Study on the Ameliorative Effect of Icariin Mediating NO/cGMP/PKGI Signalling Pathway in Alzheimer's Disease.

Objective: To investigate the effect of icariin (ICA) on cognitive function and NO/cGMP/PKGI signaling pathway in mice with Alzheimer's disease (AD). Methods: Wild-type C57BL/6 mice were used as the Control group, and APP/PS1 double transgenic mice were used to establish the AD model. The mice were randomly divided into AD group, AD+L-icariin group (10 mg/kg), and AD+H-icariin group (40 mg/kg), with 10 mice in each group. Water maze and Y-maze tests were used to evaluate the learning and memory abilities of mice. ELISA was used to measure the levels of serum Aß and cGMP. Tunel staining was used to determine the apoptosis of neurons in the hippocampus. Immunohistochemistry was used to measure the expression of Brdu, Dcx, and NeuN in the hippocampus. The protein expressions of iNOS, sGC, PKGI, Caspase3, Bax, and Bcl-2 in brain tissue were determined by Western blot. Results: Compared with the control group, the learning and memory ability of the AD group was significantly decreased, the serum levels of Aß and cGMP were increased, the neuronal apoptosis was increased, the contents of Brdu, Dcx and NeuN were decreased, the expression of iNOS, sGC, PKGI, Caspase-3 and Bax proteins was increased, and the expression of Bcl-2 protein was decreased (P < .05). Compared with the AD group, the AD mice treated with icariin (40mg/kg) showed improved learning and memory abilities, decreased serum Aß and cGMP contents, decreased neuronal apoptosis, increased Brdu, Dcx, and NeuN contents, and decreased iNOS, sGC, PKGI, Caspase-3, and Bax protein expressions. The expression of Bcl-2 protein was increased (P < .05). Conclusion: Icariin improves AD in mice by activating the NO/cGMP/PKGI signaling pathway.

Obesity, Glycemic Traits, Lifestyle Factors, and Risk of Facial Aging: A Mendelian Randomization Study in 423,999 Participants.

BACKGROUND: Several recent observational studies have associated obesity, lifestyle factors (smoking, sleep duration, and alcohol drinking), and glycemic traits with facial aging. However, whether this relationship is causal due to confounding and reverse causation is yet to be substantiated. AIMS: We aimed to assess these relationships using Mendelian randomization (MR). METHODS: For the instrumental variables, this paper selected independent single nucleotide polymorphisms (SNPs) linked to the exposures at a genome-wide state (P < 5 × 10-8) in equivalent genome-wide association studies (GWAS). Using the UK Biobank, we obtained summary-level data for facial aging on 423,999 individuals. The primary assessments were performed through the combination of complementing techniques (simple method approaches, weighted model, MR-Egger, and weighted median) and the inverse-variance-weighted method. Along with that, we examined the heterogeneity and horizontal pleiotropy through different types of sensitivity analyses. RESULTS: The correlations were (a) facial aging for body mass index (BMI, OR = 1.054, 95% CI 1.044-1.64), (b) waist/hip ratio (OR = 1.056, 95% CI 1.023-1.091), and (c) smoking (OR = 1.023, 95% CI 1.007-1.039). Equally important, the correlations for waist/hip ratio remained robust after adjusting for the genetically predicted BMI (OR = 1.028, 95% CI 1.003-1.054). However, no causal effects of alcoholic drinking, glycemic traits, and sleep duration on facial aging were observed. CONCLUSIONS: The outcomes shed light on the potential correlation of obesity and cigarette smoking with facial aging while putting forward a more comprehensive and credible foundation for the optimization of facial aging strategies. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Immunosuppressive MFAP2+ cancer associated fibroblasts conferred unfavorable prognosis and therapeutic resistance in gastric cancer.

PURPOSE: To explore the predictive merit of MFAP2+ cancer associated fibroblasts (CAFs) infiltration for clinical outcomes and adjuvant chemotherapy or immunotherapy responsiveness in gastric cancer (GC). METHODS: In this study, several independent cohorts were included respectively to dissect the relationship of clinical outcomes, therapeutic responses and tumor microenvironment with different MFAP2+ CAFs infiltration. Drug sensitivity analysis was conducted to predict the relationship between MFAP2+ CAFs infiltration and targeted drug response. Kaplan-Meier curves and the log-rank test were used to compare clinical outcomes of patients with different MFAP2+ CAFs infiltration. RESULTS: High MFAP2+ CAFs infiltration yielded inferior prognosis in terms of overall survival, progress free survival and recurrence free survival in GC. Patients with low MFAP2+ CAFs infiltration were more likely to gain benefit from adjuvant therapy. Moreover, low MFAP2+ CAFs infiltration could predict a promising response to immunotherapy in GC patients. MFAP2+ CAFs with immunosuppressive features were highly relevant to immune evasive contexture characterized by the dysfunction of CD8+ T cells. We found that MFAP2+ CAFs communicated with T cells, B cells and Macrophages through releasing macrophage migration inhibitor factor (MIF), which further suggested that MFAP2+ CAFs might promote therapeutic resistance through regulating T cells dysfunction and M2 macrophages polarization. CONCLUSION: Immunosuppressive MFAP2+ CAFs constructed an immune evasive tumor microenvironment characterized by incapacitated immune effector cells, consequently predicting inferior clinical outcomes and response on adjuvant therapy and immunotherapy in patients with GC. The potential of immunosuppressive MFAP2+ CAFs as a therapeutic target for GC deserved thoroughly exploration.

Alcohol drinking, smoking, and cutaneous melanoma risk: Mendelian randomization analysis.

OBJECTIVE: To investigate the causal relationship between poor lifestyle habits, such as smoking and drinking, and cutaneous malignant melanoma. METHOD: In the present study, alcohol consumption and smoking were used as exposure factors, and single nucleotide polymorphisms closely associated with alcohol consumption and smoking were used as instrumental variables, while cutaneous melanoma was set as an outcome variable. Two-sample Mendelian randomization analyses were run between alcohol consumption and melanoma and smoking and melanoma to investigate their causal associations, respectively. RESULTS: We found a positive and statistically significant causal effect of alcohol intake on the risk of cutaneous malignant melanoma (OR: 2.23; 95%CI: 1.11-4.47; p=0.02). The present study showed no significant causal relationship between cigarettes per day and cutaneous melanoma (OR: 0.85; 95%CI: 0.54-1.35; p=0.50) or smoking initiation and cutaneous melanoma (OR: 1.02; 95%CI: 0.74-1.39; p=0.88). CONCLUSIONS: This study provides Mendelian randomization evidence supporting alcohol consumption as a risk factor for cutaneous malignant melanoma. And the causal relationship between smoking and cutaneous malignant melanoma still needs to be further investigated.

Effects of High Levels of Copper on the Depression-Related Memory Disorders.

Depression is one of the most common psychiatric diseases worldwide. With the increase in the number of depressive episodes, cognitive dysfunction may be accelerated. Although significant findings related to the pathogenesis of depression have been reported, the precise molecular mechanisms of depression-related cognitive disorders have not yet been fully clarified. In this study, we collected serum copper levels and evaluated cognitive functions in patients with major depressive disorder (MDD) and healthy controls. Furthermore, we adopted a chronic restraint stress paradigm to induce depressive-like behaviors in mice, namely stress mice, and C57BL/6J mice were regarded as naive mice. We further measured the copper levels in hippocampus and dendritic spines of hippocampal neurons in stress mice and naive mice. Besides, we evaluated the changes of N-methyl-D-aspartic acid receptor subunit 2B (GluN2B) and postsynaptic density protein 95 (PSD95) levels in hippocampus, and dendritic spines of hippocampal neurons in stress mice with a copper inhibitor. The results revealed that high levels of copper and decreased memory scores exhibited a significant correlation in MDD patients. We further found that the copper inhibitor increased GluN2B and PSD95 levels in hippocampus, which could be involved in the regulation of dendritic spines of hippocampal neurons in stress mice. These results suggested that high levels of copper suppressed GluN2B and PSD95 levels in hippocampus, damaged synaptic function, and caused memory disorders in depression. Our findings provided a promising perspective for high levels of copper in patients with depression-related cognitive disorders, and copper may even be targeted for therapeutic manipulation.

Alcohol drinking, smoking, and cutaneous melanoma risk: Mendelian randomization analysis / Consumo de alcohol, tabaquismo y riesgo de melanoma cutáneo: análisis de aleatorización mendeliana

Objective: To investigate the causal relationship between poor lifestyle habits, such as smoking and drinking, and cutaneous malignant melanoma. Method: In the present study, alcohol consumption and smoking were used as exposure factors, and single nucleotide polymorphisms closely associated with alcohol consumption and smoking were used as instrumental variables, while cutaneous melanoma was set as an outcome variable. Two-sample Mendelian randomization analyses were run between alcohol consumption and melanoma and smoking and melanoma to investigate their causal associations, respectively. Results: We found a positive and statistically significant causal effect of alcohol intake on the risk of cutaneous malignant melanoma (OR: 2.23; 95%CI: 1.11-4.47; p = 0.02). The present study showed no significant causal relationship between cigarettes per day and cutaneous melanoma (OR: 0.85; 95%CI: 0.54-1.35; p = 0.50) or smoking initiation and cutaneous melanoma (OR: 1.02; 95%CI: 0.74-1.39; p = 0.88). Conclusions: This study provides Mendelian randomization evidence supporting alcohol consumption as a risk factor for cutaneous malignant melanoma. And the causal relationship between smoking and cutaneous malignant melanoma still needs to be further investigated.(AU)

Objetivo: Investigar la relación causal entre los malos hábitos de vida, como el tabaquismo y el consumo de alcohol, y el melanoma maligno cutáneo. Método: En el presente estudio, el consumo de alcohol y el tabaquismo se utilizaron como factores de exposición, y los polimorfismos de nucleótido único estrechamente asociados con el consumo de alcohol y el tabaquismo se utilizaron como variables instrumentales, mientras que el melanoma cutáneo se estableció como variable de resultado. Se realizaron análisis de aleatorización mendeliana de dos muestras entre el consumo de alcohol y el melanoma, y entre el tabaquismo y el melanoma, para investigar sus asociaciones causales, respectivamente. Resultados: Se encontró un efecto causal positivo y estadísticamente significativo del consumo de alcohol sobre el riesgo de melanoma maligno cutáneo (OR: 2,23; IC95%: 1,11-4,47; p = 0,02). El presente estudio no mostró una relación causal significativa entre cigarrillos por día y melanoma cutáneo (OR: 0,85; IC95%: 0,54-1,35; p = 0,50) ni entre inicio de fumar y melanoma cutáneo (OR: 1,02; IC95%: 0,74-1,39; p = 0,88). Conclusiones: Este estudio aporta pruebas de aleatorización mendeliana que apoyan el consumo de alcohol como factor de riesgo de melanoma maligno cutáneo. En cuanto a la relación causal entre el tabaquismo y el melanoma maligno cutáneo aún debe investigarse más a fondo.(AU)

Non-cytotoxic nanoparticles re-educating macrophages achieving both innate and adaptive immune responses for tumor therapy.

Macrophages are important antigen-presenting cells to combat tumor via both innate and adaptive immunity, while they are programmed to M2 phenotype in established tumors and instead promote cancer development and metastasis. Here, we develop a nanomedicine that can re-educate M2 polarized macrophages to restore their anti-tumor activities. The nanomedicine has a core-shell structure to co-load IPI549, a PI3Kγ inhibitor, and CpG, a Toll-like receptor 9 agonist. Specifically, the hydrophobic IPI549 is self-assembled into a pure drug nano-core, while MOF shell layer is coated for CpG encapsulation, achieving extra-high total drugs loading of 44%. Such nanosystem could facilitate intracellular delivery of the payloads but without any cytotoxicity, displaying excellent biocompatibility. After entering macrophages, the released IPI549 and CpG exert a synergistic effect to switch macrophages from M2 to M1 phenotype, which enables anti-tumor activities via directly engulfing tumor cells or excreting tumor killing cytokines. Moreover, tumor antigens released from the dying tumor cells could be effectively presented by the re-educated macrophages owing to the up-regulation of various antigen presenting mediators, resulting in infiltration and activation of cytotoxic T lymphocytes. As a result, the nanosystem triggers a robust anti-tumor immune response in combination with PD-L1 antibody to inhibit tumor growth and metastasis. This work provides a non-cytotoxic nanomedicine to modulate tumor immune microenvironment by reprograming macrophages.

Physical Exercise Prevented Stress-Induced Anxiety via Improving Brain RNA Methylation.

Physical exercise is effective in alleviating mental disorders by improving synaptic transmission; however, the link between body endurance training and neural adaptation has not yet been completely resolved. In this study, the authors investigated the role of RNA N6 -methyladenosine (m6A), an emerging epigenetic mechanism, in improved resilience against chronic restraint stress. A combination of molecular, behavioral, and in vivo recording data demonstrates exercise-mediated restoration of m6A in the mouse medial prefrontal cortex, whose activity is potentiated to exert anxiolytic effects. Furthermore, it is revealed that hepatic biosynthesis of one methyl donor is necessary for exercise to improve brain RNA m6A to counteract environmental stress. This novel liver-brain axis provides an explanation for brain network changes upon exercise training and provides new insights into the diagnosis and treatment of anxiety disorders.

Lasers and Intense Pulsed Light for the Treatment of Pathological Scars: A Network Meta-Analysis.

BACKGROUND: Laser and intense pulsed light (IPL) therapies have shown promising effects on pathological scars, but the comparative effectiveness of laser and IPL therapies has not yet been studied. OBJECTIVES: The aim of this study was to compare and rank the efficacy of laser and IPL therapies to determine the most effective treatment method for pathological scars. METHODS: Relevant studies published up to February 2022 were identified by searching PubMed, Web of Science, Cochrane Library, CNKI, and Wanfang databases. We defined Vancouver Scar Scale score as the primary outcome. Both frequentist and Bayesian approaches were used to perform a network meta-analysis. RESULTS: We included 25 trials with a total of 1688 participants. The rankings based on the surface under the cumulative ranking curve for the Vancouver Scar Scale score based on the Bayesian approach suggested IPL + CO2 (96.43%) > pulsed dye laser (PDL) + 1064-nm Nd:YAG (yttrium aluminum garnet) laser (86.21%) > PDL + CO2 (82.15%) > CO2 (58.97%) > 1064-nm Nd:YAG (57.03%) > PDL (52%) > 532-nm Nd:YAG (33.28%) > Er:YAG + IPL (28.38%) > Er:YAG (26.56%) > IPL (15.03%) > control (13.97%). The ranking results based on the frequentist approach were basically consistent with those based on the Bayesian approach. CONCLUSIONS: The results of the network meta-analysis showed that the combination of IPL and CO2 laser has the highest probability of being the most effective intervention. However, our conclusions must be interpreted with caution due to the relatively few evaluation indicators included in our study. Future well-designed randomized controlled trials with large sample sizes are required to confirm our conclusions.

A new perspective on depression and neuroinflammation: Non-coding RNA.

The high incidence and relapse rate of depression, as well comorbidity with other diseases, has made depression one of the primary causes of years of life lived with disability. Moreover, the unknown biological mechanism of depression has made treatment difficult. Neuroinflammation is important in the pathogenesis of depression. Neuroinflammation may affect depression by regulating the production of immune factors, immune cell activation, neuron generation, synaptic plasticity, and neurotransmission. Non-coding RNAs (ncRNAs) may be a breakthrough link between depression and neuroinflammation, as ncRNAs participate in these biological changes. We summarize the functions and mechanisms of ncRNAs in neuroinflammation and depression, and predict ncRNAs that may regulate the occurrence and progression of depression through neuritis. These findings not only broaden our understanding of the genetic regulation of depression and neuroinflammation but also provide a new perspective of the underlying mechanism and aid in the design of novel prevention, diagnosis, and treatment strategies.

Childhood trauma history is linked to abnormal brain metabolism of non-medicated adult patients with major depressive disorder.

OBJECTIVES: Childhood trauma is a risk factor that may lead to persistent brain metabolic abnormalities, predisposing individuals to major depressive disorder (MDD). To better elucidate the pathogenesis of MDD, we investigated the neurometabolic changes in unmedicated MDD patients who had experienced childhood trauma (CT). METHODS: In this study, 37 unmedicated MDD patients with CT, 35 unmedicated MDD patients without CT, and 30 healthy control participants underwent high-resolution proton magnetic resonance spectroscopy (1H-MRS) examination. Bilateral metabolic ratios of N-acetylaspartate (NAA)/creatine (Cr) and choline (Cho)/Cr in the prefrontal white matter (PWM), anterior cingulate cortex (ACC), putamen, and cerebellum were obtained. RESULTS: MDD patients showed neurometabolic changes in the cortico-striato-cerebellar (CSC) circuit. Furthermore, MDD patients showed significantly lower NAA/Cr and higher Cho/Cr ratio in the bilateral ACC and putamen, and higher NAA/Cr and lower Cho/Cr ratio in the cerebellum. Childhood trauma reduced the Cho/Cr ratio in the left ACC, which played an important role in longer and more episodes of depression. CONCLUSION: Early childhood trauma has a long-lasting impact on the metabolism of adult MDD patients, leading to abnormal choline metabolism of the left ACC. Abnormal biochemical metabolism in the CSC circuit may be an underlying pathophysiology of MDD. LIMITATION: As this is a small cross-sectional study, the impact of childhood trauma on the different stages of depression has not been observed.

Imatinib co-loaded targeted realgar nanocrystal for synergistic therapy of chronic myeloid leukemia.

Discovery of BCR-ABL1 tyrosine kinase inhibitors (TKIs) has revolutionized the therapy of chronic myeloid leukemia (CML), a malignant myeloproliferative disease characterized by abnormal activation of BCR-ABL fusion oncoprotein with protein tyrosine kinase (PTK) activity. However, the long-term treatment outcomes with TKIs are strongly limited by multiple drug resistances, resulting in relapse albeit with initial high response rate. Here, we reported a realgar (As4S4) nanocrystal-based delivery system to reverse drug resistance for synergistic CML therapy. While As4S4 is extremely insoluble in water, bovine serum albumin (BSA) was rationally screened to effectively stabilize As4S4 nanocrystal with uniformed size of ~40 nm. Imatinib (IMA), a representative TKIs, can be readily loaded into the hydrophobic domain of BSA to develop As4S4/IMA co-delivery system. Mechanistically, IMA inhibits PTK activity, while As4S4 degrades BCR-ABL1, which co-contribute to tumor suppression via complementary pathways for synergistic effect. Moreover, the nanosystem was modified with folic acid (FA) to enable tumor targetability, which has been demonstrated both in vitro and in vivo, resulting in robust tumor growth inhibition and significantly prolonged mice survival without any noticeable adverse effects. This work designed a synergistic nanoplatform for targeted CML therapy, provided a strategy to address the key limitation of As4S4 for biomedical applications, and highlighted the advantages of the combination between traditional Chinese and western medicine for diseases treatment.

Targeted silver nanoparticles for rheumatoid arthritis therapy via macrophage apoptosis and Re-polarization.

Infiltration of inflammatory cells, especially the M1 macrophages that secrete various types of inflammation cytokines, play crucial roles in the pathogenesis of rheumatoid arthritis (RA). To relief synovial inflammation, M1 macrophages must be eliminated or switched to anti-inflammatory M2 phenotype. We herein developed folic acid modified silver nanoparticles (FA-AgNPs) that can actively deliver into M1 macrophages to synergistically induce M1 macrophages reduction and M2 macrophages polarization for effective RA treatment. The AgNPs was facilely prepared, PEGylated and modified with FA to realize M1 macrophages targeting delivery via folate receptor overexpressed on M1 macrophages surface. After entering cells, FA-AgNPs dissolved and released Ag+ in response to intracellular glutathione (GSH), which is the key element to exert a series of anti-inflammatory functions, such as M1 macrophages apoptosis and reactive oxygen species (ROS) scavenging to facilitate M2 macrophages polarization, both of which contributed to RA treatment. This nano-system could passively accumulate into inflamed joints, permit potent anti-inflammatory activity, and impose strong therapeutic efficacy in mice RA models with high biosafety. After treatment, FA-AgNPs could be gradually cleared from the body mainly via feces without tissue accumulation, and did not show any appreciable long-term toxicity. This work declares the first example of using bio-active nanoparticles for RA treatment without loading any drugs, and highlights the potential of FA-AgNPs for targeted RA therapy via simultaneous M1 macrophage apoptosis and M1-to-M2 macrophages re-polarization.

Core-Shell Nanosystems for Self-Activated Drug-Gene Combinations against Triple-Negative Breast Cancer.

The combination of gene therapy with chemotherapeutics provides an efficacious strategy for enhanced tumor therapy. RNA-cleaving DNAzyme has been recognized as a promising gene-silencing tool, while its combination with chemotherapeutic drugs has been limited by the lack of an effective codelivery system to allow sufficient intracellular DNAzyme activation, which requires specific metal ions as a cofactor. Here, a self-activatable DNAzyme/drug core-shell codelivery system is fabricated to combat triple-negative breast cancer (TNBC). The hydrophobic chemotherapeutic, rapamycin (RAP), is self-assembled into the pure drug nanocore, and the metal-organic framework (MOF) shell based on coordination between Mn2+ and tannic acid (TA) is coated on the surface to coload an autophagy-inhibiting DNAzyme. The nanosystem efficiently delivers the payloads into tumor cells, and upon endocytosis, the MOF shell is disintegrated to release the therapeutics in response to an acidic endo/lysosome environment and intracellular glutathione (GSH). Notably, the coreleased Mn2+ serves as the cofactor of DNAzyme for effective self-activation, which suppresses the expression of Beclin 1 protein, the key initiator of autophagy, resulting in a significantly strengthened antitumor effect of RAP. Using tumor-bearing mouse models, the nanosystem could passively accumulate into the tumor tissue, impose potent gene-silencing efficacy, and thus sensitize chemotherapy to inhibit tumor growth upon intravenous administration, providing opportunities for combined gene-drug TNBC therapy.

Correlations Among mRNA Expression Levels of ATP7A, Serum Ceruloplasmin Levels, and Neuronal Metabolism in Unmedicated Major Depressive Disorder.

BACKGROUND: Previous studies have found that elevated copper levels induce oxidation, which correlates with the occurrence of major depressive disorder (MDD). However, the mechanism of abnormal cerebral metabolism of MDD patients remains ambiguous. The main function of the enzyme ATPase copper-transporting alpha (ATP7A) is to transport copper across the membrane to retain copper homeostasis, which is closely associated with the onset of mental disorders and cognitive impairment. However, less is known regarding the association of ATP7A expression in MDD patients. METHODS: A total of 31 MDD patients and 21 healthy controls were recruited in the present study. Proton magnetic resonance spectroscopy was used to assess the concentration levels of N-acetylaspartate, choline (Cho), and creatine (Cr) in brain regions of interest, including prefrontal white matter (PWM), anterior cingulate cortex (ACC), thalamus, lentiform nucleus, and cerebellum. The mRNA expression levels of ATP7A were measured using polymerase chain reaction (SYBR Green method). The correlations between mRNA expression levels of ATP7A and/or ceruloplasmin levels and neuronal biochemical metabolite ratio in the brain regions of interest were evaluated. RESULTS: The decline in the mRNA expression levels of ATP7A and the increase in ceruloplasmin levels exhibited a significant correlation in MDD patients. In addition, negative correlations were noted between the decline in mRNA expression levels of ATP7A and the increased Cho/Cr ratios of the left PWM, right PWM, and right ACC in MDD patients. A positive correlation between elevated ceruloplasmin levels and increased Cho/Cr ratio of the left PWM was noted in MDD patients. CONCLUSIONS: The findings suggested that the decline in the mRNA expression levels of ATP7A and the elevated ceruloplasmin levels induced oxidation that led to the disturbance of neuronal metabolism in the brain, which played important roles in the pathophysiology of MDD. The decline in the mRNA expression levels of ATP7A and the elevated ceruloplasmin levels affected neuronal membrane metabolic impairment in the left PWM, right PWM, and right ACC of MDD patients.

Serum copper and zinc levels correlate with biochemical metabolite ratios in the prefrontal cortex and lentiform nucleus of patients with major depressive disorder.

BACKGROUND: Previous studies have demonstrated that copper and zinc metabolism are associated with the development of major depressive disorder (MDD). Abnormal copper and zinc levels may be related to neurotransmission and biochemical metabolism in the brains of MDD patients, especially in the prefrontal cortex (PFC) and lentiform nucleus (LN). However, the mechanism of how copper and zinc levels contribute to neural metabolism in MDD patients remains to be deciphered. This study aimed to correlate copper and zinc levels with biochemical metabolite ratios in the PFC and LN of MDD patients. METHOD: Twenty-nine MDD patients and thirty-two healthy control (HC) volunteers were enrolled in this study. Proton magnetic resonance spectroscopy (1H-MRS) was used to determine the levels of the N-acetylaspartate (NAA), choline (Cho) and creatine (Cr) in the brain, and specifically in the PFC and LN regions. Serum copper and zinc levels were measured using atomic emission spectrometry (AES). Afterwards, copper and zinc levels were correlated with biochemical metabolite ratios in the PFC and LN regions of the brain. RESULTS: Higher serum copper and lower serum zinc levels with higher copper/zinc ratios were observed in MDD patients. NAA/Cr ratios in the PFC of MDD patients were lower compared to HC volunteers. In MDD patients, serum copper levels were negatively correlated with NAA/Cr ratios in the right PFC and right LN, while copper/zinc ratios were negatively correlated with NAA/Cr ratios in the right LN. No significant differences in serum copper and zinc levels with NAA/Cr ratios in the left PFC and left LN were observed in MDD patients. CONCLUSION: Our findings suggest that higher serum copper and lower serum zinc levels may contribute to neuronal impairment by affecting neuronal biochemical metabolite ratios in the right PFC and right LN of MDD patients. Abnormal copper and zinc levels may play an important role in the pathophysiology of MDD.

Platinated graphene oxide: A nanoplatform for efficient gene-chemo combination cancer therapy.

Cisplatin (CisPt) is one of the most effective antitumor drugs against a wide range of solid cancers, and recent studies have indicated that combination of CisPt and RNA interference (RNAi) agents would effectively enhance therapeutic index, while the development of simple yet robust dual-delivery systems still remains a challenge. Here, we demonstrated that platinated graphene oxide is an excellent platform to achieve such goal. Nano-Graphene oxide (NGO) was easily platinated by CisPt, and the resulting CisPt/NGO was characterized by several aspects. As a proof-of-concept, an antisense microRNA-21 (Anti-miR-21) was employed as a potential RNAi agent. While most previous work functionalized NGO with cationic polymers for gene delivery, we demonstrated that platinated NGO is a potent carrier to load Anti-miR-21 with improved capacity and adsorption stability. With Anti-miR-21 loading, the system displayed significantly enhanced cytotoxicity to cancer cells, suggesting a synergistic effect. Finally, the underlying mechanism of the improved efficacy was explored, which can be ascribed to the cell apoptosis induced by Anti-miR-21 for gene silencing. This work demonstrated platinated graphene oxide as an effective nanocarrier to co-deliver CisPt and gene therapy for the treatment of cancer.

Mild hypothermia inhibits the Notch 3 and Notch 4 activation and seizure after stroke in the rat model.

Ischemic brain injury is an important cause for seizure. Mild hypothermia of the brain or the whole body is an effective way to remit the post-stroke seizure. Our previous study revealed an implication of Notch 1 and 2 in the post-stroke seizure. This study further investigated the involvement of Notch 3 and 4 in post-stroke seizure and the effect of mild hypothermia on these two factors. A global cerebral ischemia (GCI) model was conducted in Sprague Dawley rats. Seizure activity was evaluated by the frequency of seizure attacks, seizure severity scores, and seizure discharges. Seizures were frequently occurred in the first and the second 24 h after GCI, however active whole-body cooling (mild hypothermia) and DAPT (Notch inhibitor) injection into the hippocampus, alone or in combination, alleviated seizure activity after GCI. Immunohistochemistry and Western blot assays revealed the up-regulation of Notch intracellular domain (NICD) 3 and 4 in the cerebral cortex and hippocampus following GCI, but mild hypothermia and DAPT inhibited the up-regulation of NICD 3 and 4. NF-κB, PPARα, PPARγ, cyclin D1, Sox2 and Pax6 are associated with the pathogenesis of diverse type of seizures. GCI induced NF-κB, cyclin D1, and Pax6 activity, but suppressed PPARγ. These effects of GCI were abolished by both mild hypothermia and DAPT treatment. This indicated the implication of Notch signaling in the effects of GCI. Collectively, mild hypothermia inhibits Notch 3 and Notch 4 activation and seizure after stroke in the rat model. This study adds to the further understanding of the pathogenesis of post-stroke seizures and the protective mechanism of mild hypothermia.

mTOR is involved in stroke-induced seizures and the anti-seizure effect of mild hypothermia.

Stroke is considered an underlying etiology of the development of seizures. Stroke leads to glucose and oxygen deficiency in neurons, resulting in brain dysfunction and injury. Mild hypothermia is a therapeutic strategy to inhibit stroke­induced seizures, which may be associated with the regulation of energy metabolism of the brain. Mammalian target of rapamycin (mTOR) signaling and solute carrier family 2, facilitated glucose transporter member (GLUT)­1 are critical for energy metabolism. Furthermore, mTOR overactivation and GLUT­1 deficiency are associated with genetically acquired seizures. It has been hypothesized that mTOR and GLUT­1 may additionally be involved in seizures elicited by stroke. The present study established global cerebral ischemia (GCI) models of rats. Convulsive seizure behaviors frequently occurred during the first and the second days following GCI, which were accompanied with seizure discharge reflected in the EEG monitor. Expression of phosphor (p)­mTOR and GLUT­1 were upregulated in the cerebral cortex and hippocampus, as evidenced by immunohistochemistry and western blot analyses. Mild hypothermia and/or rapamycin (mTOR inhibitor) treatments reduced the number of epileptic attacks, seizure severity scores and seizure discharges, thereby alleviating seizures induced by GCI. Mild hypothermia and/or rapamycin treatments reduced phosphorylation levels of mTOR and the downstream effecter p70S6 in neurons, and the amount of GLUT­1 in the cytomembrane of neurons. The present study revealed that mTOR is involved in stroke­induced seizures and the anti­seizure effect of mild hypothermia. The role of GLUT­1 in stroke­elicited seizures appears to be different from the role in seizures induced by other reasons. Further studies are necessary in order to elucidate the exact function of GLUT-1 in stroke­elicited seizures.

Synergistic effect of mild hypothermia and the Notch inhibitor DAPT against post stroke seizures.

Seizure is a serious complication of stroke, indicating poor prognosis. Notch signaling is associated with neuronal activity. Inhibition of Notch signaling suppresses seizure activity induced by kainic acid. The present study investigated the effect of the Notch inhibitor, DAPT, alone or in combination with mild hypothermia, on post-stroke seizures. A global cerebral ischemia (GCI) model was performed in Sprague Dawley (SD) male rats. Seizure activity was evaluated by the frequency of seizure attacks, seizure severity scores, and seizure discharges. Without any intervention, seizures occurred intensively between 24h and 48h following GCI. Seizure activity was confirmed using EEG monitoring. The expression of Notch intracellular domains (NICD) 1 and 2 were up-regulated in the cerebral cortex and hippocampus following GCI. DAPT was injected into the hippocampus of the rats to inhibit local Notch signaling. Active whole-body cooling was performed to maintain the core temperatures of rats at 33.5°C (mild hypothermia). Mild hypothermia and DAPT synergistically inhibited NICD 1 and 2 up-regulation, and post-stroke seizures. GCI augmented excitatory synaptic neurotransmission by up-regulating glutamate receptor subunits (GluN2A, GluA1) and the cotransporter, NKCC1, but attenuated inhibitory synaptic neurotransmission by down-regulating gamma amino acid, butyric acid (GABA), and the cotransporter, KCC2. DAPT treatment normalized the homeostasis of excitatory and inhibitory synaptic neurotransmission, suggesting that aberrant activation of Notch signaling is involved in post-stroke seizures. The present study adds to the further understanding of the pathogenesis of post-stroke seizures and the improvement of the treatment provided with hypothermia.