut-microbiota (BGM) axis, and dysregulation of this communication is pivotal in aging-related cognitive impairment. Microbiota-targeted dietary interventions and the intake of probiotics/prebiotics can increase the abundance of beneficial species, boost host immunity, and prevent gut-related diseases. This review summarizes the age-related changes in the human gut microbiota based on recent research developments. Understanding these changes will likely facilitate the design of novel therapeutic strategies to achieve healthy aging.
White matter hyperintensities (WMHs) on magnetic resonance imaging (MRI) is frequently presumed to be secondary to cerebral small vessel disease (CSVD) and associated with cognitive decline. The cerebellum plays a key role in cognition and has dense connections with other brain regions. Thus, the aim of this study was to investigate if cerebellar abnormalities could occur in CSVD patients with WMHs and the possible association with cognitive performances.

A total of 104 right-handed patients with WMHs were divided into the mild WMHs group (
= 39), moderate WMHs group (
= 37), and severe WMHs group (
= 28) according to the Fazekas scale, and 36 healthy controls were matched for sex ratio, age, education years, and acquired resting-state functional MRI. Analysis of voxel-based morphometry of gray matter volume (GMV) and seed-to-whole-brain functional connectivity (FC) was performed from the perspective of the cerebellum, and their correlations with neuropsychological variables were explored.

The analysis revealed a lower GMV in the bilateral cerebellum lobule VI and decreased FC between the left- and right-sided cerebellar lobule VI with the left anterior cingulate gyri in CSVD patients with WMHs. Both changes in structure and function were correlated with cognitive impairment in patients with WMHs.

Our study revealed damaged GMV and FC in the cerebellum associated with cognitive impairment. This indicates that the cerebellum may play a key role in the modulation of cognitive function in CSVD patients with WMHs.
Our study revealed damaged GMV and FC in the cerebellum associated with cognitive impairment. This indicates that the cerebellum may play a key role in the modulation of cognitive function in CSVD patients with WMHs.A worldwide increase in longevity is bringing novel challenges to public health and health care professionals. Cognitive impairment in the elderly may compromise living conditions and precede Alzheimer's disease (AD), the most prevalent form of dementia. Therefore, finding molecular markers associated with cognitive impairment is of crucial importance. Lipocalin 2 (LCN2), an iron-related protein, has been suggested as a potential marker for mild cognitive impairment (MCI) and AD. This study aimed at investigating the association between LCN2 measured in serum and cerebrospinal fluid (CSF) with cognitive impairment. A cross-sectional design based on two aging cohorts was used individuals diagnosed with subjective cognitive complaints (SCC), MCI, and AD from a Swedish memory clinic-based cohort, and individuals diagnosed with SCC and AD from a Portuguese cohort. Binary logistic [for the outcome cognitive impairment (MCI + AD) in the Swedish cohort and AD in the Portuguese cohort] and multinomial logistic (for the outcomes MCI and AD) regression analyses were used. No associations were found in both cohorts when controlling for sex, education, and age. This explanatory study suggests that the association between serum and CSF LCN2 concentrations with cognitive impairment reported in the literature must be further analyzed for confounders.Post-stroke anxiety (PSA) has caused wide public concern in recent years, and the study on risk factors analysis and prediction is still an open issue. With the deepening of the research, machine learning has been widely applied to various scenarios and make great achievements increasingly, which brings new approaches to this field. In this paper, 395 patients with acute ischemic stroke are collected and evaluated by anxiety scales (i.e., HADS-A, HAMA, and SAS), hence the patients are divided into anxiety group and non-anxiety group. Afterward, the results of demographic data and general laboratory examination between the two groups are compared to identify the risk factors with statistical differences accordingly. Then the factors with statistical differences are incorporated into a multivariate logistic regression to obtain risk factors and protective factors of PSA. Statistical analysis shows great differences in gender, age, serious stroke, hypertension, diabetes mellitus, drinking, and HDL-C level betweeatment.Cadmium (Cd) is an environmental contaminant, which is a potential risk factor in the progression of aging-associated neurodegenerative diseases. Herein, we have assessed the effects of chronic administration of Cd on cellular oxidative stress and its associated Alzheimer's disease (AD) pathologies in animal models. Two groups of mice were used, one group administered with saline and the other with Cd (1 mg/kg/day; intraperitoneally) for 3 months. After behavioral studies, molecular/biochemical (Immunoblotting, ELISAs, ROS, LPO, and GSH assays) and morphological analyses were performed. We observed an exacerbation of memory and synaptic deficits in chronic Cd-injected mice. Subacute and chronic Cd escalated reactive oxygen species (ROS), suppressed the master antioxidant enzymes, e.g., nuclear factor-erythroid 2-related factor 2 and heme oxygenase-1, and evoked the stress kinase phospho-c-Jun N-terminal kinase 1 signaling pathways, which may escalate AD pathologies possibly associated with amyloidogenic processes. These findings suggest the regulation of oxidative stress/ROS and its associated amyloid beta pathologies for targeting the Cd-exacerbated AD pathogenesis. In addition, these preclinical animal studies represent a paradigm for epidemiological studies of the human population exposed to chronic and subacute administration of Cd, suggesting avoiding environmental contaminants.Cytoplasmic ribonucleoproteins called stress granules (SGs) are considered as one of the main cellular solutions against stress. Their temporary presence ends with stress relief. Any factor such as chronic stress or mutations in the structure of the components of SGs that lead to their permanent presence can affect their interactions with pathological aggregations and increase the degenerative effects. SGs involved in RNA mechanisms are important factors in the pathophysiology of neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), frontotemporal degeneration (FTD), and Alzheimer's diseases (AD). Although many studies have been performed in the field of SGs and neurodegenerative disorders, so far, no systematic studies have been executed in this field. The purpose of this study is to provide a comprehensive perspective of all studies about the role of SGs in the pathogenesis of neurodegenerative disorders with a focus on the protein ingredients of these granules. This scoping review is basnerative diseases can provide new targets for treatment of these disorders.Aim To examine the feasibility of using large scale spatial, self-mobile, virtual reality, and eye tracking in older adults with and without Alzheimer's disease (AD). Methods Older adults with early stage AD (n = 38) and a control group without AD (n = 50) were asked to find their way in a large, projected VR simulation of a retirement community repeatedly over 10 trials for each of 2 days, while wearing eye tracking glasses. Feasibility measures, including tolerance, side effects, and ability to complete the VR and eye tracking were collected. This study reports the analysis of the feasibility data for the VR and eye tracking and comparison of findings between the groups. Results Over 80% of the subjects were able to complete the VR portion of the study. Only four subjects, all in the AD group, could not use the joystick and were excluded. Withdrawal rate (18%) was similar between the groups [X 2 (2) = 2.82, N = 88, p = 0.245] with most withdrawals occurring after the fourth trial. Simulation sickness was not significantly different between the groups. Only 60% of the subjects had completed eye tracking videos; more subjects in the AD group had complete eye tracking videos than the control group; X 2 (1) = 7.411, N = 88, p = 0.006. Eye tracking incompletion was primarily due to inability to calibration issues. Conclusion Virtual reality testing and eye tracking can be used in older adults with and without AD in a large-scale way-finding task, but that there are some limitations.Synaptic signaling is integral for proper brain function. During fetal development, exposure to inflammation or mild hypoxic-ischemic insult may lead to synaptic changes and neurological damage that impairs future brain function. Preterm neonates are most susceptible to these deleterious outcomes. Evaluating clinically used and novel fetal neuroprotective measures is essential for expanding treatment options to mitigate the short and long-term consequences of fetal brain injury. Magnesium sulfate is a clinical fetal neuroprotective agent utilized in cases of imminent preterm birth. By blocking N-methyl-D-aspartate receptors, magnesium sulfate reduces glutamatergic signaling, which alters calcium influx, leading to a decrease in excitotoxicity. Emerging evidence suggests that melatonin and N-acetyl-L-cysteine (NAC) may also serve as novel putative fetal neuroprotective candidates. Melatonin has important anti-inflammatory and antioxidant properties and is a known mediator of synaptic plasticity and neuronal generation. While NAC acts as an antioxidant and a precursor to glutathione, it also modulates the glutamate system. Glutamate excitotoxicity and dysregulation can induce perinatal preterm brain injury through damage to maturing oligodendrocytes and neurons. The improved drug efficacy and delivery of the dendrimer-bound NAC conjugate provides an opportunity for enhanced pharmacological intervention. Here, we review recent literature on the synaptic pathways underlying these therapeutic strategies, discuss the current gaps in knowledge, and propose future directions for the field of fetal neuroprotective agents.This report describes a unique case of chronic unilateral anterior uveitis associated with macular edema while on oral dabrafenib treatment for chronic recurrent pilocytic astrocytoma. After gradual taper of prednisolone acetate OS, the patient developed recurrent mild low-grade anterior uveitis and macular edema OS that required low dose of prednisolone acetate OS to prevent recurrences while on oral dabrafenib. When oral dabrafenib was temporarily discontinued for 3 months due to her ocular inflammation, she had no flares of her uveitis; however, her tumor increased significantly in size. The collaborative decision was made to continue her oral dabrafenib while on topical anti-inflammatory therapy for her uveitis. Clinicians should be aware of this potential unilateral sequela of uveitis secondary to dabrafenib. Further investigation should be conducted to identify factors that may place certain patients at higher risk for this complication.The aim of this report is to present a patient with traumatic optic nerve sheath hematoma (ONSH), a rare diagnosis with high potential for visual sequelae. This case involves a 41-year-old male who presented promptly following blunt trauma to the right eye and orbit that resulted in acute vision loss. Following computed tomography and ophthalmic examination, a diagnosis of ONSH was made and medical therapy with methylprednisolone was initiated. He reported significant improvements in visual symptoms following intravenous corticosteroid therapy. Although the patient reported significant improvements and had normal Snellen visual acuities in follow-up, he continued to have an inferior visual field defect at 1 week in the affected eye. ONSH causing subsequent localized compression of the optic nerve is a rare mechanism of traumatic optic neuropathy in patients following head trauma. The localized compartment syndrome of the optic nerve and subjective visual symptoms were relieved following corticosteroid therapy with no initial need for surgical decompression. Although central visual acuity returned to baseline, the patient had a persistent visual field defect and relative afferent pupillary defect.We would like to describe a case with Coats-like exudative vitreoretinopathy after cataract surgery in a patient with retinitis pigmentosa (RP) misdiagnosed as acute retinal necrosis (ARN). A patient with RP underwent cataract surgery that was complicated by macular oedema. Following sub-Tenon's injection of triamcinolone acetonide, evolution was initially favourable. However, 2 months later, after 2 sub-Tenon's injections, the patient complained again of floaters and a drop of visual acuity. Aqueous flare measured by laser flare photometry was increased and posterior segment examination showed vitreitis, posterior haemorrhages and a temporal-inferior peripheral white-yellowish area in left eye. Serology (IgGs) for varicella-zoster virus (VZV) was slightly elevated and more so for toxoplasmosis. The whole clinical context strongly evoked ARN not excluding completely ocular toxoplasmosis. Valacyclovir and clindamycin were introduced without benefit. When examining the extreme periphery of the right fellow eye, discreet yellow lesions were also detected rendering the infectious hypothesis less probable. A vitrectomy finally excluded infectious causes and the diagnosis of Coats-like exudative vitreoretinopathy in a RP patient was retained. Increased flare despite 2 sub-Tenon's injections, the presence of micro-haemorrhages, and peripheral yellow retinal necrotic areas drew our attention away from a well-known albeit rare condition of Coats-like response in RP patients, a diagnosis which has to be considered in such circumstances.We herein report a patient with Philadelphia chromosome-positive lymphoid blast crisis of chronic myeloid leukemia (CML), who presented with bilateral serous retinal detachment (SRD). A 36-year-old Asian male presented with the symptoms of decreased vision and was found to have bilateral SRD involving fovea. There was no inflammation in the anterior chamber or vitreous. Physical examination showed hepatomegaly and splenomegaly. A blood count revealed white blood cell count of 38.2 × 109/L with 51.5% blast cells. Bone marrow aspirate showed total cell count of 145 × 103/μL with 80.6% blast cells and negative neutrophil myeloperoxidase staining. Cytogenetic analysis using fluorescence in situ hybridization confirmed a 9;22 chromosomal translocation, indicating the presence of the Philadelphia chromosome. Flow cytometry analysis demonstrated expression of CD10, CD19, and positive TdT. According to morphology, immunology, cytogenetics, and molecular criteria, the patient was diagnosed as having Philadelphia chromosome-positive lymphoid blast crisis of CML.
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