Comparable efficacy and safety of generic and branded imatinib for patients with chronic myeloid leukemia in China.

Background: Generics imatinib became an alternative treatment option for chronic myeloid leukemia (CML) patients in China. However, clinicians and patients alike harbor concerns regarding the long-term safety of generic imatinib. Objectives: Patients with chronic phase CML receiving frontline imatinib treatment. Design: A retrospective study was used to evaluate the blood concentration, effectiveness, and safety of generic in 170 CML patients. Methods: Imatinib plasma concentrations were detected by high-performance liquid chromatography-tandem mass spectrometry. Results: Among the 170 patients, 73 (42.9%) patients treated with branded imatinib as first-line therapy, while 22 (12.9%) switched to generic imatinib during treatment due to economic considerations. No significant differences in trough concentrations between branded and generic imatinib (1549.9 ± 648.8 ng/mL vs 1479.0 ± 507.0 ng/mL; p = 0.95). During the 2-year follow-up, there were no significant differences in molecular response rates (major molecular response (MMR): 33.3% vs 37.0%; deep molecular response: 56.9% vs 42.9%, p = 0.17) between the branded and generic imatinib. Both groups showed similar rates of switching to second-generation tyrosine kinase inhibitor (11.8% vs 15.1%, p = 0.56). Furthermore, there were no significant differences in event-free survival or failure-free survival between branded and generic imatinib. Twenty-two (12.9%) switched to generic imatinib during treatment, 68.2% maintained their level of response, 27.3% improved, and only one patient (4.5%) lost MMR. There were no significant differences in the incidence of various adverse events. Conclusion: Generic imatinib are equally effective and safe compared to branded molecules, both for newly diagnosed patients and those who switch from branded.

Plasma MiR-190 is a potential clinical biomarker for acute respiratory distress syndrome in children and its regulatory role in ARDS cell models by targeting KLF15.

BACKGROUND: The present research aimed to investigate the clinical value of plasma miR-190 in children with acute respiratory distress syndrome (ARDS) and the impact of miR-190 on LPS-induced ARDS cell models. METHODS: The plasma miR-190 levels were measured using real-time quantitative reverse transcription PCR (RT-qPCR). LPS-treated human pulmonary microvascular endothelial cells (HPMECs) were established and then transfected with miR-190 mimic, inhibitor, or miR-negative controls. The levels of inflammatory factors were detected by enzyme-linked immunosorbent assay (ELISA). The effects of miR-190 on HPMEC proliferation and apoptosis were evaluated by CCK-8 assay and flow cytometry. The regulation of KLF15 by miR-190 was detected by luciferase report assay. RESULTS: The plasma miR-190 expression was increased in ARDS children and it was positively related to the severity and 28 day-survival. Plasma miR-190 could distinguish ARDS children from healthy children. Inhibition of miR-190 increased LPS-induced HPMEC cell proliferation and decreased cell apoptosis and inflammatory cytokines IL-6, IL-1ß, and TNF-α. KLF15 was a direct target of miR-190. CONCLUSION: Increased plasma miR-190 may be a clinical diagnostic and prognostic predictor for ARDS children. Inhibition of miR-190 may improve LPS-induced ARDS by increasing cell proliferation, inhibiting cell apoptosis and inflammatory response by targeting KLF15.

Material-driven immunomodulation and ECM remodeling reverse pulmonary fibrosis by local delivery of stem cell-laden microcapsules.

Recent progress in stem cell therapy has demonstrated the therapeutic potential of intravenous stem cell infusions for treating the life-threatening lung disease of pulmonary fibrosis (PF). However, it is confronted with limitations, such as a lack of control over cellular function and rapid clearance by the host after implantation. In this study, we developed an innovative PF therapy through tracheal administration of microfluidic-templated stem cell-laden microcapsules, which effectively reversed the progression of inflammation and fibrotic injury. Our findings highlight that hydrogel microencapsulation can enhance the persistence of donor mesenchymal stem cells (MSCs) in the host while driving MSCs to substantially augment their therapeutic functions, including immunoregulation and matrix metalloproteinase (MMP)-mediated extracellular matrix (ECM) remodeling. We revealed that microencapsulation activates the MAPK signaling pathway in MSCs to increase MMP expression, thereby degrading overexpressed collagen accumulated in fibrotic lungs. Our research demonstrates the potential of hydrogel microcapsules to enhance the therapeutic efficacy of MSCs through cell-material interactions, presenting a promising yet straightforward strategy for designing advanced stem cell therapies for fibrotic diseases.

Evaluation of Factors Influencing Postoperative Cognitive Dysfunction in Patients After Cranial Tumor Surgery.

BACKGROUND: The authors retrospectively analyzed the perioperative data of 81 patients who underwent cranial tumor surgery to explore the factors influencing POCD in patients after the surgery. METHODS: The authors evaluated preoperative cognitive dysfunction using the Mini-Mental State Examination (MMSE) score measured. For patients whose cognitive function was normal, the authors retrieved the MMSE score on the seventh day after surgery and compared it to determine whether the patients had POCD. The authors used a univariate logistic regression analysis to analyze the perioperative factors in patients, namely, age, gender, history of underlying diseases, tumor size, peritumoral edema, duration of surgery, blood loss, intraoperative fluid infusion, and type of anesthetic drugs. The authors then performed a multivariate logistic regression analysis for the statistically significant factors. RESULTS: The authors found that 23 of 81 patients (28.4%) developed POCD. Univariate logistic analysis showed that a history of diabetes mellitus, peritumoral edema, intraoperative blood loss, and anesthetic drugs were the risk factors for patients developing POCD after cranial tumor surgery. Multivariate logistic regression analysis showed that a history of diabetes mellitus, peritumoral edema, and use of ciprofol as the anesthetic drug were independent risk factors for POCD after cranial tumor surgery. CONCLUSIONS: A history of diabetes mellitus, the degree of brain tumor edema, and the choice of anesthetic drugs significantly influence the occurrence of POCD in patients after cranial tumor surgery.

Clinical significance and potential mechanism of AEBP1 in glioblastoma.

Glioblastomas (GBM), the most common primary brain tumor, lack accurate prognostic markers and have a poor prognosis. Our study was designed to identify effective biomarkers for GBM prognosis analysis and development of precise treatments. Differentially expressed genes (DEGs) between GBM patients and controls were analyzed from the Xena database and GEPIA. Based on the screened DEGs, univariate COX and LASSO regression analysis were performed to identify the most relevant genes associated with GBM prognosis. Genes highly expressed in GBM patients were selected to construct receiver operating characteristic analysis and enrichment analysis was constructed on groups of high and low expression of adipocyte enhancer-binding protein 1 (AEBP1). CIBERSORT, ssGSEA and ESTIMATE were used to perform immune infiltration analysis. About 3297 DEGs were identified using data from Xena database; 8 prognostic genes were identified. AEBP1, which plays a role in neuronal differentiation and development, was positively correlated in GBMs with immune infiltration; its high expression in cancer patients is associated with short overall survival and advanced tumor staging. This study suggests that AEBP1 could serve as a prognostic marker for GBMs and that patients with high expression may have a better response to immunotherapy.

Development of parenting difficulties in infectious disease pandemic inventory.

BACKGROUND: The objective of this study was to develop the Parenting Difficulties in Infectious Disease Pandemic Inventory (PDIDPI) for the assessment of parenting difficulties during the coronavirus disease 2019 (COVID-19) pandemic and to examine its psychometric properties. METHODS: The 31-item PDIDPI was developed on the basis of the results of focus group interviews. An exploratory factor analysis using principal axis factoring was conducted to examine the PDIDPI factor structure. The internal consistency was assessed using Cronbach α values. The test-retest reliability was assessed using the intraclass correlation coefficient (ICC). The concurrent validity was established by examining the correlations of the PDIDPI with Fear of COVID-19 Scale and Center for Epidemiologic Studies Depression Scale (CESD) scores. RESULTS: We determined that the PDIDPI has seven factors: infection, school and learning, life change, care burden, daily living, health care, and emotion and behavior. The PDIDPI also had good internal consistency (α = 0.685-0.929) and acceptable test-retest reliability (ICC = 0.404-0.794). Regarding concurrent validity, the overall PDIDPI and its seven factors were all significantly associated with depression, determined by the CESD (r = 0.223-0.370), but not all factors were significantly associated with fear of COVID-19 (r = 0.082-0.203). CONCLUSIONS: Our findings support the psychometric properties of the PDIDPI, confirming its utility for evaluating the multifaceted challenges parents face in child management during the COVID-19 pandemic.

Incense-burning smoke ingredient Auramine enhances lincRNA-p21 expression for chemosensitization in p53-mutated non-small cell lung cancer.

Incense-burning smoke is a deleterious air pollutant that initiates cytotoxic effects by inducing apoptosis in lung epithelial cells and also acts as a risk factor for lung cancers. Auramine, an ingredient of incense smoke, has been implicated in tumor progression and cellular sensitivity in non-small cell lung cancer (NSCLC) towards anti-cancer agents through unclear mechanisms. Tumor protein p53 (TP53)-activated long intergenic non-coding RNA-p21 (lincRNA-p21) undertakes a pivotal role in regulating cell apoptosis and chemosensitivity. TP53 mutations prevalent in 50% of NSCLC, contribute to diminished therapeutic efficacy. However, the influence of auramine on chemotherapy-induced lincRNA-p21 expression and apoptosis in NSCLC with different TP53 genetic statuses remains unexplored. This study disclosed that both wild-type p53 (wtp53) and mutant p53 (mutp53) mediate lincRNA-p21 expression, albeit through distinct promoter enhancers, p53-response element (p53RE) and non-B DNA structure G-quadruplex (GQ), respectively. Intriguingly, auramine functions as an effective stabilizer of the GQ structure, augmenting mutp53-mediated lincRNA-p21 expression and enhancing apoptosis and cellular sensitivity to chemotherapy in mutp53-expressing NSCLC cells. These findings suggest a mechanism by which mutp53, in the presence of auramine, is endowed with tumor-suppressing function akin to wtp53, thereby aiding in combating chemoresistance in NSCLC cells harboring TP53 mutations.

Reactive Oxygen Species Responsive Multifunctional Fusion Extracellular Nanovesicles: Prospective Treatments for Acute Heart Transplant Rejection.

Heart transplantation offers life-saving treatment for patients with end-stage heart failure; however, ischemia-reperfusion injury (IRI) and subsequent immune responses remain significant challenges. Current therapies primarily target adaptive immunity, with limited options available for addressing IRI and innate immune activation. Although plant-derived vesicle-like nanoparticles show promise in managing diseases, their application in organ transplantation complications is unexplored. Here, this work develops a novel reactive oxygen species (ROS)-responsive multifunctional fusion extracellular nanovesicles carrying rapamycin (FNVs@RAPA) to address early IRI and Ly6C+Ly6G- inflammatory macrophage-mediated rejection in heart transplantation. The FNVs comprise Exocarpium Citri grandis-derived extracellular nanovesicles with anti-inflammatory and antioxidant properties, and mesenchymal stem cell membrane-derived nanovesicles expressing calreticulin with macrophage-targeting ability. A novel ROS-responsive bio-orthogonal chemistry approach facilitates the active targeting delivery of FNVs@RAPA to the heart graft site, effectively alleviating IRI and promoting the polarization of Ly6C+Ly6G- inflammatory macrophages toward an anti-inflammatory phenotype. Hence, FNVs@RAPA represents a promising therapeutic approach for mitigating early transplantation complications and immune rejection. The fusion-targeted delivery strategy offers superior heart graft site enrichment and macrophage-specific targeting, promising improved transplant outcomes.

The water extract of Rheum palmatum has antioxidative properties and inhibits ROS production in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Rheum palmatum (RP) is a widely used traditional herb, which possesses antioxidant properties, inhibits ROS production and reduces fever. AIM OF THE STUDY: The aim of this study was to examine the antioxidative properties of the water extract of RP on oxidative-stressed mice. MATERIALS & METHODS: Forty mice were administered with DL-homocysteine (DL-Hcy) to induce oxidative stress and were divided into four groups: 1) CK: NaCl and water; 2) DL-Hcy: DL-Hcy and water; 3) DL-Hcy+50RP: DL-Hcy with 50 mg kg-1 body weight (BW) d-1 RP; and 4) DL-Hcy+150RP: DL-Hcy with 150 mg kg-1 BW d-1 RP. Rhein (0.3 mg g-1 dry matter) was the main active ingredient in RP. RESULTS: When compared with Dl-Hcy mice, the mice with supplementary RP mitigated oxidative stress by reducing the liver concentrations of superoxide dismutase (SOD) by 27% and glutathione peroxidase (GSH-Px) by 32%, and the reactive oxygen species (ROS) in the kidney and spleen. These responses were more pronounced in DL-Hcy+150RP than DL-Hcy+50RP mice. RP also exhibited therapeutic effects on liver steatosis, chronic kidney nephritis and intestinal villus width shortening caused by oxidative stress, and concomitantly decreased the serum glucose concentration (RP vs. DL-HCY, 2.3 vs. 4.1 mmol L-1). CONCLUSION: It was concluded that RP possesses antioxidant and therapeutic properties that can mitigate lesions on organs and prevent diabetes in oxidative-stressed mice. This study highlights the potential of RP as a medicinal supplement for animals in the future.

Oral administration of osthole mitigates maladaptive behaviors through PPARα activation in mice subjected to repeated social defeat stress.

Psychological stress induces neuroinflammatory responses, which are associated with the pathogenesis of various psychiatric disorders, such as posttraumatic stress disorder and anxiety. Osthole-a natural coumarin isolated from the seeds of the Chinese herb Cnidium monnieri-exerts anti-inflammatory and antioxidative effects on the central nervous system. However, the therapeutic benefits of osthole against psychiatric disorders remain largely unknown. We previously demonstrated that mice subjected to repeated social defeat stress (RSDS) in the presence of aggressor mice exhibited symptoms of posttraumatic stress disorder, such as social avoidance and anxiety-like behaviors. In this study, we investigated the therapeutic effects of osthole and the underlying molecular mechanisms. Osthole exerted therapeutic effects on cognitive behaviors, mitigating anxiety-like behaviors and social avoidance in a mouse model of RSDS. The anti-inflammatory response induced by the oral administration of osthole was strengthened through the upregulation of heme oxygenase-1 expression. The expression of PPARα was inhibited in mice subjected to RSDS. Nonetheless, osthole treatment reversed the inhibition of PPARα expression. We identified a positive correlation between heme oxygenase-1 expression and PPARα expression in osthole-treated mice. In conclusion, osthole has potential as a Chinese herbal medicine for anxiety disorders. When designing novel drugs for psychiatric disorders, researchers should consider targeting the activation of PPARα.

Correlation in retinal thickness and macular retina plus choroidal microcirculation in pediatric myopia.

To analyze the relationship in retinal thickness, macula retina and choroidal microcirculation in pediatric patients with myopia. Pediatric patients with high myopia (high myopia group, n = 30, 60 eyes) and pediatric patients with low to moderate myopia (low myopia group, n = 30, 60 eyes) admitted to our hospital from January 2021 to January 2022 were randomly selected as the study subjects. Retinal thickness, the blood density of retina, and the blood density of the choroid were collected in each area of the macula by taking optical coherence tomography (OCT) and OCT angiography (OCTA). Pearson correlation analysis was conducted to compare the results from the 2 groups. Outer retinal thickness showed a weak positive correlation with Superficial vascular complex flow density (SVD) and deep vascular complex flow density (DVD) (P < .05), but no significant correlation with choroidal capillary density (P > .05); inner retinal thickness showed a weak positive correlation with SVD and DVD (P < .05), but no significant correlation with choroidal capillary density (P > .05). In pediatric patients with myopia, there is a positive correlation between the blood flow density of macular retina and retinal thickness, and the retinal thickness will become thinner with increasing myopia.

Cigarette smoke promotes IL-6-dependent lung cancer migration and osteolytic bone metastasis.

Lung cancer stands as a major contributor to cancer-related fatalities globally, with cigarette smoke playing a pivotal role in its development and metastasis. Cigarette smoke is also recognized as a risk factor for bone loss disorders like osteoporosis. However, the association between cigarette smoke and another bone loss disorder, lung cancer osteolytic bone metastasis, remains largely uncertain. Our Gene Set Enrichment Analysis (GSEA) indicated that smokers among lung cancer patients exhibited higher expression levels of bone turnover gene sets. Both The Cancer Genome Atlas (TCGA) database and our clinic samples demonstrated elevated expression of the osteolytic factor IL-6 in ever-smokers with bone metastasis among lung cancer patients. Our cellular experiments revealed that benzo[α]pyrene (B[α]P) and cigarette smoke extract (CSE) promoted IL-6 production and cell migration in lung cancer. Activation of the PI3K, Akt, and NF-κB signaling pathways was involved in cigarette smoke-augmented IL-6-dependent migration. Additionally, cigarette smoke lung cancer-secreted IL-6 promoted osteoclast formation. Importantly, blocking IL-6 abolished cigarette smoke-facilitated lung cancer osteolytic bone metastasis in vivo. Our findings provide evidence that cigarette smoke is a risk factor for osteolytic bone metastasis. Thus, inhibiting IL-6 may be a valuable therapeutic strategy for managing osteolytic bone metastasis in lung cancer patients who smoke.

A case of death after the severing three appendiceal arteries during appendectomy.

INTRODUCTION: Acute appendicitis is one of the most common acute abdominal issues requiring surgery and is usually treated by appendectomy. During the process of removing the appendix, the appendiceal artery is severed. In most individuals, the appendix is supplied by only one appendiceal artery. CASE PRESENTATION: A 50-year-old man underwent appendectomy. During the surgical procedure, the appendix artery and two accessory arteries of the appendix were severed, leading to massive hemorrhaging in the abdominal cavity, which ultimately resulted in the patient's unfortunate demise. CONCLUSION: Through this case, we hope that surgeons can learn more about the anatomy of the appendiceal artery and understand the possibility of accessory arteries to the appendix. During surgery, the blood vessels supplying the appendix should be carefully explored, and the "one-size-fits-all approach" should be avoided. Moreover, attention should be given to complications after appendectomy, and timely symptomatic treatment should be provided. Key points 1. Rare typing: The case of death due to improper handling of the accessory appendicular artery during appendectomy in patients with three appendiceal arteries is currently unreported. 2. Detailed anatomical knowledge: Surgeons performing an appendectomy need to make a detailed exploration of the blood vessel supply of the appendix to avoid ignoring anatomically different blood vessels. 3. Avoid a one-size-fits-all approach: In the surgical process, a "one-size-fits-all" approach should be avoided, that is, the same surgical approach should not be used in all cases, but should be adjusted according to the anatomical characteristics of the individual. 4. Observation of postoperative bleeding: In the perioperative period, peritoneal drainage should be closely observed. If a large amount of bloody fluid is found, timely surgical treatment should be carried out. 5. Attention to complications: Surgeons should pay.

Proteomic Stratification of Prognosis and Treatment Options for Small Cell Lung Cancer.

Small cell lung cancer (SCLC) is a highly malignant and heterogeneous cancer with limited therapeutic options and prognosis prediction models. Here, we analyzed formalin-fixed, paraffin-embedded (FFPE) samples of surgical resections by proteomic profiling, and stratified SCLC into three proteomic subtypes (S-I, S-II, and S-III) with distinct clinical outcomes and chemotherapy responses. The proteomic subtyping was an independent prognostic factor and performed better than current tumor-node-metastasis or Veterans Administration Lung Study Group staging methods. The subtyping results could be further validated using FFPE biopsy samples from an independent cohort, extending the analysis to both surgical and biopsy samples. The signatures of the S-II subtype in particular suggested potential benefits from immunotherapy. Differentially overexpressed proteins in S-III, the worst prognostic subtype, allowed us to nominate potential therapeutic targets, indicating that patient selection may bring new hope for previously failed clinical trials. Finally, analysis of an independent cohort of SCLC patients who had received immunotherapy validated the prediction that the S-II patients had better progression-free survival and overall survival after first-line immunotherapy. Collectively, our study provides the rationale for future clinical investigations to validate the current findings for more accurate prognosis prediction and precise treatments.

From Feeling Tough to Mental Growth: Coping with Sexual Bullying During Childhood in Gay and Bisexual Men.

This qualitative study was conducted to understand how gay and bisexual men (GBM) in Taiwan cope with childhood bullying because of their sexual orientation or gender nonconformity. We explored their journey from feeling disturbed to receiving social support, developing coping strategies, and achieving self-growth. Colaizzi's phenomenological approach was used to investigate subject experiences. Semi-structured interviews were conducted with 21 GBM who had experienced high-level sexual bullying in childhood. Relevant data were collected to assess their experiences of sexual bullying, their coping strategies, and subjective effects of corresponding adjustments in interpersonal interactions. Subject experiences concentrated on six themes related to sexual bullying and coping strategies: bullying at developmental stages, bullying everywhere, facing bullying alone, various impacts of bullying, overcoming challenges of interpersonal relationships, and building a strong and carefree self. Our findings can provide mental health professionals with key insights into the contexts of sexual bullying and the associated psychological distress in GBM. This study further clarifies the coping responses of these individuals and their psychological growth following such adverse experiences.

Fructus Jujubae cooperated with water-expelling members in Shizao decoction alleviated intestinal injury and malignant ascites by modulating gut microbiota and metabolic homeostasis.

BACKGROUND: Shizao decoction (SZD) consisted of Euphorbia kansui (EK), Euphorbia pekinensis (EP), Daphne genkwa (DG), and Fructus Jujubae (FJ) is a classic Chinese herbal medicine formula for treating malignant ascites, which is closely related to the modulation of gut microbiota by our previous study. For water-expelling members (WEM) including EK, EP, and DG may have side effects on the intestine, FJ is employed for detoxification and effectivity enhancement of WEM. However, the underlying mechanism for the compatibility of WEM and FJ is still unknown. PURPOSE: To investigate the effect of the compatibility of WEM with FJ in SZD on malignant ascites and elucidate the potential mechanism from the perspective of the modulation of gut microbiota and related metabolic function. METHODS: Qualitative and quantitative evaluation of main components was conducted for comprehensive characterization of SZD and WEM. The effect of WEM and SZD was compared on malignant ascites effusion (MAE) rats. The intestinal injury was evaluated by HE staining and oxidative damage. Ascites weight, urine amount, fecal water content, the expression of aquaporins, and cytokines in ascites (IL-6, VEGF, and TNF-α) were measured to estimate the water-expelling activity. The intestinal flora was detected by 16S rDNA sequencing and the content of fecal short-chain fatty acids (SCFAs) was analyzed using gas chromatography-mass spectrometry. Pseudo-germ-free (PGF) and fecal bacteria transplantation animal experiments were subsequently employed to validate this finding. The fecal metabolomics and correlation analysis were finally conducted to explore the related metabolic changes. RESULTS: 51 and 33 components were identified in SZD and WEM, respectively. Compared to WEM alone, the compatibility with FJ remarkably reduced intestinal oxidative damage in MAE rats. Ascites was also relieved by downregulating the expression of AQP3 in the colon and decreasing the levels of IL-6, TNF-α and VEGF in ascites. The diversity of gut microbiota was reversed with an increase in Lactobacillus and Clostridia_UCG-014 while a decrease in Colidextribacter. Under the PGF condition, compatibility of WEM with FJ failed to reduce intestinal injury and alleviate MA significantly, but this effect was further enhanced after FMT. 23 potential fecal metabolites were finally identified. Correlation analysis further showed that Lactobacillus and Clostridia_UCG-014 were positively correlated with SCFAs and l-tryptophan. Colidextribacter was negatively correlated with thymidine but positively correlated with ursodeoxycholic acid and deoxycholic acid. CONCLUSION: FJ cooperated with WEM reduced intestinal injury and alleviated malignant ascites by modulating gut microbiota, short-chain fatty and tryptophan metabolism. These findings provide a scientific basis for the clinical application of FJ from SZD and the safe usage of SZD.

Interplay between glypican-1, amyloid-ß and tau phosphorylation in human neural stem cells.

INTRODUCTION: Alzheimer's disease (AD) is characterized by accumulation of amyloid beta (Aß) and hyperphosphorylated tau (Tau-P) in the brain. Aß enhances the activity of kinases involved in the formation of Tau-P. Phosphorylation at Thr 181 determines the propagation of multiple tau phosphorylations. Aß is derived from the amyloid precursor protein (APP). Cleavage of APP by ß-secretase also initiates release of heparan sulfate (HS) from the proteoglycan glypican-1 (GPC1). OBJECTIVES: In this study, we have explored possible connections between GPC1 expression, HS release, APP processing and Tau-P formation in human neural stem cells. METHODS: GPC1 formation was suppressed by using CRISPR/Cas9 and increased by using a vector encoding GPC1. HS release from GPC1 was increased by growing cells in medium containing Arg and ascorbate. Effects were monitored by immunofluorescence microscopy and slot immunoblotting using antibodies/antisera recognizing Aß, GPC1, HS released from GPC1, total Tau, and Tau phosphorylated at Thr-181, 217 or 231. The latter have been used as blood biomarkers for AD. RESULTS: Suppression of GPC1 expression resulted in increased phosphorylation at Thr 181 and Thr 217. When GPC1 was overexpressed, phosphorylation at Thr 217 decreased. Stimulation of HS release from GPC1 diminished tau phosphorylation at all of the three Thr positions, while expression of GPC1 was unaffected. Simultaneous stimulation of HS release and APP processing by the cytokine TNF-α also suppressed tau phosphorylation. CONCLUSION: The increased release of GPC1-derived HS may interfere with Aß formation and/or Aß interaction with tau.

Rupestonic Acid Derivative YZH-106 Promotes Lysosomal Degradation of HBV L- and M-HBsAg via Direct Interaction with PreS2 Domain.

Hepatitis B surface antigen (HBsAg) is not only the biomarker of hepatitis B virus (HBV) infection and expression activity in hepatocytes, but it also contributes to viral specific T cell exhaustion and HBV persistent infection. Therefore, anti-HBV therapies targeting HBsAg to achieve HBsAg loss are key approaches for an HBV functional cure. In this study, we found that YZH-106, a rupestonic acid derivative, inhibited HBsAg secretion and viral replication. Further investigation demonstrated that YZH-106 promoted the lysosomal degradation of viral L- and M-HBs proteins. A mechanistic study using Biacore and docking analysis revealed that YZH-106 bound directly to the PreS2 domain of L- and M-HBsAg, thereby blocking their entry into the endoplasmic reticulum (ER) and promoting their degradation in cytoplasm. Our work thereby provides the basis for the design of a novel compound therapy to target HBsAg against HBV infection.

Repetitive Administration of Low-Dose Lipopolysaccharide Improves Repeated Social Defeat Stress-Induced Behavioral Abnormalities and Aberrant Immune Response.

Repetitive exposure of innate immune cells to a subthreshold dosage of endotoxin components may modulate inflammatory responses. However, the regulatory mechanisms in the interactions between the central nervous system (CNS) and the immune system remain unclear. This study aimed to investigate the effects of lipopolysaccharide (LPS) preconditioning in repeated social defeat stress (RSDS)-induced abnormal immune responses and behavioral impairments. This study aimed to elucidate the mechanisms that underlie the protective effects of repeated administration of a subthreshold dose LPS on behavioral impairments using the RSDS paradigm. LPS preconditioning improved abnormal behaviors in RSDS-defeated mice, accompanied by decreased monoamine oxidases and increased glucocorticoid receptor expression in the hippocampus. In addition, pre-treated with LPS significantly decreased the recruited peripheral myeloid cells (CD11b+CD45hi), mainly circulating inflammatory monocytes (CD11b+CD45hiLy6ChiCCR2+) into the brain in response to RSDS challenge. Importantly, we found that LPS preconditioning exerts its protective properties by regulating lipocalin-2 (LCN2) expression in microglia, which subsequently induces expressions of chemokine CCL2 and pro-inflammatory cytokine. Subsequently, LPS-preconditioning lessened the resident microglia population (CD11b+CD45intCCL2+) in the brains of the RSDS-defeated mice. Moreover, RSDS-associated expressions of leukocytes (CD11b+CD45+CCR2+) and neutrophils (CD11b+CD45+Ly6G+) in the bone marrow, spleen, and blood were also attenuated by LPS-preconditioning. In particular, LPS preconditioning also promoted the expression of endogenous antioxidants and anti-inflammatory proteins in the hippocampus. Our results demonstrate that LPS preconditioning ameliorates lipocalin 2-associated microglial activation and aberrant immune response and promotes the expression of endogenous antioxidants and anti-inflammatory protein, thereby maintaining the homeostasis of pro-inflammation/anti-inflammation in both the brain and immune system, ultimately protecting the mice from RSDS-induced aberrant immune response and behavioral changes.