A two-stage computational framework for identifying antiviral peptides and their functional types based on contrastive learning and multi-feature fusion strategy.

Antiviral peptides (AVPs) have shown potential in inhibiting viral attachment, preventing viral fusion with host cells and disrupting viral replication due to their unique action mechanisms. They have now become a broad-spectrum, promising antiviral therapy. However, identifying effective AVPs is traditionally slow and costly. This study proposed a new two-stage computational framework for AVP identification. The first stage identifies AVPs from a wide range of peptides, and the second stage recognizes AVPs targeting specific families or viruses. This method integrates contrastive learning and multi-feature fusion strategy, focusing on sequence information and peptide characteristics, significantly enhancing predictive ability and interpretability. The evaluation results of the model show excellent performance, with accuracy of 0.9240 and Matthews correlation coefficient (MCC) score of 0.8482 on the non-AVP independent dataset, and accuracy of 0.9934 and MCC score of 0.9869 on the non-AMP independent dataset. Furthermore, our model can predict antiviral activities of AVPs against six key viral families (Coronaviridae, Retroviridae, Herpesviridae, Paramyxoviridae, Orthomyxoviridae, Flaviviridae) and eight viruses (FIV, HCV, HIV, HPIV3, HSV1, INFVA, RSV, SARS-CoV). Finally, to facilitate user accessibility, we built a user-friendly web interface deployed at https://awi.cuhk.edu.cn/∼dbAMP/AVP/.

Predicting Anti-inflammatory Peptides by Ensemble Machine Learning and Deep Learning.

Inflammation is a biological response to harmful stimuli, aiding in the maintenance of tissue homeostasis. However, excessive or persistent inflammation can precipitate a myriad of pathological conditions. Although current treatments such as NSAIDs, corticosteroids, and immunosuppressants are effective, they can have side effects and resistance issues. In this backdrop, anti-inflammatory peptides (AIPs) have emerged as a promising therapeutic approach against inflammation. Leveraging machine learning methods, we have the opportunity to accelerate the discovery and investigation of these AIPs more effectively. In this study, we proposed an advanced framework by ensemble machine learning and deep learning for AIP prediction. Initially, we constructed three individual models with extremely randomized trees (ET), gated recurrent unit (GRU), and convolutional neural networks (CNNs) with attention mechanism and then used stacking architecture to build the final predictor. By utilizing various sequence encodings and combining the strengths of different algorithms, our predictor demonstrated exemplary performance. On our independent test set, our model achieved an accuracy, MCC, and F1-score of 0.757, 0.500, and 0.707, respectively, clearly outperforming other contemporary AIP prediction methods. Additionally, our model offers profound insights into the feature interpretation of AIPs, establishing a valuable knowledge foundation for the design and development of future anti-inflammatory strategies.

Hsa_circ_0000285-Mediated miR-599/RGS17 Axis Participates in the Pathogenesis of Abdominal Aortic Aneurysm by Regulating the Functions of Vascular Smooth Muscle Cells.

OBJECTIVE: Abdominal aortic aneurysm (AAA) is characterized by vascular smooth muscle cell (VSMC) injury. Circ_0000285 has been declared to drive cancer development, but its role in AAA remains unclear. We thus intended to disclose circ_0000285's role and molecular mechanism in AAA. METHODS: VSMCs were exposed to hydrogen peroxide (H2O2) to induce cell injury. Circ_0000285, miR-599, and regulator of G protein signaling 17 (RGS17) mRNA expressions were ascertained by conducting RT-qPCR assay while the levels of RGS17 protein was ascertained via western blotting. MiR-599's predicted binding with circ_0000285 and RGS17 were validated by means of the dual-luciferase reporter experiment. Cell proliferation was evaluated through the CCK-8 and EdU assays. Cell apoptosis was assessed via the caspase-3 activity assay. RESULTS: The AAA samples and H2O2-treated VSMCs manifested high expressions of circ_0000285 and RGS17 as well as a poor miR-599 expression. H2O2 treatment impaired the proliferation of VSMCs while stimulating their apoptosis. Circ_0000285 overexpression further repressed cell proliferation and enhanced apoptosis in H2O2-treated VSMCs while miR-599 enrichment partly reversed these effects. Circ_0000285 directly bound to miR-599, and miR-599 interacted with RGS17 3'UTR. RGS17 overexpression also suppressed cell proliferation and stimulated apoptosis in H2O2-treated VSMCs. Nevertheless, these effects were offset by miR-599 enrichment. CONCLUSION: Circ_0000285 governed the miR-599/RGS17 network to regulate H2O2-induced VSMC injuries, thereby promoting the development of AAA.

Elevated ADAM-like Decysin-1 (ADAMDEC1) expression is associated with increased chemo-sensitivity and improved prognosis in breast cancer patients.

Background: Chemoresistance is problematic and its mechanisms are unclear in breast cancer. More predictive markers are urgently required. Methods: GSE32646, GSE34138, and GSE20271 were downloaded from the Gene Expression Omnibus (GEO) database to identify differentially expressed genes (DEGs) between chemosensitive and chemoresistant tumors. LinkedOmics was used to analyze ADAM-like Decysin-1 (ADAMDEC1) expression among patients with different clinical characteristics and detect co-expression genes for functional analysis. Tumor Immune Estimation Resource (TIMER) and an integrated repository portal for tumor-immune system interactions (TISIDB) were used to investigate the association between the target gene and the immune response. Gene Set Cancer Analysis (GSCA) was utilized to explore the related pathways of ADAMDEC1 and evaluate the correlation between the expression of ADAMDEC1 and drug sensitivity. RNA22, miRWalk, and miRmap were used to predict the upstream micro ribonucleic acids (miRNAs) regulating ADAMDEC1 expression, while DIANA-LncBase v2 was applied to predict the upstream long non-coding ribonucleic acids (lncRNAs). Kaplan-Meier curve analysis was applied to determine the survival time. Results: We identified that ADAMDEC1 was upregulated among chemosensitive triple-negative breast cancer (TNBC) tissues in GSE32646, GSE34138, and GSE20271. Higher expression of ADAMDEC1 indicated longer survival in breast cancer. Next, we found that ADAMDEC1 was significantly related to the immune response in breast cancer through functional enrichment analysis and further meta-data validation. Moreover, we recognized that hsa-miR-4534 was the potential upstream miRNA regulating ADAMDEC1 expression and Taurine Up-Regulated 1 (TUG1) was the most likely upstream lncRNA of ADAMDEC1 and hsa-miR-4534. Finally, the correlation between ADAMDEC1 and chemosensitivity was confirmed through drug database analysis. Conclusions: Elevated ADAMDEC1 expression is associated with increased chemosensitivity and better prognosis in breast cancer patients.

Soluble CD163 and CD163 Expression on Monocytes Associated with Chronic Hepatitis B Inflammation and HBsAg Loss.

Background and Aims: Monocyte/macrophage-associated CD163 is an indicator of the severity of liver inflammation and cirrhosis, but the difference of soluble CD163 (sCD163) levels in chronic hepatitis B (CHB) patients and hepatitis B surface antigen (HBsAg)-loss patients is unclear. Herein, we aimed to compare the sCD163 levels in CHB patients and HBsAg-loss patients with or without antiviral treatment. Methods: sCD163 and CD163 expression on monocytes were compared among four groups, healthy subjects, treatment-naïve CHB patients, spontaneous HBsAg-loss patients, and treatment-related HBsAg-loss patients. The correlation between sCD163 levels and clinical parameters in CHB patients was analyzed. A group of 80 patients with hepatitis B virus (HBV) infection and liver biopsy were recruited. Results: sCD163 levels were higher in the CHB group than in the other three groups. sCD163 levels were higher in treatment-related HBsAg-loss patients than in spontaneous HBsAg-loss patients. sCD163 levels were negatively correlated with hepatitis B e-antigen (HBeAg) and HBsAg levels in HBeAg-positive patients. Liver biopsy results further demonstrated that sCD163 levels were elevated in CHB patients with substantial inflammation (A≥2) or fibrosis (F≥2). The sCD163 model was more sensitive in predicting inflammation than other noninvasive models. Its levels were higher in patients with normal alanine aminotransferase levels and significant inflammation (A≥2) than in patients with no or mild inflammation. Conclusions: sCD163 and CD163 expression on monocytes were associated with CHB inflammation and HBsAg loss, and may be used as markers to predict HBV-specific immune activation.

Hepatitis B virus middle surface antigen loss promotes clinical variant persistence in mouse models.

Hepatitis B virus (HBV) middle surface antigen (MHBs) mutation or deletion occurs in patients with chronic HBV infection. However, the functional role of MHBs in HBV infection is still an enigma. Here, we reported that 7.33% (11/150) isolates of CHB patients had MHBs start codon mutations compared with 0.00% (0/146) in acute hepatitis B (AHB) patients. Interestingly, MHBs loss accounted for 11.88% (126/1061) isolates from NCBI GenBank, compared with 0.09% (1/1061) and 0.00% (0/1061) for HBV large surface antigen (LHBs) loss and HBV small surface antigen (SHBs) loss, respectively. One persistent HBV clone of genotype B (B56, MHBs loss) from a CHB patient was hydrodynamically injected into BALB/c mice. B56 persisted for >70 weeks in BALB/c mice, whereas B56 with restored MHBs (B56M+) was quickly cleared within 28 days. Serum cytokine assays demonstrated that CXCL1, CXCL2, IL-6 and IL-33 were significantly increased during rapid HBV clearance in B56M+ mice. Furthermore, the enhancers and promoters of B56 were proved to be required for B56 persistence in mice. Ablating MHBs expression improved the persistence of a new clone (HBV1.3, genotype B) which was recreated by using enhancers and promoters of B56. These data demonstrated that MHBs deletion can promote the persistence of specific HBV variants in a hydrodynamic mouse model. MHBs re-expression restored a rapid clearance of HBV, which was accompanied by cytokine responses including the elevation of CXCL1, CXCL2, IL-6 and IL-33.

CaMK4 is a downstream effector of the α1G T-type calcium channel to determine the angiogenic potential of pulmonary microvascular endothelial cells.

Pulmonary microvascular endothelial cells (PMVECs) uniquely express an α1G-subtype of voltage-gated T-type Ca2+ channel. We have previously revealed that the α1G channel functions as a background Ca2+ entry pathway that is critical for the cell proliferation, migration, and angiogenic potential of PMVECs, a novel function attributed to the coupling between α1G-mediated Ca2+ entry and constitutive Akt phosphorylation and activation. Despite this significance, mechanism(s) that link the α1G-mediated Ca2+ entry to Akt phosphorylation remain incompletely understood. In this study, we demonstrate that Ca2+/calmodulin-dependent protein kinase (CaMK) 4 serves as a downstream effector of the α1G-mediated Ca2+ entry to promote the angiogenic potential of PMVECs. Notably, CaMK2 and CaMK4 are both expressed in PMVECs. Pharmacological blockade or genetic knockdown of the α1G channel led to a significant reduction in the phosphorylation level of CaMK4 but not the phosphorylation level of CaMK2. Pharmacological inhibition as well as genetic knockdown of CaMK4 significantly decreased cell proliferation, migration, and network formation capacity in PMVECs. However, CaMK4 inhibition or knockdown did not alter Akt phosphorylation status in PMVECs, indicating that α1G/Ca2+/CaMK4 is independent of the α1G/Ca2+/Akt pathway in sustaining the cells' angiogenic potential. Altogether, these findings suggest a novel α1G-CaMK4 signaling complex that regulates the Ca2+-dominated angiogenic potential in PMVECs.

An integrative pan-cancer analysis of COPB1 based on data mining.

BACKGROUND: Cancer will become the leading cause of death worldwide in the 21st century, meanwhile, immunotherapy is the most popular cancer treatment method in recent years. COPI Coat Complex Subunit Beta 1 (COPB1) relates to human innate immunity. However, the role of COPB1 in pan-cancer remains unclear. OBJECTIVE: The purpose of this study was to explore the relationship between COPB1 mRNA expression and tumor infiltrating lymphocytes and immune examination sites in pan-cancer. METHODS: Data from multiple online databases were collected. The BioGPS, UALCAN Database, COSMIC, cBioPortal, Cancer Regulome tools, Kaplan-Meier Plotter and TIMER website were utilized to perform the analysis. RESULTS: Upregulation of COPB1 has been widely observed in tumor tissues compared with normal tissues. Although COPB1 has poor prognosis in pan-cancer, COPB1 high expression was beneficial to the survival of ESCA patients. Unlike ESCA, COPB1 expression in STAD was positively correlated with tumor infiltrating lymphocytes, including B cells, CD8+ T cells, neutrophils, macrophages, and dendritic cells. Finally, we also found that the expression of COPB1 in STAD was positively correlated with PD-L1 and CTLA4. CONCLUSIONS: COPB1 may be a prognostic biomarker for pan-carcinoma, and also provide an immune anti-tumor strategy for STAD based on the expression of COPB1.

α1G T-type calcium channel determines the angiogenic potential of pulmonary microvascular endothelial cells.

Pulmonary microvascular endothelial cells (PMVECs) display a rapid angioproliferative phenotype, essential for maintaining homeostasis in steady-state and promoting vascular repair after injury. Although it has long been established that endothelial cytosolic Ca2+ ([Ca2+]i) transients are required for proliferation and angiogenesis, mechanisms underlying such regulation and the transmembrane channels mediating the relevant [Ca2+]i transients remain incompletely understood. In the present study, the functional role of the microvascular endothelial site-specific α1G T-type Ca2+ channel in angiogenesis was examined. PMVECs intrinsically possess an in vitro angiogenic "network formation" capacity. Depleting extracellular Ca2+ abolishes network formation, whereas blockade of vascular endothelial growth factor receptor or nitric oxide synthase has little or no effect, suggesting that the network formation is a [Ca2+]i-dependent process. Blockade of the T-type Ca2+ channel or silencing of α1G, the only voltage-gated Ca2+ channel subtype expressed in PMVECs, disrupts network formation. In contrast, blockade of canonical transient receptor potential (TRP) isoform 4 or TRP vanilloid 4, two other Ca2+ permeable channels expressed in PMVECs, has no effect on network formation. T-type Ca2+ channel blockade also reduces proliferation, cell-matrix adhesion, and migration, three major components of angiogenesis in PMVECs. An in vivo study demonstrated that the mice lacking α1G exhibited a profoundly impaired postinjury cell proliferation in the lungs following lipopolysaccharide challenge. Mechanistically, T-type Ca2+ channel blockade reduces Akt phosphorylation in a dose-dependent manner. Blockade of Akt or its upstream activator, phosphatidylinositol-3-kinase (PI3K), also impairs network formation. Altogether, these findings suggest a novel functional role for the α1G T-type Ca2+ channel to promote the cell's angiogenic potential via a PI3K-Akt signaling pathway.

Penehyclidine effects the angiogenic potential of pulmonary microvascular endothelial cells.

The present study sought to determine the pharmacological effects of penehyclidine, an anticholinergic agent, on the angiogenic capacity of pulmonary microvascular endothelial cells (PMVECs). In vitro Matrigel network formation assay, cell proliferation assay, cell-matrix adhesion assay, and wound-healing assay were performed in PMVECs with or without exposure to penehyclidine or, in some cases, glycopyrrolate or acetylcholine, over a concentration range. In addition, the phosphorylation state of Akt and ERK, as well as the endogenous level of mTOR and RICTOR were examined in PMVECs by Western blot following the cells exposure to penehyclidine or, for some proteins, glycopyrrolate or acetylcholine. Finally, Western blot for Akt phosphorylation and in vitro Matrigel network formation assay were performed in PMVECs following their exposure to penehyclidine with or without phosphoinositide 3-kinase (PI3K) inhibitor LY294002 or mTOR inhibitor torin-1. We found that, in PMVECs, penehyclidine affected the network formation and cell migration, but not proliferation or cell-matrix adhesion, in a concentration-specific manner, i.e., penehyclidine increased the network formation and cell migration at lower concentrations but increased these processes at higher concentrations. Coincidentally, we observed that penehyclidine concentration-specifically affected the phosphorylation state of Akt in PMVECs, i.e., increased Akt phosphorylation at lower concentrations and decreased it at higher concentrations. In contrast, glycopyrrolate was found straightly to decrease network formation and Akt phosphorylation in a concentration-dependent manner. Further, we demonstrated that PI3K or mTOR blockade abolished both the enhanced network formation and the increased Akt phosphorylation by penehyclidine. Hence, penehyclidine may differentially alter the angiogenic capacity of PMVECs through affecting the Akt signaling pathway downstream of PI3K and mTOR. Findings from this study suggest a unique pharmacological feature of penehyclidine, which may imply its clinical and therapeutic value in modulating angiogenesis.

[Effects of nerve growth factor-insulin composite gel on deep second degree scald wound healing in diabetic rats].

OBJECTIVE: To prepare nerve growth factor (NGF)-insulin composite gel and observe the effects of NGF-insulin composite gel on deep second degree scald wound healing in diabetic rats. METHODS: Carbomer 980, NGF (4 000 U), and insulin (800 U) were used to prepare the insulin gel, NGF gel, and NGF-insulin composite gel. The character of NGF-insulin composite gel was observed, and the in vitro drug release was tested. Seventy-five SPF Wistar male rats, weighing 200-250 g, were divided into 5 groups randomly, 15 rats each group: normal control group (group A), diabetes control group (group B), insulin gel treatment group (group C), NGF gel treatment group (group D), and NGF-insulin composite gel treatment group (group E). The type 1 diabetes rat model was established by intraperitoneal injection of Streptozotocin (55 mg/kg) in groups B, C, D, and E, while the rats in group A were injected with the same dose of citric acid and calcium citrate buffer. After modeling success, deep second degree scald wound on the back was made with constant temperature water bath box. Wounds were treated with carbomer blank gel in groups A and B, with insulin composite gel in group C, with NGF gel in group D, and with NGF-insulin composite gel in group E, once a day. At 3, 7, 11, 15, and 21 days after injury, the scald wound healing was observed and healing rate was calculated; the full-thickness skin specimens were harvested from 3 rats of each group for histological and immuohistochemical staining observation. RESULTS: The NGF-insulin composite gel was clear and transparent, and had good moisture retention capacity and adhesion; it was easy to apply and clean up. The drug release in vitro lasted more than 24 hours and maintained for 30 days. No rat died during the experiment. At 3 days after injury, wound area did not reduce in all groups; at 7, 11, 15, and 21 days, group E had the highest wound healing rate, and group B had the lowest; significant differences were found between group E and group B and when compared with the other groups (P < 0.05). HE staining showed that group E surpassed other groups in the growth of granulation tissue and collagen fiber. Immunohistochemical results showed that the CD34 and proliferating cell nuclear antigen (PCNA) expressed at 3 days, and the number of positive cells increased gradually with time; the microvessel density and PCNA expression were highest in group E and were lowest in group B, showing significant differences when compared with the other groups and between group E and group B (P < 0.05). CONCLUSION: NGF-insulin composite gel can improve deep second degree scald wound healing in diabetic rats.

[Effects of nerve growth factor mixed insulin on angiogenesis of burn wounds and expressions of Bcl-2 and Bax in diabetic rats].

OBJECTIVE: To explore the possible mechanism of nerve growth factor (NGF) mixed insulin on the angiogenesis of burn wounds and the effect on the expressions of Bcl-2 and Bax in diabetic rats. METHODS: A total of 75 SPF male Wistar rats, weighing 200-220 g, were selected randomly and divided into nomal control (group A, n = 15), the rats with diabetic control (group B, n = 15), insulin treatment (group C, n = 15), NGF treatment (group D, n = 15), NGF and insulin treatment (group E, n = 15) groups. In groups B, C, D, and E, streptozotocin was given by intraperitoneal injection at dose of 10 mg/kg on the 1st day and 50 mg/kg on the 3rd day to prepare the diabetic rat models. In group A, citric acid buffer at the same dose was given. After 1 month of diabetic models, second degree scald was made on the back of the rats, and then wounds were treated with 3-layer normal saline gauze in groups A and B, with 3-layer gauze containing 5 U Novolin 30R and subcutaneous injection of Novolin 30R (4-6 U/kg) everyday in group C, with 3-layer gauze containing 5 mL NGF (25 U/mL) in group D, and with a combination of groups C and D in group E. At 7, 11, 15, and 21 days, the wound healing rate was calculated; at 3, 7, 11, 15, and 21 days, the expressions of Bcl-2, Bax, and CD34 were determined and the microvascular density was measured by immunohistochemistry staining. RESULTS: All rats survived till experiment was finished. The area of wounds became smaller gradually with time. Group E was better than other groups in the wound healing rate (P < 0.05), the skin keratosis, the hair growth, and the granulation tissue and collagen fibers growth. With time, the expressions of CD34 and Bcl-2 increased gradually, reached the peak at 15 days and decreased at 21 days; the expression was stronger in group E than in other groups (P < 0.05). At 3 days, Bax did not express; at 7 days, Bax began to express in new vascular endothelial cells and the expression increased gradually with time; the expression was weaker in group E than in other groups (P < 0.05). CONCLUSION: A combination of NGF and insulin local application can enhance the angiogenesis of the burn wound in diabetic rats and accelerate wound healing by increasing the expression of Bcl-2 and decreasing the expression of Bax and restraining apoptosis of the wounds vascular endothelial cells of diabetic rats.