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Different kinds of biological databases publicly available nowadays provide us a goldmine of multidiscipline big data. The Cancer Genome Atlas is a cancer database including detailed information of many patients with cancer. DrugBank is a database including detailed information of approved, investigational and withdrawn drugs, as well as other nutraceutical and metabolite structures. PubChem is a chemical compound database including all commercially available compounds as well as other synthesisable compounds. Protein Data Bank is a crystal structure database including X-ray, cryo-EM and nuclear magnetic resonance protein three-dimensional structures as well as their ligands. On the other hand, artificial intelligence (AI) is playing an important role in the drug discovery progress. The integration of such big data and AI is making a great difference in the discovery of novel targeted drug. In this review, we focus on the currently available advanced methods for the discovery of highly effective lead compounds with great absorption, distribution, metabolism, excretion and toxicity properties.

Human retroviruses, including human T cell leukemia virus type 1 (HTLV-1) and HIV type 1 (HIV-1), encode an antisense gene in the negative strand of the provirus. Besides coding for proteins, the messenger RNAs (mRNAs) of retroviral antisense genes have also been found to regulate transcription directly. Thus, it has been proposed that retroviruses likely localize their antisense mRNAs to the nucleus in order to regulate nuclear events; however, this opposes the coding function of retroviral antisense mRNAs that requires a cytoplasmic localization for protein translation. Here, we provide direct evidence that retroviral antisense mRNAs are localized predominantly in the nuclei of infected cells. The retroviral 3′ LTR induces inefficient polyadenylation and nuclear retention of antisense mRNA. We further reveal that retroviral antisense RNAs retained in the nucleus associate with chromatin and have transcriptional regulatory function. While HTLV-1 antisense mRNA is recruited to the promoter of C-C chemokine receptor type 4 (CCR4) and enhances transcription from it to support the proliferation of HTLV-1–infected cells, HIV-1 antisense mRNA is recruited to the viral LTR and inhibits sense mRNA expression to maintain the latency of HIV-1 infection. In summary, retroviral antisense mRNAs are retained in nucleus, act like long noncoding RNAs instead of mRNAs, and contribute to viral persistence.

Renal fibrosis commonly occurs in the process of chronic kidney diseases. Here, we explored the role of Jumonji domain containing 3 (Jmjd3)/interferon regulatory factor 4 (IRF4) axis in activation of myeloid fibroblasts and transition of M2 macrophages into myofibroblasts transition (M2MMT) in kidney fibrosis. In mice, Jmjd3 and IRF4 were highly induced in interstitial cells of kidneys with folic acid or obstructive injury. Jmjd3 deletion in myeloid cells or Jmjd3 inhibitor reduced the levels of IRF4 in injured kidneys. Myeloid Jmjd3 depletion impaired bone marrow-derived fibroblasts activation and M2MMT in folic acid or obstructive nephropathy, resulting in reduction of extracellular matrix (ECM) proteins expression, myofibroblasts formation and renal fibrosis progression. Pharmacological inhibition of Jmjd3 also prevented myeloid fibroblasts activation, M2MMT, and kidney fibrosis development in folic acid nephropathy. Furthermore, IRF4 disruption inhibited myeloid myofibroblasts accumulation, M2MMT, ECM proteins accumulation, and showed milder fibrotic response in obstructed kidneys. Bone marrow transplantation experiment showed that wild-type mice received IRF4 -/- bone marrow cells presented less myeloid fibroblasts activation in injured kidneys and exhibited much less kidney fibrosis after unilateral ureteral obstruction. Myeloid Jmjd3 deletion or Jmjd3 inhibitor attenuated expressions of IRF4, α-smooth muscle actin and fibronectin and impeded M2MMT in cultured monocytes exposed to IL-4. Conversely, overexpression IRF4 abrogated the effect of myeloid Jmjd3 deletion on M2MMT. Thus, Jmjd3/IRF4 signaling has a crucial role in myeloid fibroblasts activation, M2 macrophages to myofibroblasts transition, extracellular matrix protein deposition, and kidney fibrosis progression.

HTLV-1 is an oncovirus that encodes a transactivator Tax and a regulatory gene HBZ. HTLV-1 early or infectious replication depends on Tax; during HTLV-1 late infection, HBZ plays a crucial role in driving the proliferation of infected cells and maintaining viral persistence. The biphasic replication pattern of HTLV-1 dictated by Tax and HBZ represents a result of viral host adaptation, but how HTLV-1 coordinates Tax and HBZ expression to facilitate early and late infection remains elusive. Here we reveal that HBZ RNA splicing exhibits distinct patterns in Tax+ and Tax- HTLV-1 infected cells. We demonstrate that Tax interacts with the host spliceosome and inhibits HBZ splicing by competitively binding splicing factors including WDR83 and GPATCH1. As a result, Tax confers a natural constraint on HBZ, counterbalancing its anti-replication effect at HTLV-1 early infection, while unleashing HBZ to drive HTLV-1 mitotic propagation during late infection. The splicing-dependent restriction of HBZ by Tax thus represents a critical interplay central to HTLV-1 persistence.

Background Dorsal flap based on proper digital artery perforator has been commonly used in wound coverage of fingertip; yet a small diameter and short length poses a risk of pedicle kinking or occlusion. The present study aims to present our preliminary results of using a double-pivot perforator flap based on the end dorsal branch of proper digital artery to repair finger pulp defect. Methods We designed a double-pivot flap based on the end-dorsal perforator branch of proper digital artery, raised from the dorsal aspect of the middle phalanx, with inclusion of both the perforator and a section of the trunk of the artery. This modified procedure forms a pedicle with a larger diameter and length than traditional designs. Twelve patients (12 fingers) each with a soft-tissue defect of the fingertip were successfully treated and followed up in this retrospective study. Results All the flaps survived without showing any signs of necrosis; three cases presented with transient venous flow disorder, these self-resolving without requiring any additional treatment. At final follow-up (12–33 months, mean 20 months), mean static two-point discrimination on the flap was 7.0 mm (range, 6–9). Conclusion The double-pivot proper digital artery flap serves as a reliable option in fingertip reconstruction offering added benefits of having greater rotation flexibility, a lower risk of vessel kinking or occlusion, and good recovery of cutaneous sensation.

Hypertension-induced renal injury is characterized by robust inflammation and tubulointerstitial fibrosis. Jumonji domain containing-3 (JMJD3) is closely linked with inflammatory response and fibrogenesis. Here we examined the effect of myeloid JMJD3 ablation on kidney inflammation and fibrosis in deoxycorticosterone acetate (DOCA)/salt hypertension. Our results showed that JMJD3 is notably induced in the kidneys with hypertensive injury. DOCA/salt stress causes an elevation in blood pressure that was no difference between myeloid specific JMJD3-deficient mice and wild-type control mice. Compared with wild-type control mice, myeloid JMJD3 ablation ameliorated kidney function and injury of mice in response to DOCA/salt challenge. Myeloid JMJD3 ablation attenuated collagen deposition, extracellular matrix proteins expression, and fibroblasts activation in injured kidneys following DOCA/salt treatment. Furthermore, myeloid JMJD3 ablation blunts inflammatory response in injured kidneys after DOCA/salt stress. Finally, myeloid JMJD3 ablation precluded myeloid myofibroblasts activation and protected against macrophages to myofibroblasts transition in injured kidneys. These beneficial effects were accompanied by reduced expression of interferon regulator factor 4. In summary, JMJD3 ablation in myeloid cells reduces kidney inflammation and fibrosis in DOCA salt-induced hypertension. Inhibition of myeloid JMJD3 may be a novel potential therapeutic target for hypertensive nephropathy. Myeloid JMJD3 deficiency reduces inflammatory response, myeloid fibroblasts activation, macrophages to myofibroblasts transition, and delays kidney fibrosis progression.

The discovery of targeted drugs heavily relies on three-dimensional (3D) structures of target proteins. When the 3D structure of a protein target is unknown, it is very difficult to design its corresponding targeted drugs. Although the 3D structures of some proteins (the so-called undruggable targets) are known, their targeted drugs are still absent. As increasing crystal/cryogenic electron microscopy structures are deposited in Protein Data Bank, it is much more possible to discover the targeted drugs. Moreover, it is also highly probable to turn previous undruggable targets into druggable ones when we identify their hidden allosteric sites. In this review, we focus on the currently available advanced methods for the discovery of novel compounds targeting proteins without 3D structure and how to turn undruggable targets into druggable ones.

Advancing renal fibrosis is the common histopathological feature of chronic obstructive nephropathy, representing the final pathway of nearly all chronic and progressive nephropathies. Increasing evidences suggest that circular RNAs (circRNAs) are crucial regulatory molecules present at virtually every level of the cellular pathophysiological process. Nonetheless, there are a few evidences for the role of circRNAs in renal fibrosis induced by obstructive nephropathy. We performed RNA-seq analysis to analyze the expression profiles of circRNAs in the obstructed kidneys to identify the potential circRNAs and their network. With silk ligated the left ureter to establish a mice unilateral ureteral obstruction (UUO) model. Renal tissue circRNAs were obtained and were screened by a circRNA microarray. The circRNA-miRNA-mRNA regulatory network and the target genes were visualized using Cytoscape software. The microarray results showed that 5454 and 2935 circRNAs were detected in the control and UUO group, respectively. There were 605 circRNAs up-regulated and 745 circRNAs down-regulated in the obstructive kidneys. The top 5 up-regulated and down-regulated circRNAs were chosen for predicting the circRNA/miRNA/target mRNAs triple network. The GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) analysis showed that these circRNAs and the triple network were enriched in the process of apoptosis, p53 signaling pathway, cell growth and cell death, which might participate in the pathogenesis of obstructive nephrology. Our results show that the dis-regulated circRNAs might play crucial roles in the pathogenesis of obstructive nephropathy, which proceeds to identify novel therapeutic targets for chronic kidney disease.

Local anesthetics in spinal anesthesia have neurotoxic effects, resulting in severe neurological complications. Intrathecal monosialoganglioside (GM1) administration has a therapeutic effect on bupivacaine-induced neurotoxicity. The aim of this study was to determine the underlying mechanisms of bupivacaine-induced neurotoxicity and the potential neuroprotective role of GM1. A rat spinal cord neurotoxicity model was established by injecting bupivacaine (5%, 0.12 μL/g) intrathecally. The protective effect of GM1 (30 mg/kg) was evaluated by pretreating the animals with it prior to the bupivacaine regimen. The neurological and locomotor functions were assessed using standard tests. The histomorphological changes, neuron degeneration and apoptosis, and endoplasmic reticulum stress (ERS) relevant markers were analyzed using immunofluorescence, quantitative real-time PCR, and Western blotting. Bupivacaine resulted in significant neurotoxicity in the form of aberrant neurolocomoter functions and spinal cord histomorphology and neuronal apoptosis. Furthermore, the ERS specific markers were significantly upregulated during bupivacaine-induced neurotoxicity. These neurotoxic effects were ameliorated by GM1. Pretreatment with GM1 protects against bupivacaine-induced neurotoxicity via the inhibition of the GRP78/PERK/eIF2α/ATF4-mediated ERS.

Esophageal squamous cell carcinoma (ESCC) accounts for over 90% of all esophageal tumors. However, the molecular mechanism underlying ESCC development and prognosis remains unclear, and there are still no effective molecular biomarkers for diagnosing or predicting the clinical outcome of patients with ESCC. Here, using bioinformatics analyses, we attempted to identify potential biomarkers and therapeutic targets for ESCC. Differentially expressed genes (DEGs) between ESCC and normal esophageal tissue samples were obtained through comprehensive analysis of three publicly available gene expression profile datasets from the Gene Expression Omnibus database. The biological roles of the DEGs were identified by Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Moreover, the Cytoscape 3.7.1 platform and subsidiary tools such as Molecular Complex Detection (MCODE) and CytoHubba were used to visualize the protein-protein interaction (PPI) network of the DEGs and identify hub genes. A total of 345 DEGs were identified between normal esophageal and ESCC samples, which were enriched in the KEGG pathways of the cell cycle, endocytosis, pancreatic secretion, and fatty acid metabolism. Two of the highest scoring models were selected from the PPI network using Molecular Complex Detection. Moreover, CytoHubba revealed 21 hub genes with a valuable influence on the progression of ESCC in these patients. Among these, the high expression levels of five genes—SPP1, SPARC, BGN, POSTN, and COL1A2—were associated with poor disease-free survival of ESCC patients, as indicated by survival analysis. Taken together, we identified that elevated expression of five hub genes, including SPP1, is associated with poor prognosis in ESCC patients, which may serve as potential prognostic biomarkers or therapeutic target for ESCC.