Alzheimer's disease (AD) is an irreversible, age-related progressive neurological disorder, and the most common type of dementia in aged people. Neuropathological lesions of AD are neurofibrillary tangles (NFTs), and senile plaques comprise the accumulated amyloid-beta (Aβ), loaded with metal ions including Cu, Fe, or Zn. Some reports have identified metal dyshomeostasis as a neurotoxic factor of AD, among which Cu ions seem to be a central cationic metal in the formation of plaque and soluble oligomers, and have an essential role in the AD pathology. Cu-Aβ complex catalyzes the generation of reactive oxygen species (ROS) and results in oxidative damage. Several studies have indicated that oxidative stress plays a crucial role in the pathogenesis of AD. The connection of copper levels in AD is still ambiguous, as some researches indicate a Cu deficiency, while others show its higher content in AD, and therefore there is a need to increase and decrease its levels in animal models, respectively, to study which one is the cause. For more than twenty years, many in vitro studies have been devoted to identifying metals' roles in Aβ accumulation, oxidative damage, and neurotoxicity. Towards the end, a short review of the modern therapeutic approach in chelation therapy, with the main focus on Cu ions, is discussed. Despite the lack of strong proofs of clinical advantage so far, the conjecture that using a therapeutic metal chelator is an effective strategy for AD remains popular. However, some recent reports of genetic-regulating copper transporters in AD models have shed light on treating this refractory disease. This review aims to succinctly present a better understanding of Cu ions' current status in several AD features, and some conflicting reports are present herein.

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Copper Toxicity Links to Pathogenesis of Alzheimer's Disease and Therapeutics Approaches.

Background Cuproptosis is a copper-dependent cell death mechanism that is associated with tumor progression, prognosis, and immune response. However, the potential role of cuproptosis-related genes (CRGs) in the tumor microenvironment (TME) of triple-negative breast cancer (TNBC) remains unclear. Patients and methods In total, 346 TNBC samples were collected from The Cancer Genome Atlas database and three Gene Expression Omnibus datasets, and were classified using R software packages. The relationships between the different subgroups and clinical pathological characteristics, immune infiltration characteristics, and mutation status of the TME were examined. Finally, a nomogram and calibration curve were constructed to predict patient survival probability to improve the clinical applicability of the CRG_score. Results We identified two CRG clusters with immune cell infiltration characteristics highly consistent with those of the immune-inflamed and immune-desert clusters. Furthermore, we demonstrated that the gene signature can be used to evaluate tumor immune cell infiltration, clinical features, and prognostic status. Low CRG_scores were characterized by high tumor mutation burden and immune activation, good survival probability, and more immunoreactivity to CTLA4, while high CRG_scores were characterized by the activation of stromal pathways and immunosuppression. Conclusion This study revealed the potential effects of CRGs on the TME, clinicopathological features, and prognosis of TNBC. The CRGs were closely associated with the tumor immunity of TNBC and are a potential tool for predicting patient prognosis. Our data provide new directions for the development of novel drugs in the future.

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Prognostic analysis of cuproptosis-related gene in triple-negative breast cancer

Copper is an essential transition metal frequently increased in cancer known to strongly influence essential cellular processes. Targeted therapy protocols utilizing both novel and repurposed drug agents initially demonstrate strong efficacy, before failing in advanced cancers as drug resistance develops and relapse occurs. Overcoming this limitation involves the development of strategies and protocols aimed at a wider targeting of the underlying molecular changes. Receptor Tyrosine Kinase signaling pathways, epigenetic mechanisms and cell metabolism are among the most common therapeutic targets, with molecular investigations increasingly demonstrating the strong influence each mechanism exerts on the others. Interestingly, all these mechanisms can be influenced by intracellular copper. We propose that copper chelating agents, already in clinical trial for multiple cancers, may simultaneously target these mechanisms across a wide variety of cancers, serving as an excellent candidate for targeted combination therapy. This review summarizes the known links between these mechanisms, copper, and copper chelation therapy.

Copper: An Intracellular Achilles' Heel Allowing the Targeting of Epigenetics, Kinase Pathways, and Cell Metabolism in Cancer Therapeutics.

Obsessive-compulsive disorder (OCD) is a psychiatric disorder characterized by obsessions and/or compulsions. Different striatal subregions belonging to the cortico-striato-thalamic circuitry (CSTC) play an important role in the pathophysiology of OCD. The transcriptomes of 3 separate striatal areas (putamen (PT), caudate nucleus (CN) and accumbens nucleus (NAC)) from postmortem brain tissue were compared between 6 OCD and 8 control cases. In addition to network connectivity deregulation, different biological processes are specific to each striatum region according to the tripartite model of the striatum and contribute in various ways to OCD pathophysiology. Specifically, regulation of neurotransmitter levels and presynaptic processes involved in chemical synaptic transmission were shared between NAC and PT. The Gene Ontology terms cellular response to chemical stimulus, response to external stimulus, response to organic substance, regulation of synaptic plasticity, and modulation of synaptic transmission were shared between CN and PT. Most genes harboring common and/or rare variants previously associated with OCD that were differentially expressed or part of a least preserved coexpression module in our study also suggest striatum subregion specificity. At the transcriptional level, our study supports differences in the 3 circuit CSTC model associated with OCD.

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Initial findings of striatum tripartite model in OCD brain samples based on transcriptome analysis.

Deciphering the mechanism of Fang-Ji-Di-Huang-Decoction in ameliorating psoriasis-like skin inflammation via the inhibition of IL-23/Th17 cell axis

Copper is an essential element in cells; it can act as either a recipient or a donor of electrons, participating in various reactions. However, an excess of copper ions in cells is detrimental as these copper ions can generate free radicals and increase oxidative stress. In multicellular organisms, copper metabolism involves uptake, distribution, sequestration, and excretion, at both the cellular and systemic levels. Mammalian enterocytes take in bioavailable copper ions from the diet in a Ctr1-dependent manner. After incorporation, cuprous ions are delivered to ATP7A, which pumps Cu+ from enterocytes into the blood. Copper ions arrive at the liver through the portal vein and are incorporated into hepatocytes by Ctr1. Then, Cu+ can be secreted into the bile or the blood via the Atox1/ATP7B/ceruloplasmin route. In the bloodstream, this micronutrient can reach peripheral tissues and is again incorporated by Ctr1. In peripheral tissue cells, cuprous ions are either sequestrated by molecules such as metallothioneins or targeted to utilization pathways by chaperons such as Atox1, Cox17, and CCS. Copper metabolism must be tightly controlled in order to achieve homeostasis and avoid disorders. A hereditary or acquired copper unbalance, including deficiency, overload, or misdistribution, may cause or aggravate certain diseases such as Menkes disease, Wilson disease, neurodegenerative diseases, anemia, metabolic syndrome, cardiovascular diseases, and cancer. A full understanding of copper metabolism and its roles in diseases underlies the identification of novel effective therapies for such diseases.

The molecular mechanisms of copper metabolism and its roles in human diseases

ΔNp63αplays key roles in cell survival and proliferation. So its expression is always tightly controlled in cells. We previously reported that DNA damage down-regulates transcription of ΔNp63αin FaDu and HaCat cells, which contributes to cell apoptosis. In the present study, we found that DNA damage induces down-regulation of ΔNp63αvia facilitating its proteasomal degradation in cell lines such as MDA-MB-231 and MCF10A. Further investigation revealed that transcription of WWP1 is stimulated by DNA damage in these cells. Knock-down of WWP1 abrogates DNA damage-induced down-regulation of ΔNp63αand partially rescues cell apoptosis. Interestingly, DNA damage may stimulate WWP1 through different mechanisms in different cell types: it up-regulates transcription of WWP1 in a p53-dependent manner in MCF10A and HEK293 cells, while miR-452 may be involved in DNA damage-induced up-regulation of WWP1 in MDA-MB-231 cells. Our study demonstrates a novel pathway which regulates ΔNp63αupon cellular response to chemotherapeutic agents.

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DNA damage induces expression of WWP1 to target ΔNp63α to degradation.

Aging is a biological process of progressive deterioration of physiological functions, which poses a serious threat to individual health and a heavy burden on public health systems. As population aging continues, research into anti-aging drugs that prolong life and improve health is of particular importance. In this study, the polysaccharide from stems and leaves of Chuanminshen violaceum was obtained with water extraction and alcohol precipitation, and then separated and purified with DEAE anion exchange chromatography and gel filtration to obtain CVP-AP-I. We gavaged natural aging mice with CVP-AP-I and performed serum biochemical analysis, histological staining, quantitative real-time PCR (qRT-PCR) and ELISA kit assays to analyze inflammation and oxidative stress-related gene and protein expression in tissues, and 16SrRNA to analyze intestinal flora. We found that CVP-AP-I significantly improved oxidative stress and inflammatory responses of the intestine and liver, restored the intestinal immune barrier, and balanced the dysbiosis of intestinal flora. In addition, we revealed the potential mechanism behind CVP-AP-I to improve intestinal and liver function by regulating intestinal flora balance and repairing the intestinal immune barrier to regulate the intestinal-liver axis. Our results indicated that C. violaceum polysaccharides possessed favorable antioxidant, anti-inflammatory and potentially anti-aging effects in vivo.

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Polysaccharide from aerial part of Chuanminshen violaceum alleviates oxidative stress and inflammatory response in aging mice through modulating intestinal microbiota

Currently, the prognosis of hepatocellular carcinoma (HCC) is poor, and there is a lack of effective targeted therapy. As key mediators of the immune response, the prognostic value of antigen-presenting cells (APCs) in HCC still remains unclear. In this study, we aimed to identify APC-related genomic subtypes and develop a novel prognostic model in HCC. Our results indicated that overall survival (OS) and the level of immune infiltration significantly differed between different APC clusters. By analyzing the gene expression profile between APC clusters, APC-related genomic subtypes were identified. There was a significant difference in OS and tumor microenvironment infiltration in HCC patients with different genomic subtypes. With the aid of genomic subtypes, significantly differentially expressed genes were screened to generate a novel prognostic model. The risk score of the model had a significant positive correlation with APCs and was associated with immune checkpoint expressions. Through the clinical cohort collected from the First Affiliated Hospital of Wenzhou Medical University, the prognostic value of the risk score was further validated. Moreover, after the risk score and clinical characteristics were combined, a nomogram was constructed to evaluate the prognosis for HCC patients. In conclusion, we mainly identified the APC-related genomic subtypes and generated a novel prognostic model to improve the prognostic prediction and targeted therapy for HCC patients.

Identification and Validation of Genomic Subtypes and a Prognostic Model Based on Antigen-Presenting Cells and Tumor Microenvironment Infiltration Characteristics in Hepatocellular Carcinoma

Ji Chen

Papers

The molecular mechanisms of copper metabolism and its roles in human diseases

DNA damage induces expression of WWP1 to target ΔNp63α to degradation.

Polysaccharide from aerial part of Chuanminshen violaceum alleviates oxidative stress and inflammatory response in aging mice through modulating intestinal microbiota

Identification and Validation of Genomic Subtypes and a Prognostic Model Based on Antigen-Presenting Cells and Tumor Microenvironment Infiltration Characteristics in Hepatocellular Carcinoma