Fan Zhu

Schizophrenia is a severe neurodevelopmental disorder with a complex and largely unresolved pathogenesis. Accumulating evidence indicates that mitochondrial dysfunction is a consistent pathological hallmark of schizophrenia, suggesting that impaired mitochondrial homeostasis may represent a convergent mechanism underlying disease vulnerability. BCL2/adenovirus E1B 19 kDa interacting protein 3 (BNIP3) is a critical regulator of mitochondrial integrity and apoptosis. However, its role in schizophrenia has not yet been elucidated. Human endogenous retroviruses W family envelope (ERVWE1) has been implicated as a potential risk factor in schizophrenia, but the molecular mechanisms by which it contributes to neuronal pathology remain poorly understood. In this study, we investigated whether ERVWE1 induces mitochondrial dysfunction and neuronal apoptosis through the regulation of BNIP3. Bioinformatic analysis of the public dataset GSE53987 revealed significantly elevated BNIP3 expression in the brain tissues of patients with schizophrenia, accompanied by enrichment of mitochondria-related pathways. Consistently, BNIP3 expression was also increased in the peripheral blood of schizophrenia patients and positively correlated with ERVWE1 levels. Mechanistically, ERVWE1 upregulated BNIP3 expression by suppressing miR-27b-3p, a microRNA that directly targets BNIP3. The resulting increase in BNIP3 led to marked mitochondrial structural and functional impairment, characterized by reduced mitochondrial aspect ratio, enhanced mitochondria permeability transition pore (mPTP) opening, and decreased mitochondrial DNA (mtDNA) copy number. These mitochondrial defects subsequently triggered cytochrome c release into the cytosol, activating the intrinsic mitochondrial apoptotic pathway. Collectively, this study provides the first evidence that the ERVWE1/miR-27b-3p/BNIP3 axis contributes to mitochondrial dysfunction and neuronal apoptosis in schizophrenia. Our findings identify a previously unrecognized molecular pathway linking endogenous retroviral activity to mitochondrial pathology, offering novel insights into the mechanisms and potential therapeutic targets for schizophrenia.

Hepatitis B virus (HBV) infection remains a significant global health burden, primarily due to its chronic complications, including acute exacerbation, cirrhosis, hepatocellular carcinoma (HCC), and related sequelae. Acute exacerbation of chronic hepatitis B (CHB-AE) is common and often represents the earliest clinical manifestation. The Hepatitis B virus X protein (HBx) (17-kDa) is not only essential for viral replication but also plays a role in the development of HCC. To investigate the role of HBx mutation in CHB-AE progression, we enrolled 33 hospitalized CHB-AE patients and 31 patients with HBV-related liver failure (controls) from mainland China between January 2017 and June 2018. Single mutation 36 of HBx was significantly more prevalent in CHB-AE patients (p < 0.05), whereas Joint Mutation 1 was more frequent in HBV-related liver failure patients (p < 0.05). HBx mutations, including Single mutation 36 and Joint Mutations 2 and 3, were significantly associated with high HBV DNA levels (p < 0.05), while Joint mutation 1 predominated in the low HBV DNA group (p < 0.01). Age-stratified analysis showed that Single mutation 36 and Joint Mutation 2 were more common in younger patients (p < 0.05), whereas Joint mutation 1 was more frequent in older age (≥35 years old) (p < 0.05). Moreover, antiviral therapy markedly reduced the prevalence of Joint mutation 1 from 82.98% in treatment-naïve patients to 29.41% in treatment-experienced patients (p < 0.0001). These findings suggest that specific HBx mutations are associated with viral replication levels, disease progression, and patient demographics. Such mutations may serve as molecular markers for disease severity and potential therapeutic targets in both CHB-AE and HBV-related liver failure.

The human endogenous retrovirus type W envelope glycoprotein (ERVWE1), located at chromosome 7q21-22, has been implicated in the pathophysiology of schizophrenia. Our previous studies have shown elevated ERVWE1 expression in schizophrenia patients. Growing evidence suggests that autophagy dysfunction contributes to schizophrenia, yet the relationship between ERVWE1 and autophagy remains unclear. In this study, bioinformatics analysis of the human prefrontal cortex RNA microarray dataset (GSE53987) revealed that differentially expressed genes were predominantly enriched in autophagy-related pathways. Clinical data further demonstrated that serum levels of microtubule-associated protein 1 light chain 3β (LC3B), a key marker of macroautophagy, were significantly elevated in schizophrenia patients compared to controls, and positively correlated with ERVWE1 expression. Cellular and molecular experiments suggested that ERVWE1 promoted macroautophagy by increasing the LC3B II/I ratio, enhancing autophagosome formation, and reducing sequestosome 1 (SQSTM1) expression via upregulation of NADPH oxidase activator 1 (NOXA1). Concurrently, NOXA1 downregulated the expression of key micromitophagy-related genes, including PTEN-induced kinase 1 (PINK1), Parkin RBR E3 ubiquitin-protein ligase (Parkin), and the pyruvate dehydrogenase E1 subunit α 1 (PDHA1). As a result, ERVWE1, via NOXA1, inhibited micromitophagy by suppressing the expression of PINK1, Parkin, and PDHA1, thereby leading to impaired production of mitochondrial-derived vesicles (MDVs). Mechanistically, ERVWE1 enhanced NOXA1 transcription by upregulating upstream transcription factor 2 (USF2). In conclusion, ERVWE1 promotes macroautophagy and inhibits micromitophagy through USF2-NOXA1 axis, providing novel mechanistic insight into the role autophagy dysregulation in schizophrenia. These findings suggest that targeting autophagy pathways may offer novel therapeutic strategies for schizophrenia treatment.

HERVs (Human endogenous retroviruses) are remnants of ancient exogenous retroviruses that have integrated into the human genome, particularly in germ-line cells. Among these, the envelope protein gene HERV-W env (Human endogenous retroviruses W family envelope protein), located on chromosome 7 and primarily expressed in the human placenta, has been closely linked to various neuropsychiatric disorders, including schizophrenia, as well as autoimmune diseases and cancer. Recent studies have highlighted the abnormal expression of cytokines as a key factor in the pathophysiology of schizophrenia. Notably, elevated serum levels of IL-1β (interleukin 1 beta) in schizophrenia, a cytokine associated with inflammation, are a characteristic feature of pyroptosis—a form of pro-inflammatory programmed cell death. Although previous research has observed significant upregulation of pyroptosis-related genes such as CASP1 (Caspase-1), NLRP3 (NLR family pyrin domain containing 3), and IL1B (interleukin 1 beta) in the serum of schizophrenia patients, and extensive neuron pyroptosis has been documented in various neuropsychiatric disorders, including Alzheimer’s disease, epilepsy, and multiple sclerosis, the occurrence of neuron pyroptosis in schizophrenia remains uncertain. Furthermore, the mechanisms underlying pyroptosis in schizophrenia and its potential connection with HERV-W env have yet to be fully elucidated. In this study, we found that the expression levels of pyroptosis-related genes, specifically CASP1, GSDMD (Gasdermin D), and IL1B, were significantly elevated in patients with schizophrenia compared to healthy controls. Furthermore, our analysis revealed a strong positive correlation between HERV-W env expression and the levels of CASP1/GSDMD/IL1B in these patients. Experimental evidence further demonstrated that HERV-W env promoted the activation of Caspase-1 and the cleavage of Gasdermin D, leading to increased release of LDH (lactate dehydrogenase) and IL-1β. Importantly, inhibitors targeting NLRP3, CASP1, and GSDMD significantly reduced the releases of LDH and IL-1β induced by HERV-W env, whereas BID (BH3 interacting domain death agonist) inhibitors did not have a notable effect. This suggests that HERV-W env induces CASP1–GSDMD-dependent pyroptosis through the NLRP3–CASP1–GSDMD signaling pathway. As pyroptosis is increasingly recognized for its connection to neurodegenerative diseases, this study provides insights into the molecular mechanisms of neuronal pyroptosis mediated by the NLRP3 inflammasome in the context of HERV-W env. Additionally, it explores the potential facilitation of HERV-W env in the development of schizophrenia via pyroptosis, proposing that certain pyroptosis indicators could serve as potential biomarkers for schizophrenia. Based on our existing research results and the findings of previous researchers, we infer that HERV-W env acts as a bridge in the onset and progression of schizophrenia. Furthermore, HERV-W env may serve as a potential target for the clinical treatment of schizophrenia, suggesting that monoclonal antibody therapy targeting HERV-W env could represent a novel approach to managing this disease.

Background: Increasingly studies highlight the crucial role of the ancestral retrovirus envelope protein ERVWE1 in the pathogenic mechanisms of schizophrenia, a severe psychiatric disorder affecting approximately 1% of the global population. Recent studies also underscore the significance of circular RNAs (circRNAs), crucial for neurogenesis and synaptogenesis, in maintaining neuronal functions. However, the precise relationship between ERVWE1 and circRNAs in the etiology of schizophrenia remains elusive. Results: This study observed elevated levels of hsa_circ_0001810 (circ_0001810) in the blood samples of schizophrenia patients, displaying a significant positive correlation with ERVWE1 expression. Interestingly, in vivo studies demonstrated that ERVWE1 upregulated circ_0001810 in neuronal cells. Circ_0001810, acting as a competing endogenous RNA (ceRNA), bound to miR-1197 and facilitated the release of adenylate kinase 2 (AK2). The bioinformatics analysis of the schizophrenia datasets revealed increased levels of AK2 and enrichment of mitochondrial dynamics. Notably, miR-1197 was reduced in schizophrenia patients, while AK2 levels were increased. Additionally, AK2 showed positive correlations with ERVWE1 and circ_0001810. Further studies demonstrated that AK2 led to mitochondrial dysfunction, characterized by loss of intracellular ATP, mitochondrial depolarization, and disruption of mitochondrial dynamics. Our comprehensive investigation suggested that ERVWE1 influenced ATP levels, promoted mitochondrial depolarization, and disrupted mitochondrial dynamics through the circ_0001810/AK2 pathway. Conclusions: Circ_0001810 and AK2 were increased in schizophrenia and positively correlated with ERVWE1. Importantly, ERVWE1 triggered mitochondrial dysfunction through circ_0001810/miR-1197/AK2 pathway. Recent focus on the impact of mitochondrial dynamics on schizophrenia development had led to our discovery of a novel mechanism by which ERVWE1 contributed to the etiology of schizophrenia, particularly through mitochondrial dynamics. Moreover, these findings collectively proposed that circ_0001810 might serve as a potential blood-based biomarker for schizophrenia. Consistent with our previous theories, ERVWE1 is increasingly recognized as a promising therapeutic target for schizophrenia.

Purpose Chronic hepatitis B virus (HBV) infection is the primary risk factor for the malignant progression of hepatocellular carcinoma (HCC). It has been reported that HBV X protein (HBx) possesses oncogenic properties, promoting hepatocarcinogenesis and chemoresistance. However, the detailed molecular mechanisms are not fully understood. Here, we aim to investigate the effects of miR-128-3p/SPG21 axis on HBx-induced hepatocarcinogenesis and chemoresistance. Methods The expression of SPG21 in HCC was determined using bioinformatics analysis, quantitative real-time PCR (qRT-PCR), western blotting, and immunohistochemistry (IHC). The roles of SPG21 in HCC were elucidated through a series of in vitro and in vivo experiments, including real-time cellular analysis (RTCA), matrigel invasion assay, and xenograft mouse model. Pharmacologic treatment and flow cytometry were performed to demonstrate the potential mechanism of SPG21 in HCC. Results SPG21 expression was elevated in HCC tissues compared to adjacent non-tumor tissues (NTs). Moreover, higher SPG21 expression correlated with poor overall survival. Functional assays revealed that SPG21 fostered HCC tumorigenesis and invasion. MiR-128-3p, which targeted SPG21, was downregulated in HCC tissues. Subsequent analyses showed that HBx amplified TRPM7-mediated calcium influx via miR-128-3p/SPG21, thereby activating the c-Jun N-terminal kinase (JNK) pathway. Furthermore, HBx inhibited doxorubicin-induced apoptosis by engaging the JNK pathway through miR-128-3p/SPG21. Conclusion The study suggested that SPG21, targeted by miR-128-3p, might be involved in enhancing HBx-induced carcinogenesis and doxorubicin resistance in HCC via the TRPM7/Ca²⁺/JNK signaling pathway. This insight suggested that SPG21 could be recognized as a potential oncogene, offering a novel perspective on its role as a prognostic factor and a therapeutic target in the context of HCC.

Whey protein hydrolysates are recognized for their substantial functional and biological properties. Their high digestibility and amino acid composition make them a valuable ingredient to hydrolyzed whey infant formulas, enhancing both product functionality and nutritional values for infant growth. It is important to understand the functional and biological properties of whey protein hydrolysates for their applications in infant formula systems. This review explored preparation methods of whey protein hydrolysates for infant formula‐based applications. The effects of whey protein hydrolysate on the physicochemical and biological properties of hydrolyzed whey infant formulas were summarized. The influences of whey protein hydrolysates on the functional and nutritional properties of formulas from manufacturing to infant consumption were discussed. Whey protein hydrolysates are crucial components in the preparation of infant formula, tailored to meet the functional and nutritional demands of the product. The selection of enzyme types and hydrolysis parameters is decisive for obtaining “optimal” whey protein hydrolysates that match the intended characteristics. “Optimal” whey protein hydrolysates offer diverse functionalities, including solubility, emulsification and production stability to hydrolyzed whey infant formulas during manufacturing processes and formulations. They simultaneously promote protein digestibility, infant growth and other potential health benefits, including reduced allergenic potential, as supported by in vitro, in vivo and clinical trials. Overall, the precise selection of enzymes and hydrolysis parameters in the production of whey protein hydrolysates is crucial in achieving the desired characteristics and functional benefits for hydrolyzed whey infant formulas, making them critical in the development of infant nutrition products.

Human endogenous retroviruses (HERVs) are remnants of retroviral infections in human germline cells from millions of years ago. Among these, ERVW-1 (also known as HERV-W-ENV, ERVWE1, or ENVW) encodes the envelope protein of the HERV-W family, which contributes to the pathophysiology of schizophrenia. Additionally, neuropathological studies have revealed cell death and disruption of iron homeostasis in the brains of individuals with schizophrenia. Here, our bioinformatics analysis showed that differentially expressed genes in the human prefrontal cortex RNA microarray dataset (GSE53987) were mainly related to ferroptosis and its associated pathways. Clinical data demonstrated significantly lower expression levels of ferroptosis-related genes, particularly Glutathione peroxidase 4 (GPX4) and solute carrier family 3 member 2 (SLC3A2), in schizophrenia patients compared to normal controls. Further in-depth analyses revealed a significant negative correlation between ERVW-1 expression and the levels of GPX4/SLC3A2 in schizophrenia. Studies indicated that ERVW-1 increased iron levels, malondialdehyde (MDA), and transferrin receptor protein 1 (TFR1) expression while decreasing glutathione (GSH) levels and triggering the loss of mitochondrial membrane potential, suggesting that ERVW-1 can induce ferroptosis. Ongoing research has shown that ERVW-1 reduced the expression of GPX4 and SLC3A2 by inhibiting their promoter activities. Moreover, Ferrostatin-1 (Fer-1), the ferroptosis inhibitor, reversed the iron accumulation and mitochondrial membrane potential loss, as well as restored the expressions of ferroptosis markers GSH, MDA, and TFR1 induced by ERVW-1. In conclusion, ERVW-1 could promote ferroptosis by downregulating the expression of GPX4 and SLC3A2, revealing a novel mechanism by which ERVW-1 contributes to neuronal cell death in schizophrenia.