Natural products in traditional Chinese medicine: molecular mechanisms and therapeutic targets of renal fibrosis and state-of-the-art drug delivery systems.

Renal fibrosis (RF) is the end stage of several chronic kidney diseases. Its series of changes include excessive accumulation of extracellular matrix, epithelial-mesenchymal transition (EMT) of renal tubular cells, fibroblast activation, immune cell infiltration, and renal cell apoptosis. RF can eventually lead to renal dysfunction or even renal failure. A large body of evidence suggests that natural products in traditional Chinese medicine (TCM) have great potential for treating RF. In this article, we first describe the recent advances in RF treatment by several natural products and clarify their mechanisms of action. They can ameliorate the RF disease phenotype, which includes apoptosis, endoplasmic reticulum stress, and EMT, by affecting relevant signaling pathways and molecular targets, thereby delaying or reversing fibrosis. We also present the roles of nanodrug delivery systems, which have been explored to address the drawback of low oral bioavailability of natural products. This may provide new ideas for using natural products for RF treatment. Finally, we provide new insights into the clinical prospects of herbal natural products.

POLE3 is a repressor of unintegrated HIV-1 DNA required for efficient virus integration and escape from innate immune sensing.

Unintegrated retroviral DNA is transcriptionally silenced by host chromatin silencing factors. Here, we used the proteomics of isolated chromatin segments method to reveal viral and host factors associated with unintegrated HIV-1DNA involved in its silencing. By gene silencing using siRNAs, 46 factors were identified as potential repressors of unintegrated HIV-1DNA. Knockdown and knockout experiments revealed POLE3 as a transcriptional repressor of unintegrated HIV-1DNA. POLE3 maintains unintegrated HIV-1DNA in a repressive chromatin state, preventing RNAPII recruitment to the viral promoter. POLE3 and the recently identified host factors mediating unintegrated HIV-1 DNA silencing, CAF1 and SMC5/SMC6/SLF2, show specificity toward different forms of unintegrated HIV-1DNA. Loss of POLE3 impaired HIV-1 replication, suggesting that repression of unintegrated HIV-1DNA is important for optimal viral replication. POLE3 depletion reduces the integration efficiency of HIV-1. POLE3, by maintaining a repressive chromatin structure of unintegrated HIV-1DNA, ensures HIV-1 escape from innate immune sensing in primary CD4+ T cells.

Understanding latent HIV-1 reservoirs through host genomics approaches.

Genetically intact HIV-1 proviruses are a major concern with regard to curing infection because they cause viral rebound after the cessation of antiretroviral therapy. However, intact proviruses are not prevalent in HIV-1 reservoirs. As such, it is essential to precisely determine the position of these proviruses before putting forward a better antiretroviral cure. Recently, a revised HIV-1 deeply latent reservoir concept has been proposed, stating that the progress of the establishment of HIV-1 reservoirs is influenced by immune-mediated selection during the course of infection. This selection force leads to the persistence of genetically intact proviruses as those with the best fit to avoid clearance. This hypothesis refreshes our understanding of HIV-1 latent reservoirs. For this reason, we reviewed current studies relevant to this theme and provide our perspectives to reinforce the overall understanding of HIV-1 latency in the context of the host genome.

A systematic review of the barcoding strategy that contributes to COVID-19 diagnostics at a population level.

The outbreak of SARS-CoV-2 has made us more alert to the importance of viral diagnostics at a population level to rapidly control the spread of the disease. The critical question would be how to scale up testing capacity and perform a diagnostic test in a high-throughput manner with robust results and affordable costs. Here, the latest 26 articles using barcoding technology for COVID-19 diagnostics and biologically-relevant studies are reviewed. Barcodes are molecular tags, that allow proceeding an array of samples at once. To date, barcoding technology followed by high-throughput sequencing has been made for molecular diagnostics for SARS-CoV-2 infections because it can synchronously analyze up to tens of thousands of clinical samples within a short diagnostic time. Essentially, this technology can also be used together with different biotechnologies, allowing for investigation with resolution of single molecules. In this Mini-Review, I first explain the general principle of the barcoding strategy and then put forward recent studies using this technology to accomplish COVID-19 diagnostics and basic research. In the meantime, I provide the viewpoint to improve the current COVID-19 diagnostic strategy with potential solutions. Finally, and importantly, two practical ideas about how barcodes can be further applied in studying SARS-CoV-2 to accelerate our understanding of this virus are proposed.

The Dynamic Linkage between Provirus Integration Sites and the Host Functional Genome Property Alongside HIV-1 Infections Associated with Antiretroviral Therapy.

(1) Background: The HIV-1 latent reservoir harboring replication-competent proviruses is the major barrier in the quest for an HIV-1 infection cure. HIV-1 infection at all stages of disease progression is associated with immune activation and dysfunctional production of proinflammatory soluble factors (cytokines and chemokines), and it is expected that during HIV-1 infection, different immune components and immune cells, in turn, participate in immune responses, subsequently activating downstream biological pathways. However, the functional interaction between HIV-1 integration and the activation of host biological pathways is presently not fully understood. (2) Methods: In this work, I used genes targeted by proviruses from published datasets to seek enriched immunologic signatures and host biological pathways alongside HIV-1 infections based on MSigDb and KEGG over-representation analysis. (3) Results: I observed that different combinations of immunologic signatures of immune cell types and proinflammatory soluble factors appeared alongside HIV-1 infections associated with antiretroviral therapy. Moreover, enriched KEGG pathways were often related to "cancer specific types", "immune system", "infectious disease viral", and "signal transduction". (4) Conclusions: The observations in this work suggest that the gene sets harboring provirus integration sites may define specific immune cells and proinflammatory soluble factors during HIV-1 infections associated with antiretroviral therapy.

MicroRNA schizophrenia: Etiology, biomarkers and therapeutic targets.

The three sets of symptoms associated with schizophrenia-positive, negative, and cognitive-are burdensome and have serious effects on public health, which affects up to 1% of the population. It is now commonly believed that in addition to the traditional dopaminergic mesolimbic pathway, the etiology of schizophrenia also includes neuronal networks, such as glutamate, GABA, serotonin, BDNF, oxidative stress, inflammation and the immune system. Small noncoding RNA molecules called microRNAs (miRNAs) have come to light as possible participants in the pathophysiology of schizophrenia in recent years by having an impact on these systems. These small RNAs regulate the stability and translation of hundreds of target transcripts, which has an impact on the entire gene network. There may be improved approaches to treat and diagnose schizophrenia if it is understood how these changes in miRNAs alter the critical related signaling pathways that drive the development and progression of the illness.

Study on the application of model transfer technology in the extraction process of Xiao'er Xiaoji Zhike oral liquid / 药学学报

The modernization and development of traditional Chinese medicine has led to higher standards for the quality of traditional Chinese medicine products. The extraction process is a crucial component of traditional Chinese medicine production, and it directly impacts the final quality of the product. However, the currently relied upon methods for quality assurance of the extraction process, such as simple wet chemical analysis, have several limitations, including time consumption and labor intensity, and do not offer precise control of the extraction process. As a result, there is significant value in incorporating near-infrared spectroscopy (NIRS) in the production process of traditional Chinese medicine to improve the quality control of the final products. In this study, we focused on the extraction process of Xiao'er Xiaoji Zhike oral liquid (XXZOL), using near-infrared spectra collected by both a Fourier transform near-infrared spectrometer and a portable near-infrared spectrometer. We used the concentration of synephrine, a quality control index component specified by the pharmacopoeia, to achieve rapid and accurate detection in the extraction process. Moreover, we developed a model transfer method to facilitate the transfer of models between the two types of near-infrared spectrometers (analytical grade and portable), thus resolving the low resolution, poor performance, and insufficient prediction accuracy issues of portable instruments. Our findings enable the rapid screening and quality analysis of XXZOL onsite, which is significant for quality monitoring during the traditional Chinese medicine production process.

Anti-inflammatory and antioxidant activity of astragalus polysaccharide in ulcerative colitis: A systematic review and meta-analysis of animal studies.

Background: Accumulated evidence indicates that astragalus polysaccharide (APS) may have a beneficial impact on ulcerative colitis (UC) by suppressing inflammation and decreasing oxidative stress. Nevertheless, the credibility of the evidence for this practice is unclear. Therefore, we intended to conduct a systematic review and meta-analysis of animal studies to assess the anti-inflammatory and antioxidant activity of APS when used in the treatment of UC. Methods: Electronic bibliographic databases including PubMed, EMBASE, Web of Science, Chinese Biomedical Literature (CBM), Wanfang Database, CQVIP Database and China National Knowledge Infrastructure (CNKI) were retrieved for relevant animal studies. The methodological quality of animal studies was evaluated based on the SYstematic Review Center for Laboratory animal Experimentation (SYRCLE's RoB tool). A meta-analysis was performed according to the Cochrane Handbook for Systematic Reviews of Interventions by using STATA 12.0 software. This study was registered with PROSPERO, number CRD42021272595. Results: Twenty qualified publications involving 591 animals were included in this study. There was a significant association of APS with levels of disease activity index (DAI), colon macroscopic damage index (CMDI), colon histopathologic score (CHS), myeloperoxidase (MPO), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1ß (IL-1ß), superoxide dismutase (SOD) and malondialdehyde (MDA) compared with that in the control group. Sensitivity analysis that eliminated one study at each stage did not change these results. Egger's test and funnel plot showed that publication bias was existed. Conclusion: In this meta-analysis, APS treatment significantly mitigated colonic damage by reducing the levels of MPO, TNF-α, IL-6, IL-1ß, and MDA and recovering the SOD activity. These results demonstrated a protective role of APS in the treatment of UC and showed that the anti-inflammatory and antioxidant activity were implicated in the underlying mechanisms. Hence, APS may represent a promising candidate for treating UC. However, due to potential publication bias, a cautious interpretation is needed. Systematic Review Registration: (https://www.crd.york.ac.uk/PROSPERO/).

Unpacking the cultural paradox of attentive care for institutionalized people with intellectual disabilities.

This study contributes to the under-researched area of culture in institutional care for people with intellectual disabilities in an East Asian context. Drawing upon in-depth interviews with 20 women frontline care workers for institutionalized people with intellectual disabilities in Taiwan, we examined culture-specific caring relations such as the fictive kinships of Confucian care ethics (i.e., respect for elders and affection for the young), the charity paradigm, and religious compassion, which can induce attentive and respectful care in institutional spaces but also relegate residents to stigmatized subordination in a hierarchy of caring relations and legitimatize the voluntary exploitation of women workers. In situating the relational nature of care and the dis-enabling potentials of culture at the disability-care-place intersection, we promote an ethics of engagement that values and dignifies both recipients and providers of care.

Molecular phylogeography and species distribution modelling evidence of 'oceanic' adaptation for Actinidia eriantha with a refugium along the oceanic-continental gradient in a biodiversity hotspot.

BACKGROUND: Refugia is considered to be critical for maintaining biodiversity; while discerning the type and pattern of refugia is pivotal for our understanding of evolutionary processes in the context of conservation. Interglacial and glacial refugia have been studied throughout subtropical China. However, studies on refugia along the oceanic-continental gradient have largely been ignored. We used a liana Actinidia eriantha, which occurs across the eastern moist evergreen broad-leaved forests of subtropical China, as a case study to test hypotheses of refugia along the oceanic-continental gradient and 'oceanic' adaptation. RESULTS: The phylogeographic pattern of A. eriantha was explored using a combination of three cpDNA markers and 38 nuclear microsatellite loci, Species distribution modelling and dispersal corridors analysis. Our data showed intermediate levels of genetic diversity [haplotype diversity (hT) = 0.498; unbiased expected heterozygosity (UHE) = 0.510] both at the species and population level. Microsatellite loci revealed five clusters largely corresponding to geographic regions. Coalescent time of cpDNA lineages was dated to the middle Pliocene (ca. 4.03 Ma). Both geographic distance and climate difference have important roles for intraspecific divergence of the species. The Zhejiang-Fujian Hilly Region was demonstrated to be a refugium along the oceanic-continental gradient of the species and fit the 'refugia in refugia' pattern. Species distribution modelling analysis indicated that Precipitation of Coldest Quarter (importance of 44%), Temperature Seasonality (29%) and Mean Temperature of Wettest Quarter (25%) contributed the most to model development. By checking the isolines in the three climate layers, we found that A. eriantha prefer higher precipitation during the coldest quarter, lower seasonal temperature difference and lower mean temperature during the wettest quarter, which correspond to 'oceanic' adaptation. Actinidia eriantha expanded to its western distribution range along the dispersal corridor repeatedly during the glacial periods. CONCLUSIONS: Overall, our results provide integrated evidence demonstrating that the Zhejiang-Fujian Hilly Region is a refugium along the oceanic-continental gradient of Actinidia eriantha in subtropical China and that speciation is attributed to 'oceanic' adaptation. This study gives a deeper understanding of the refugia in subtropical China and will contribute to the conservation and utilization of kiwifruit wild resources in the context of climate change.

Antioxidant and Anti-inflammatory Properties of Resveratrol in Diabetic Nephropathy: A Systematic Review and Meta-analysis of Animal Studies.

Background: Accumulated experimental evidence suggests that resveratrol may have an effect on diabetic nephropathy by inhibiting inflammation and decreasing oxidative stress. However, the credibility of the evidence for this practice is unclear. Thus, we aimed to perform a systematic review and meta-analysis of animal studies to evaluate the antioxidant and anti-inflammatory properties of resveratrol when used in the treatment of diabetic nephropathy. Methods: Electronic bibliographic databases including PubMed, EMBASE, and Web of Science were searched for relevant studies. The methodological quality of animal studies was assessed based on the SYstematic Review Center for Laboratory animal Experimentation Risk of Bias (SYRCLE's RoB) tool. A meta-analysis was performed based on the Cochrane Handbook for Systematic Reviews of Interventions by using RevMan 5.4 software. This study was registered within International Prospective Register of Systematic Reviews (PROSPERO) as number CRD42021293784. Results: Thirty-six qualified studies involving 726 animals were included. There was a significant association of resveratrol with the levels of blood glucose (BG), serum creatinine (Scr), blood urea nitrogen (BUN), catalase (CAT), superoxide dismutase (SOD), malondialdehyde (MDA), glutathione (GSH), glutathione peroxidase (GPx), and interleukin-1ß (IL-1ß). Nevertheless, resveratrol treatment did not effectively decrease the levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). In addition, more remarkable antioxidant and hypoglycemic effects were observed in type 2 diabetic nephropathy rather than in type 1 diabetic nephropathy based on subgroup analysis. Conclusion: In this meta-analysis, resveratrol can exert its antioxidant activities by reducing the levels of MDA and recovering the activities of SOD, CAT, GSH, and GPx. With regard to pro-inflammatory cytokines, resveratrol had a positive effect on the reduction of IL-1ß. However, the analysis indicated that resveratrol had no effect on IL-6 and TNF-α levels, probably because of the methodological quality of the studies and their heterogeneity. Current evidence supports the antioxidant and anti-inflammatory properties of resveratrol, but its relationship with the levels of some inflammatory cytokines such as IL-6 and TNF-α in animals with diabetic nephropathy needs further elucidation.

Current status and prospect of virtual reality technique's application in wound repair / 中华烧伤杂志

As a new technology of drug-free treatment, virtual reality technique has been used in various medical fields, and is being increasingly applied in the field of wound repair. Virtual reality technology can alleviate the pain caused by acute and chronic wounds, relieve the psychological anxiety of patients with wounds, and then facilitate the recovery of patients. This paper reviews the research progress of virtual reality technique's application as a clinical adjuvant therapy in wound repair in three aspects: pain treatment, psychological treatment, and functional rehabilitation, analyzes the advantages and disadvantages of this technique, and discusses the prospects of its further application in the field of wound repair.

Population Pharmacokinetics of Polymyxin B and Dosage Optimization in Renal Transplant Patients.

Currently, polymyxin B has been widely used in the treatment of multidrug-resistant Gram-negative pathogen infections. Due to the limited pharmacokinetic/pharmacodynamic data, the optimal dosage regimen for the recently proposed therapeutic target of the area under the concentration-time curve over 24 h in steady state divided by the minimum inhibitory concentration 50-100 mg⋅h/L has not yet been established. Moreover, most studies have focused on critically ill patients, yet there have been no studies in the field of renal transplantation. To optimize the dosage strategy and reduce the risk of toxicity, a population pharmacokinetics model of polymyxin B with the Phoenix NLME program was developed in our study. A total of 151 plasma samples from 50 patients were collected in the present study. Polymyxin B plasma concentrations were measured by high-performance liquid chromatography-tandem mass spectrometry. A one-compartment model adequately described the data, and the clearance and volume of distribution were 1.18 L/h and 12.09 L, respectively. A larger creatinine clearance was associated with increased clearance of polymyxin B (p < 0.01). Monte Carlo simulation showed that a regimen of a 75 mg loading dose with a 50 mg maintenance dose was a better option to achieve an optimal therapeutic effect (minimum inhibitory concentration ≤1 mg/L) and to reduce the incidence of side effects for patients with renal impairments. The developed model suggested that dosing adjustment should be based on renal function in renal transplant patients.

Primula sunhangii (Primulaceae): a new species from Hubei, Central China.

This report provides a description of Primula sunhangii from the Shennongjia Forestry District, Hubei Province in Central China, which is categorized as a new species of the primrose family. Primula sunhangii is morphologically similar to P. involucrata Wall. ex Duby in terms of its simple umbel, efarinose, and prolonged bracts. However, P. sunhangii is distinguished by its glabrous sepal, short petiole (compare with blade) and cylindrical calyx and capsule. Molecular phylogenetic analysis based on nuclear and cpDNA genes demonstrates that P. sunhangii and P. involucrata are closely related. Combining genetic and morphological data, the recognition of P. sunhangii as a unique new species is supported.

Geum sunhangii (Rosaceae), a new species from Hubei Province, China.

Geum sunhangii - first discovered in Shennongjia National Nature Reserve, Hubei Province, China - is described as a new species of Rosaceae. Compared to all known Chinese Geum species, the new species differs by possessing jointed styles, imbricate petals and a reniform radical leaf terminal leaflet. Most significantly, the jointed style is curved at an obtuse or a right angle. In addition, the inclusion of this species within the genus Geum was supported by phylogenetic analysis using the sequence data of a nuclear ribosomal internal transcribed spacer (nrITS) and a chloroplast trnL-trnF intergenic spacer. The new species was found to be closely related to G. rivale and G. aleppicum.

The chromatin landscape at the HIV-1 provirus integration site determines viral expression.

HIV-1 persists lifelong in memory cells of the immune system as latent provirus that rebounds upon treatment interruption. Therefore, the latent reservoir is the main target for an HIV cure. Here, we studied the direct link between integration site and transcription using LEDGINs and Barcoded HIV-ensembles (B-HIVE). LEDGINs are antivirals that inhibit the interaction between HIV-1 integrase and the chromatin-tethering factor LEDGF/p75. They were used as a tool to retarget integration, while the effect on HIV expression was measured with B-HIVE. B-HIVE tracks insert-specific HIV expression by tagging a unique barcode in the HIV genome. We confirmed that LEDGINs retarget integration out of gene-dense and actively transcribed regions. The distance to H3K36me3, the marker recognized by LEDGF/p75, clearly increased. LEDGIN treatment reduced viral RNA expression and increased the proportion of silent provirus. Finally, silent proviruses obtained after LEDGIN treatment were located further away from epigenetic marks associated with active transcription. Interestingly, proximity to enhancers stimulated transcription irrespective of LEDGIN treatment, while the distance to H3K36me3 only changed after treatment with LEDGINs. The fact that proximity to these markers are associated with RNA expression support the direct link between provirus integration site and viral expression.

Exploring histone loading on HIV DNA reveals a dynamic nucleosome positioning between unintegrated and integrated viral genome.

The aim of the present study was to understand the biology of unintegrated HIV-1 DNA and reveal the mechanisms involved in its transcriptional silencing. We found that histones are loaded on HIV-1 DNA after its nuclear import and before its integration in the host genome. Nucleosome positioning analysis along the unintegrated and integrated viral genomes revealed major differences in nucleosome density and position. Indeed, in addition to the well-known nucleosomes Nuc0, Nuc1, and Nuc2 loaded on integrated HIV-1 DNA, we also found NucDHS, a nucleosome that covers the DNase hypersensitive site, in unintegrated viral DNA. In addition, unintegrated viral DNA-associated Nuc0 and Nuc2 were positioned slightly more to the 5' end relative to their position in integrated DNA. The presence of NucDHS in the proximal region of the long terminal repeat (LTR) promoter was associated with the absence of RNAPII and of the active histone marks H3K4me3 and H3ac at the LTR. Conversely, analysis of integrated HIV-1 DNA showed a loss of NucDHS, loading of RNAPII, and enrichment in active histone marks within the LTR. We propose that unintegrated HIV-1 DNA adopts a repressive chromatin structure that competes with the transcription machinery, leading to its silencing.

Androgen deprivation therapy for prostate cancer and the risk of hematologic disorders.

PURPOSE: This study aimed to investigate the association between androgen deprivation therapy (ADT) and the risk of subsequently developing hematologic disorders in patients with prostate cancer. MATERIALS AND METHODS: This population-based nationwide cohort study utilized data from the Taiwan National Health Insurance Research Database between 1997 and 2013. The patients were divided into three groups-those who received ADT only (ADT-only group), those who had radiotherapy (RT) only (RT-only group), and those treated with radical prostatectomy (RP) only (RP-only group). The study outcome was newly diagnosed hematologic disorder, including anemia and hematologic malignancy. Propensity score-matched, Cox regression, and Kaplan-Meier curve analyses were performed to investigate the risk of subsequently developing hematologic disorders after ADT. RESULTS: Of the 17,168 patients with prostate cancer who were included in the study, 13,318 met the inclusion and exclusion criteria. After propensity score matching, 1,797, 1,797, and 1,797 patients treated with ADT only, RT only, and RP only, respectively, who had a median follow-up period of 4.32 years were included in the study cohort. Compared with the patients treated with RP only, those who received ADT and RT were significantly at increased risk of subsequently developing hematologic disorders (ADT: adjusted hazard ratio [aHR]: 1.60, 95% confidence interval [CI]: 1.29-1.97; RT: aHR, 1.98, 95% CI: 1.62-2.42) according to the Cox regression analysis. Based on the Kaplan-Meier curve analysis, patients with bone metastasis who received ADT only had the lowest cumulative probabilities of not developing hematologic disorders. Moreover, a significantly increased risk of hematologic disorders was observed with the increasing duration of ADT (P for trend < .001). CONCLUSIONS: The use of ADT in patients with prostate cancer may increase the risk of subsequently developing hematologic disorders.

Silene sunhangii (Caryophyllaceae), a new species from China.

Silene sunhangii, a new species of Caryophyllaceae known from only three populations in Hubei and Hunan provinces of central China, is described. Both morphological and molecular data were used to assess the taxonomic status and relationships of this species. Morphologically, S. sunhangii is most similar to S. platyphylla Franch. from which it differs most readily in having 3-veined elliptical leaves without pubescence, tasseled catacorolla, pale purple to red petals without a linear lobe or narrow tooth and lanceolate, bifid to one third. A phylogenetic analysis based on nuclear ITS region identified the new species as a well-supported, independent lineage. Our new species is nested within a grade that encompasses species representing a polyphyletic Silene sect. Physolychnis (Benth.) Bocquet. Both the genetic and morphological data support the recognition of Silene sunhangii as a distinct species, although there is inconsistency between these two datasets as to the relationships of the new species.