Association of Vitamin D Levels with Risk of Cognitive Impairment and Dementia: A Systematic Review and Meta-Analysis of Prospective Studies.

Background: Emerging evidence suggests the potential relationship between vitamin D deficiency and risk of cognitive impairment or dementia. To what extent the excess risk of dementia conferred by vitamin D deficiency is less clear. Objective: We summarized the current evidence from several aspects and further quantified these associations. Methods: We collected relevant prospective cohort studies by searching PubMed, Embase and Cochrane up to July 2023. The pooled relative risks (RR) were evaluated by random-effects models. Dose-response analyses were conducted by the method of two-stage generalized least squares regression. Results: Of 9,267 identified literatures, 23 were eligible for inclusion in the meta-analyses, among which 9 and 4 literatures were included in the dose-response analyses for the risk of dementia and Alzheimer's disease (AD). Vitamin D deficiency exhibited a 1.42 times risk for dementia (95% confidence interval (CI) = 1.21-1.65) and a 1.57-fold excess risk for AD (95% CI = 1.15-2.14). And vitamin D deficiency was associated with 34% elevated risk with cognitive impairment (95% CI = 1.19-1.52). Additionally, vitamin D was non-linearly related to the risk of dementia (pnonlinearity = 0.0000) and AD (pnonlinearity = 0.0042). The approximate 77.5-100 nmol/L 25-hydroxyvitamin D [25(OH)D] was optimal for reducing dementia risk. And the AD risk seemed to be decreased when the 25(OH)D level >40.1 nmol/L. Conclusions: Vitamin D deficiency was a risk factor for dementia, AD, and cognitive impairment. The nonlinear relationships may further provide the optimum dose of 25(OH)D for dementia prevention.

Nickel-Catalyzed Regioselectivity-Switchable Hydroheteroarylation of Vinylarenes with Electron-Rich Heteroarenes.

We report the first example of a regioselectivity switch in the hydroheteroarylation of vinylarenes with electron-rich heteroarenes, including benzofurans, benzothiophenes, and indoles, using an expedient ligand-controlled strategy. In the presence of NaOtBu, Ni(IMesMe)[P(OEt)3]Br2 yields C2-alkylated heteroarenes with high branched selectivity, whereas the use of Ni(IPr*OMe)[P(OEt)3]Br2 favors the formation of the corresponding linear products. This robust method also provides easy access to a range of C2-alkylated electron-rich heteroarenes without employing directing groups.

Free Water MR Imaging of White Matter Microstructural Changes is a Sensitive Marker of Amyloid Positivity in Alzheimer's Disease.

BACKGROUND: Extracellular free water (FW) resulting from white matter degeneration limits the sensitivity of diffusion tensor imaging (DTI) in predicting Alzheimer's disease (AD). PURPOSE: To evaluate the sensitivity of FW-DTI in detecting white matter microstructural changes in AD. To validate the effectiveness of FW-DTI indices to predict amyloid-beta (Aß) positivity in mild cognitive impairment (MCI) subtypes. STUDY TYPE: Retrospective. POPULATION: Thirty-eight Aß-negative cognitively healthy (CH) controls (68.74 ± 8.28 years old, 55% female), 15 Aß-negative MCI patients (MCI-n) (68.87 ± 8.83 years old, 60% female), 29 Aß-positive MCI patients (MCI-p) (73.03 ± 7.05 years old, 52% female), and 29 Aß-positive AD patients (72.93 ± 9.11 years old, 55% female). FIELD STRENGTH/SEQUENCE: 3.0T; DTI, T1 -weighted, T2 -weighted, T2 star-weighted angiography, and Aß PET (18 F-florbetaben or 11 C-PIB). ASSESSMENT: FW-corrected and standard diffusion indices were analyzed using trace-based spatial statistics. Area under the curve (AUC) in distinguishing MCI subtypes were compared using support vector machine (SVM). STATISTICAL TESTS: Chi-squared test, one-way analysis of covariance, general linear regression analyses, nonparametric permutation tests, partial Pearson's correlation, receiver operating characteristic curve analysis, and linear SVM. A P value <0.05 was considered statistically significant. RESULTS: Compared with CH/MCI-n/MCI-p, AD showed significant change in tissue compartment indices of FW-DTI. No difference was found in the FW index among pair-wise group comparisons (the minimum FWE-corrected P = 0.114). There was a significant association between FW-DTI indices and memory and visuospatial function. The SVM classifier with tissue radial diffusivity as an input feature had the best classification performance of MCI subtypes (AUC = 0.91), and the classifying accuracy of FW-DTI was all over 89.89%. DATA CONCLUSION: FW-DTI indices prove to be potential biomarkers of AD. The classification of MCI subtypes based on SVM and FW-DTI indices has good accuracy and could help early diagnosis. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 2.

Comparison of micronutrients in adult enteral formulas widely used in clinical practice.

In recent decades, great progress in the area of enteral nutrition has provided a large variety and commercial availability of enteral formulas, usually produced by the nutrition divisions of several pharmaceutical or dairy manufacturers, with specific compositions for each type of disease or patient condition. Despite the widespread use of enteral formulas, both in hospitals and at home, studies performed on the micronutrient compositions of adult enteral formulas are few in China. The content of micronutrients in 31 commercially available adult enteral formulas in the Chinese market was compared with the Chinese dietary reference intakes (DRIs), the tolerable upper limits (UL), the limit requirements in Food Safety National Standards General Rules of Foods for Special Medical Purposes (GB 29922-2013), and the European Society for Clinical Nutrition and Metabolism (ESPEN) micronutrient guideline (2022). The micronutrient content was calculated by multiplying the value provided on the nutrition label for each product by the daily energy dose of 1500 and 1800 Kcal/day. The research results showed that most adult enteral formulas were generally suitable for patients on long-term total enteral nutrition support in the Chinese market, and foods for special medical purpose (FSMP) formulas were more suitable than enteral nutrition preparation (ENP) formulas. However, the vitamin D, vitamin K, and iron content in these formulas should be appropriately increased to the limit recommended by the ESPEN micronutrient guideline. The results could provide a basis for manufacturers to research and develop more suitable enteral formulas and help clinical dietitians administer more effective enteral nutrition support for patients on long-term total enteral nutrition in clinical practice, especially individualized treatment.

The therapeutic effect of wasp venom (Vespa magnifica, Smith) and its effective part on rheumatoid arthritis fibroblast-like synoviocytes through modulating inflammation, redox homeostasis and ferroptosis.

ETHNOPHARMACOLOGICAL RELEVANCE: Rheumatoid arthritis (RA) is a chronic inflammatory disease that is related to the aberrant proliferation of fibroblast-like synoviocytes (FLS). Wasp venom (WV, Vespa magnifica, Smith), an insect secretion, has been used to treat RA in Chinese Jingpo national minority's ancient prescription. However, the potential mechanisms haven't been clarified. AIM OF THE STUDY: The purposes of this paper were two-fold. First, to investigate which was the best anti-RA effective part of WV-I (molecular weight less than 3 kDa), WV-II (molecular weight 3-10 kDa) and WV-III (molecular weight more than 10 kDa) that were separated from WV. Second, to explore the underlying molecular mechanism of WV and WV-II that was best effective part in RA. MATERIALS AND METHODS: The wasps were electrically stimulated and the secretions were collected. WV-I, WV-II and WV-III were acquired by ultracentrifuge method according to molecular weight. Next, WV, WV-I, WV-II and WV-III were identified by HPLC. Functional annotation and pathway analysis of WV used to bioinformatics analysis. RNA-seq analyses were constructed to identify differentially expressed genes (DEGs). GO and KEGG pathway analyses were performed by Metascape database. STRING was used to analyze the PPI network from DEGs. Next, PPI network was visualized using Cytoscape that based on MCODE. The pivotal genes of PPI network and MCODE analysis were verified by qRT-PCR. Subsequently, MH7A cells were performed by MTT assay to evaluate the ability of inhibiting cell proliferation. Luciferase activity assay was conducted in HepG2/STAT1 or HepG2/STAT3 cells to assess STAT1/3 sensitivity of WV, WV-I, WV-II and WV-III. Additionally, interleukin (IL)-1ß and IL-6 expression levels were detected by ELISA kits. Intracellular thioredoxin reductase (TrxR) enzyme was evaluated by TrxR activity assay kit. ROS levels, lipid ROS levels and Mitochondrial membrane potential (MMP) were assessed by fluorescence probe. Cell apoptosis and MMP were measured by using flow cytometry. Furthermore, the key proteins of JAK/STAT signaling pathway, protein levels of TrxR and glutathione peroxidase 4 axis (GPX4) were examined by Western blotting assay. RESULTS: RNA-sequencing analysis of WV displayed be related to oxidation-reduction, inflammation and apoptosis. The data displayed that WV, WV-II and WV-III inhibited significantly cells proliferation in human MH7A cell line compared to WV-I treatment group, but WV-III had no significant suppressive effect on luciferase activity of STAT3 compared with IL-6-induced group. Combined with earlier reports that WV-III contained major allergens, we selected WV and WV-II further to study the mechanism of anti-RA. In addition, WV and WV-II decreased the level of IL-1ß and IL-6 in TNF-α-induced MH7A cells via inactivating of JAK/STAT signaling pathway. On the other hand, WV and WV-II down-regulated the TrxR activity to produce ROS and induce cell apoptosis. Furthermore, WV and WV-II could accumulate lipid ROS to induce GPX4-mediated ferroptosis. CONCLUSIONS: Taken together, the experimental results revealed that WV and WV-II were potential therapeutic agents for RA through modulating JAK/STAT signaling pathways, redox homeostasis and ferroptosis in MH7A cells. Of note, WV-II was an effective part and the predominant active monomer in WV-II will be further explored in the future.

The effect of episodic foresight on intertemporal decision-making: the role of future self-continuity and perceived control.

To investigate the mechanism of episodic foresight of different valences on intertemporal decision-making, this study examined the mediating role of future self-continuity in the influence of episodic foresight on intertemporal decision-making and the moderating role of perceived control in two experiments. The results found that (1) future self-continuity mediated the effect of episodic foresight on individuals' intertemporal decision-making; and (2) perceived control moderated the indirect effect of episodic foresight on intertemporal decision-making through future self-continuity. Under low perceived control, individuals with positive episodic foresight had stronger future self-continuity and preferred future options, while individuals with negative episodic foresight had lower future self-continuity. In contrast, under high perceived control, individuals with different episodic foresight potencies did not show significant differences in their future self-continuity levels, but all showed higher levels and tended to choose the delayed option when faced with an intertemporal choice. From the perspective of the self-cognition, this study provided new insights into the relationship between episodic foresight and intertemporal decision-making and the psychological mechanisms of intertemporal decision-making.

Ligand-Controlled Nickel-Catalyzed Tandem Isomerization/Regiodivergent Hydroheteroarylation of α-Alkenes with Heteroarenes.

We herein describe an accessible ligand-controlled nickel-catalyzed tandem isomerization/regiodivergent hydroheteroarylation of α-alkenes with a series of heteroarenes, wherein the NHC ligand of heteroleptic Ni(II) complexes of the type Ni(NHC)[P(OEt)3]Br2 displayed significant effects on regulation. In the presence of NaOtBu, Ni(IMes)[P(OEt)3]Br2 enables C═C bond isomerization of α-alkenes over up to four sp3 carbon atoms to afford branched products, while Ni(IPr*OMe)[P(OEt)3]Br2 greatly deactivates α-alkene isomerization and favors the formation of linear products.

Association between variants of MTHFR genes and psychiatric disorders: A meta-analysis.

Background: Psychiatric disorders have seriously affected human life, one of the risk genes related to psychosis is the methylenetetrahydrofolatereductase (MTHFR) gene. This gene has a potential role in psychiatric disorders. Therefore, a meta-analysis is conducted to investigate the correlations between two prevalent MTHFR single nucleotide polymorphisms (SNPs), MTHFR C677T, A1298C, severe psychological disorders (schizophrenia, major depression, bipolar disorder). Methods: A total of 81 published studies were screened and selected by a search of electronic databases up to April 2022. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the association between MTHFR polymorphism and psychiatric disorders susceptibility by using random effect models. Results: We found that MTHFR C677T polymorphism is significantly related to schizophrenia and major depression in the overall population. MTHFR C677T has been linked to an increased risk of bipolar disorder in the recessive model (TT vs. CT + CC). Ethnic subgroup analysis shows that schizophrenia and major depression significantly correlate with MTHFR C677T and A1298C in Asian populations but not Caucasians. Besides, schizophrenia is correlated substantially with MTHFR C677T in the African population. However, the MTHFR A1298C polymorphism is only marginally linked to major depression. Conclusion: Findings of the current study revealed that MTHFR may contribute to the common pathogenesis of psychiatric diseases and that its variants may be essential in controlling the expression of psychosis-related genes. This study could help the researchers and health specialists in the early diagnosis and treatment of psychiatric disorders.

Iron-Catalyzed Oxidative Amination of Benzylic C(sp3)-H Bonds with Anilines.

Iron-catalyzed oxidative amination of benzylic C(sp3)-H bonds with anilines bearing electron-withdrawing groups (EWGs) or electron-donating groups (EDGs) is realized based on simple variations of N-substituents on imidazolium cations in novel ionic Fe(III) complexes. The structural modification of the imidazolium cation resulted in regulation of the redox potential and the catalytic performance of the iron metal center. Using DTBP as oxidant, [HItBu][FeBr4] showed the highest catalytic activity for anilines bearing EWGs, while [HIPym][FeBr4] was more efficient for EDG-substituted anilines. This work provides alternative access to benzylamines with the advantages of both a wide substrate scope and iron catalysis.

Chemical constituents with inhibition against TNF-α from Merrillanthus hainanensis.

Two new steroidal glycosides oxystauntoside A (1) and oxystauntoside B (2), together with sixteen known compounds (3-18) were isolated from the 95% ethanol extract of Merrillanthus hainanensis. Their structures were characterized by extensive spectroscopic analysis including NMR and mass spectra and single crystal X-ray crystallography. The absolute configuration of 1 and 2 were further determined by ECD calculations. All of these compounds were isolated from M. hainanensis for the first time. All the fractions and compounds were tested for the anti-inflammatory activity against the TNF-α factor. The ethyl acetate fraction showed the most potent inhibition (71.3%) at 10 µg/mL and compounds 5 (78.9%) and 9 (73.4%) in this fraction with both carboxyl and phenolic hydroxyl groups showed significant inhibition at 10 µM. Our study provided the first scientific report for the medicinal value of M. hainanensis.

Co-delivery of cisplatin and oleanolic acid by silica nanoparticles-enhanced apoptosis and reverse multidrug resistance in lung cancer.

Multidrug resistance (MDR) of chemotherapy is one of the significant concerns in cancer therapy. Here in our study, cisplatin (DDP) and oleanolic acid (OA) were co-loaded in mesoporous silica nanoparticles (Nsi) to construct DDP/OA-Nsi and solve the DDP-resistance in lung cancer therapy. The cytotoxicity and apoptosis assays demonstrated that in DDP-resistant A549/DDP cells, the cytotoxicity of DDP/OA-Nsi was significantly higher than that of free DDP or DDP single delivery system (DDP-Nsi). The intracellular drug accumulation study revealed that the intracellular DDP concentration in the DDP/OA-Nsi group was also higher than that in free DDP and DDP-Nsi groups. In the A549/DDP xenograft tumor model, DDP/OA-Nsi showed the best anticancer effect. In summary, DDP/OA-Nsi was a promising drug delivery system to solve MDR in lung cancer therapy.

KIF11 Promotes Proliferation of Hepatocellular Carcinoma among Patients with Liver Cancers.

BACKGROUND: Hepatocellular carcinoma (HCC) lacks effective treatments and has a poor prognosis. Therefore it is needed to develop more effective drug targets. Kinesin family member 11 (KIF11) has been reported to affect the progression of several cancers, and its high expression associates with the prognosis of patients. However, the relevant mechanisms of KIF11 in HCC progression have not been studied. METHOD: Through the cancer genome atlas (TCGA) database and immunohistochemical (IHC) staining of patients' specimens, we determined that KIF11 was highly expressed in HCC tissues and associated with prognosis. We established a KIF11 stably depleted hepatoma cell line, through cell-cloning experiments and cell counting kit-8 (CCK-8) assays to detect the effects on proliferation in vitro. The role of KIF11 in promoting cell proliferation was verified in mice. RESULT: The expression of KIF11 was negatively correlated with the overall survival (OS) and disease-free survival (DFS) and positively correlated with tumor size of HCC patients. KIF11 depletion inhibits cell proliferation and tumor growth in vitro and in vivo. Conclusion. KIF11 can be used as a positive correlation marker for HCC prognosis and served as a potential therapeutic target.

Update on the association between alpha-synuclein and tau with mitochondrial dysfunction: Implications for Parkinson's disease.

The critical role of mitochondrial dysfunction in the pathological mechanisms of neurodegenerative disorders, particularly Parkinson's disease (PD), is well established. Compelling evidence indicates that Parkinson's proteins (e.g., α-synuclein, Parkin, PINK1, DJ-1, and LRRK2) are associated with mitochondrial dysfunction and oxidative stress in PD. Significantly, there is a possible central role of alpha-synuclein (α-Syn) in the occurrence of mitochondrial dysfunction and oxidative stress by the mediation of different signaling pathways. Also, tau, traditionally considered as the main component of neurofibrillary tangles, aggregates and amplifies the neurotoxic effects on mitochondria by interacting with α-Syn. Moreover, oxidative stress caused by mitochondrial dysfunction favors assembly of both α-Syn and tau and also plays a key role in the formation of protein aggregates. In this review, we provide an overview of the relationship between these two pathological proteins and mitochondrial dysfunction in PD, and also summarize the underlying mechanisms in the interplay of α-Syn aggregation and phosphorylated tau targeting the mitochondria, to find new strategies to prevent PD processing.

The influence of theoretical knowledge on similarity judgment.

The similarity of the features between two entities has been assumed to be the essential factor for distinguishing these two entities across a variety of cognitive acts; however, the mechanism underlying the similarity processing remains unclear. The perceptual-based account suggests that similarity judgment is based on perceptual features between entities, whereas other accounts assume that similarity judgment relies heavily on one's previous knowledge of the entities. In Experiment 1, we explored the influence of theoretical knowledge on similarity judgment when perceptual features conflict with conceptual information. In Experiment 2, we examined whether categorization tasks further influence the results of the similarity judgment. Our results showed that the theoretical knowledge contributed to the overall similarity of the stimuli. In addition, carrying out a categorization task or not did not contribute more to the processes of the similarity judgment. Overall, these findings suggest that the conceptual information is more important than perceptual features while judging the similarity of two entities; if sufficient theoretical knowledge is available, the criteria for carrying out the categorization task might be consistent with those for the similarity judgment in the present study.

Dynamin-related protein 1: A protein critical for mitochondrial fission, mitophagy, and neuronal death in Parkinson's disease.

Parkinson's disease (PD) that afflicts millions of individuals worldwide is associated with deposits of aggregate-prone proteins (e.g., α-synuclein) and with mitochondrial dysfunction in neuronal cells. Mitochondria are the main source of reactive oxygen species, provide energy for neuronal cells, and are regarded as dynamic organelles that are determined by mitochondrial fission, fusion, and mitophagy to maintain mitochondrial homeostasis. Growing evidence reveals that several dynamics-related proteins, such as dynamin-related protein 1 (Drp1), mediate mitochondrial fission, fusion, and mitophagy, to protect against neurodegeneration in PD. More importantly, not only is Drp1-mediated fission required for mitophagy that exerts a protective effect on neurons, but abnormal mitochondrial fission and mitophagy can drive neuronal survival or cell death (i.e., autophagy, apoptosis, and necroptosis), suggesting that Drp1 may play a pivotal role in the pathogenesis of PD. Also, PD-related proteins such as α-synuclein, leucine-rich repeat kinase-2, PTEN-induced putative kinase 1, and Parkin have been proven to interact with Drp1, thus contributing to mitochondrial dynamics and clearance, as well as neuronal fate. Here, we review the roles of Drp1 in mitochondrial fission, dynamics, mitophagy, bulk autophagy, apoptosis, and necroptosis for a better understanding of mitochondrial disturbances in PD-associated neurodegeneration and summarize the advances of novel chemical compounds targeting Drp1 to provide new insight into potential PD therapies.

Bu-Yin-Qian-Zheng Formula Ameliorates MPP+-Induced Mitochondrial Dysfunction in Parkinson's Disease via Parkin.

As a typical traditional Chinese medicine, Bu-Yin-Qian-Zheng Formula (BYQZF) has been shown to have neuroprotective effects in patients with Parkinson's disease (PD), particularly by ameliorating mitochondrial dysfunction and regulating expression of the parkin protein. However, the underlying mechanisms by which BYQZF affects mitochondrial function through parkin are unclear. Accordingly, in this study, we evaluated the mechanisms by which BYQZF ameliorates mitochondrial dysfunction through parkin in PD. We constructed a parkin-knockdown cell model and performed fluorescence microscopy to observe transfected SH-SY5Y cells. Quantitative real-time reverse transcription polymerase chain reaction and western blotting were conducted to detect the mRNA and protein expression levels of parkin. Additionally, we evaluated the cell survival rates, ATP levels, mitochondrial membrane potential (ΔΨm), mitochondrial morphology, parkin protein expression, PINK1 protein expression, and mitochondrial fusion and fission protein expression after treatment with MPP+ and BYQZF. Our results showed that cell survival rates, ATP levels, ΔΨm, mitochondrial morphology, parkin protein levels, PINK1 protein levels, and mitochondrial fusion protein levels were reduced after MPP+ treatment. In contrast, mitochondrial fission protein levels were increased after MPP+ treatment. Moreover, after transient transfection with a negative control plasmid, the above indices were significantly increased by BYQZF. However, there were no obvious differences in these indices after transient transfection with a parkin-knockdown plasmid. Our findings suggest that BYQZF has protective effects on mitochondrial function in MPP+-induced SH-SY5Y cells via parkin-dependent regulation of mitochondrial dynamics.

Mangiferin: A multipotent natural product preventing neurodegeneration in Alzheimer's and Parkinson's disease models.

Alzheimer's disease (AD) and Parkinson's disease (PD) are recognized as the universal neurodegenerative diseases, with the involvement of misfolded proteins pathology, leading to oxidative stress, glial cells activation, neuroinflammation, mitochondrial dysfunction, and cellular apoptosis. Several discoveries indicate that accumulation of pathogenic proteins, i.e. amyloid ß (Aß), the microtubule-binding protein tau, and α-synuclein, are parallel with oxidative stress, neuroinflammation, and mitochondrial dysfunction. Whether the causative factors are misfolded proteins or these pathophysiological changes, leading to neurodegeneration still remain ambiguous. Importantly, directing pharmacological researches towards the prevention of AD and PD seem a promising approach to detect these complicating mechanisms, and provide new insight into therapy for AD and PD patients. Mangiferin (MGF, 2-C-ß-D-glucopyranosyl-1, 3, 6, 7-tetrahydroxyxanthone), well-known as a natural product, is detached from multiple plants, including Mangifera indica L. With the structure of C-glycosyl and phenolic moiety, MGF possesses multipotent properties starting from anti-oxidant effects, to the alleviation of mitochondrial dysfunction, neuroinflammation, and cellular apoptosis. In particular, MGF can cross the blood-brain barrier to exert neuronal protection. Different researches implicate that MGF is able to protect the central nervous system from oxidative stress, mitochondrial dysfunction, neuroinflammation, and apoptosis under in vitro and in vivo models. Additional facts support that MGF plays a role in improving the declined memory and cognition of rat models. Taken together, the neuroprotective capacity of MGF may stand out as an agent candidate for AD and PD therapy.

Anti-Cancer Effects of Pristimerin and the Mechanisms: A Critical Review.

As a quinonemethide triterpenoid extracted from species of the Celastraceae and Hippocrateaceae, pristimerin has been shown potent anti-cancer effects. Specifically, it was found that pristimerin can affect many tumor-related processes, such as apoptosis, autophagy, migration and invasion, vasculogenesis, and drug resistance. Various molecular targets or signaling pathways are also involved, such as cyclins, reactive oxygen species (ROS), microRNA, nuclear factor kappa B (NF-κB), mitogen-activated protein kinase (MAPK), and PI3K/AKT/mammalian target of rapamycin (mTOR) pathways. In this review, we will focus on the research about pristimerin-induced anti-cancer activities to achieve a deeper understanding of the targets and mechanisms, which offer evidences suggesting that pristimerin can be a potent anti-cancer drug.