In Silico Prediction of Quercetin Analogs for Targeting Death-Associated Protein Kinase 1 (DAPK1) Against Alzheimer's Disease.

Alzheimer's Disease (AD) is a progressive neurodegenerative disorder that greatly affects the health and life quality of the elderly population. Existing drugs mainly alleviate symptoms but fail to halt disease progression, underscoring the urgent need for the development of novel drugs. Based on the neuroprotective effects of flavonoid quercetin in AD, this study was designed to identify potential AD-related targets for quercetin and perform in silico prediction of promising analogs for the treatment of AD. Database mining suggested death-associated protein kinase 1 (DAPK1) as the most promising AD-related target for quercetin among seven protein candidates. To achieve better biological effects for the treatment of AD, we devised a series of quercetin analogs as ligands for DAPK1, and molecular docking analyses, absorption, distribution, metabolism, and excretion (ADME) predictions, as well as molecular dynamics (MD) simulations, were performed. The energy for drug-protein interaction was predicted and ranked. As a result, quercetin-A1a and quercetin-A1a1 out of 19 quercetin analogs exhibited the lowest interaction energy for binding to DAPK1 than quercetin, and they had similar dynamics performance with quercetin. In addition, quercetin-A1a and quercetin-A1a1 were predicted to have better water solubility. Thus, quercetin-A1a and quercetin-A1a1 could be promising agents for the treatment of AD. Our findings paved the way for further experimental studies and the development of novel drugs.

Loss of lncRNA LINC01056 leads to sorafenib resistance in HCC.

BACKGROUND AND AIMS: Sorafenib is a major nonsurgical option for patients with advanced hepatocellular carcinoma (HCC); however, its clinical efficacy is largely undermined by the acquisition of resistance. The aim of this study was to identify the key lncRNA involved in the regulation of the sorafenib response in HCC. MATERIALS AND METHODS: A clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) single-guide RNA (sgRNA) synergistic activation mediator (SAM)-pooled lncRNA library was applied to screen for the key lncRNA regulated by sorafenib treatment. The role of the identified lncRNA in mediating the sorafenib response in HCC was examined in vitro and in vivo. The underlying mechanism was delineated by proteomic analysis. The clinical significance of the expression of the identified lncRNA was evaluated by multiplex immunostaining on a human HCC microtissue array. RESULTS: CRISPR/Cas9 lncRNA library screening revealed that Linc01056 was among the most downregulated lncRNAs in sorafenib-resistant HCC cells. Knockdown of Linc01056 reduced the sensitivity of HCC cells to sorafenib, suppressing apoptosis in vitro and promoting tumour growth in mice in vivo. Proteomic analysis revealed that Linc01056 knockdown in sorafenib-treated HCC cells induced genes related to fatty acid oxidation (FAO) while repressing glycolysis-associated genes, leading to a metabolic switch favouring higher intracellular energy production. FAO inhibition in HCC cells with Linc01056 knockdown significantly restored sensitivity to sorafenib. Mechanistically, we determined that PPARα is the critical molecule governing the metabolic switch upon Linc01056 knockdown in HCC cells and indeed, PPARα inhibition restored the sorafenib response in HCC cells in vitro and HCC tumours in vivo. Clinically, Linc01056 expression predicted optimal overall and progression-free survival outcomes in HCC patients and predicted a better sorafenib response. Linc01056 expression indicated a low FAO level in HCC. CONCLUSION: Our study identified Linc01056 as a critical epigenetic regulator and potential therapeutic target in the regulation of the sorafenib response in HCC.

SIRT1/P53 in retinal pigment epithelial cells in diabetic retinopathy: a gene co-expression analysis and He-Ying-Qing-Re formula treatment.

Objective: Diabetic retinopathy (DR) is a severe diabetic complication that leads to severe visual impairment or blindness. He-Ying-Qing-Re formula (HF), a traditional Chinese medicinal concoction, has been identified as an efficient therapy for DR with retinal vascular dysfunction for decades and has been experimentally reported to ameliorate retinal conditions in diabetic mice. This study endeavors to explore the therapeutic potential of HF with key ingredients in DR and its underlying novel mechanisms. Methods: Co-expression gene modules and hub genes were calculated by weighted gene co-expression network analysis (WGCNA) based on transcriptome sequencing data from high-glucose-treated adult retinal pigment epithelial cell line-19 (ARPE-19). The chromatographic fingerprint of HF was established by ultra-performance liquid chromatography coupled with high-resolution mass spectrometry (UPLC-Q-TOF-MS). The molecular affinity of the herbal compound was measured by molecular docking. Reactive oxygen species (ROS) was measured by a DCFDA/H2DCFDA assay. Apoptosis was detected using the TUNEL Assay Kit, while ELISA, Western blot, and real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) were used for detecting the cytokine, protein, and mRNA expressions, respectively. Results: Key compounds in HF were identified as luteolin, paeoniflorin, and nobiletin. For WGCNA, ME-salmon ("protein deacetylation") was negatively correlated with ME-purple ("oxidative impairment") in high-glucose-treated ARPE-19. Luteolin has a high affinity for SIRT1 and P53, as indicated by molecular docking. Luteolin has a hypoglycemic effect on type I diabetic mice. Moreover, HF and luteolin suppress oxidative stress production (ROS and MDA), inflammatory factor expression (IL-6, TNF-α, IL1-ß, and MCP-1), and apoptosis, as shown in the in vivo and in vitro experiments. Concurrently, treatment with HF and luteolin led to an upregulation of SIRT1 and a corresponding downregulation of P53. Conclusion: Using HF and its active compound luteolin as therapeutic agents offers a promising approach to diabetic retinopathy treatment. It primarily suppressed protein acetylation and oxidative stress via the SIRT1/P53 pathway in retinal pigment epithelial cells.

Updated Insights into Probiotics and Hepatobiliary Diseases.

Hepatobiliary diseases have a high prevalence worldwide, with a wide range of diseases involved in the liver and biliary system. Modifications in gut microbiota have been proven to have an association with unbalanced intestinal homeostasis and the dysfunction of host metabolism and the immune system, which can be the risk factors for many hepatobiliary diseases, such as nonalcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), nonalcoholic fatty steatohepatitis (NASH), hepatitis, cirrhosis, hepatocellular carcinoma (HCC) and cholestasis, as well as infection due to liver transplantation. Probiotics are commonly used gut microbiota-targeted strategies to treat dysbiosis and intestinal dysfunction, as well as the gut-liver axis, which can enhance the effectiveness of probiotics in the management of liver diseases. Recent studies have explored more potential single or mixed strains of probiotics, and bioinformatics methods can be used to investigate the potential mechanisms of probiotics on liver diseases. In this review, we summarize the preclinical and clinical studies on the role of probiotics in hepatobiliary diseases from 2018 to 2023, revealing the possible mechanism of probiotics in the treatment of hepatobiliary diseases and discussing the limitations of probiotics in treating hepatobiliary diseases. This review provides updated evidence for the development of probiotic products, exploration of new probiotic strains, and support for clinical studies. Further studies should focus on the safety, viability, and stability of probiotics, as well as medication dosage and duration in clinical practice.

Multifunctional coatings fabricated from Chinese hemp-derived superhydrophobic micro-nanocellulose.

Ecologically feasible strategies for constructing superhydrophobic surfaces offer versatile applications in waterproofing, self-cleaning, selective absorption, and corrosion protection. Herein, we prepared low-surface-energy branched-chain-enriched micronanorod (F@SiO2@MNC) by hydrolyzing silane coupling agent and modifying fluoropolymer using micro-nanocellulose extracted from waste straw (Chinese hemp). These rods were sprayed and adhered to various substrates precoated with a binder, resulting in superhydrophobic surfaces. F@SiO2@MNC addition allowed for the formation of stable spherical liquid droplets when in contact with different types of aqueous liquids. Furthermore, these surfaces demonstrated excellent self-cleaning, robustness, abrasion resistance, UV resistance, cycling stability, and other multifunctionalities. They significantly enhanced the mechanical properties of filter paper, effectively separated oil water mixtures, and improved the corrosion resistance of metals. Our proposed strategy represents a novel approach for developing multifunctional coatings assembled from micronanocellulose.

PARD3 drives tumorigenesis through activating Sonic Hedgehog signalling in tumour-initiating cells in liver cancer.

BACKGROUND: Par-3 Family Cell Polarity Regulator (PARD3) is a cellular protein essential for asymmetric cell division and polarized growth. This study aimed to study the role of PARD3 in hepatic tumorigenesis. METHODS: The essential role of PARD3 in mediating hepatic tumorigenesis was assessed in diet-induced spontaneous liver tumour and syngeneic tumour models. The mechanism of PARD3 was delineated by bulk and single-cell RNA sequencing. The clinical significance of PARD3 was identified by tissue array analysis. RESULTS: PARD3 was overexpressed in tumour tissues and PARD3 overexpression was positively correlated with high tumour stage as well as the poor prognosis in patients. In models of spontaneous liver cancer induced by choline-deficient, amino acid-defined (CDAA) and methionine-choline-deficient (MCD) diets, upregulation of PARD3 was induced specifically at the tumorigenesis stage rather than other early stages of liver disease progression. Site-directed knockout of PARD3 using an adeno-associated virus 8 (AAV8)-delivered CRISPR/Cas9 single-guide RNA (sgRNA) plasmid blocked hepatic tumorigenesis, while PARD3 overexpression accelerated liver tumour progression. In particular, single-cell sequencing analysis suggested that PARD3 was enriched in primitive tumour cells and its overexpression enhanced tumour-initiating cell (TICs). Overexpression of PARD3 maintained the self-renewal ability of the CD133+ TIC population within hepatocellular carcinoma (HCC) cells and promoted the in vitro and in vivo tumorigenicity of CD133+ TICs. Transcriptome analysis revealed that Sonic Hedgehog (SHH) signalling was activated in PARD3-overexpressing CD133+ TICs. Mechanistically, PARD3 interacted with aPKC to further activate SHH signalling and downstream stemness-related genes. Suppression of SHH signalling and aPKC expression attenuated the in vitro and in vivo tumorigenicity of PARD3-overexpressing CD133+ TICs. Tissue array analysis revealed that PARD3 expression was positively associated with the phosphorylation of aPKC, SOX2 and Gli1 and that the combination of these markers could be used to stratify HCC patients into two clusters with different clinicopathological characteristics and overall survival prognoses. The natural compound berberine was selected as a potent suppressor of PARD3 expression and could be used as a preventive agent for liver cancer that completely blocks diet-induced hepatic tumorigenesis in a PARD3-dependent manner. CONCLUSION: This study revealed PARD3 as a potential preventive target of liver tumorigenesis via TIC regulation.

Epigenetic inhibitors for cancer treatment.

Epigenetics is a heritable and reversible modification that occurs independent of the alteration of primary DNA sequence but remarkably affects genetic expression. Aberrant epigenetic regulators are frequently observed in cancer progression not only influencing the behavior of tumor cells but also the tumor-associated microenvironment (TME). Increasing evidence has shown their great potential as biomarkers to predict clinical outcomes and chemoresistance. Hence, targeting the deregulated epigenetic regulators would be a compelling strategy for cancer treatment. So far, current epigenetic drugs have shown promising efficacy in both preclinical trials and clinical treatment of cancer, which encourages research discoveries on the development of novel epigenetic inhibitors either from natural compounds or artificial synthesis. However, only a few have been approved by the FDA, and more effort needs to be put into the related research. This chapter will update the applications and latest progress of epigenetic inhibitors in cancer treatment and provide prospects for the future development of epigenetic drugs.

Effects and mechanisms of anti-diabetic dietary natural products: an updated review.

Diabetes is a global public health issue, characterized by an abnormal level of blood glucose. It can be classified into type 1, type 2, gestational, and other rare diabetes. Recent studies have reported that many dietary natural products exhibit anti-diabetic activity. In this narrative review, the effects and underlying mechanisms of dietary natural products on diabetes are summarized based on the results from epidemiological, experimental, and clinical studies. Some fruits (e.g., grape, blueberry, and cherry), vegetables (e.g., bitter melon and Lycium barbarum leaves), grains (e.g., oat, rye, and brown rice), legumes (e.g., soybean and black bean), spices (e.g., cinnamon and turmeric) and medicinal herbs (e.g., Aloe vera leaf and Nigella sativa), and vitamin C and carotenoids could play important roles in the prevention and management of diabetes. Their underlying mechanisms include exerting antioxidant, anti-inflammatory, and anti-glycation effects, inhibiting carbohydrate-hydrolyzing enzymes, enhancing insulin action, alleviating insulin resistance, modulating the gut microbiota, and so on. This review can provide people with a comprehensive knowledge of anti-diabetic dietary natural products, and support their further development into functional food to prevent and manage diabetes.

Genipin-activating PPARγ impedes CCR2-mediated macrophage infiltration into postoperative liver to suppress recurrence of hepatocellular carcinoma.

A high postoperative tumour recurrence rate has significantly rendered a poorer prognosis in hepatocellular carcinoma (HCC) patients. The aim of this study is to identify a natural compound genipin as a potential and effective candidate to suppress the postoperative recurrence of HCC. Clinical analysis revealed that infiltration of macrophage into the adjacent tissue but not HCC predicted patients' poor prognosis on recurrence-free survival. Genipin intervention suppressed the Ly6C+CD11b+F4/80+ pro-inflammatory macrophage infiltration in the postoperative liver of mice. Adoptive transfer of pro-inflammatory monocytic cells completely abolished the inhibitory effect of genipin on HCC recurrence. Transcriptomic analysis on FACs-sorted macrophages from the postoperative livers of mice revealed that PPARγ signalling was involved in the regulatory effect of genipin. Genipin is directly bound to PPARγ, causing PPARγ-induced p65 degradation, which in turn suppressed the transcriptional activation of CCR2 signalling. PPARγ antagonist GW9662 abrogated the effects of genipin on CCR2-medaited macrophage infiltration as well as HCC recurrence. Cytokine array analysis identified that genipin intervention potently suppressed the secretion of CCL2 further partially contributed to the pro-inflammatory macrophage infiltration into the postoperative liver. Multiplex immunostaining on tissue array of human HCC revealed that PPARγ expression was inversely associated with CCL2 and the macrophage infiltration in the adjacent liver of HCC patients. Our works provide scientific evidence for the therapeutic potential of genipin as a PPARγ agonist in preventing postoperative recurrence of HCC.

CRISPR/Cas9 screens unravel miR-3689a-3p regulating sorafenib resistance in hepatocellular carcinoma via suppressing CCS/SOD1-dependent mitochondrial oxidative stress.

AIMS: Therapeutic outcome of sorafenib in hepatocellular carcinoma (HCC) is undermined by the development of drug resistance. This study aimed to identify the critical microRNA (miRNA) which is responsible for sorafenib resistance at the genomic level. METHODS: CRISPR/Cas9 screen followed by gain- and loss-of-function assays both in vitro and in vivo were applied to identify the role of miR-3689a-3p in mediating sorafenib response in HCC. The upstream and downstream molecules of miR-3689a-3p and their mechanism of action were investigated. RESULTS: CRISPR/Cas9 screening identified miR-3689a-3p was the most up-regulated miRNA in sorafenib sensitive HCC. Knockdown of miR-3689a-3p significantly increased sorafenib resistance, while its overexpression sensitized HCC response to sorafenib treatment. Proteomic analysis revealed that the effect of miR-3689a-3p was related to the copper-dependent mitochondrial superoxide dismutase type 1 (SOD1) activity. Mechanistically, miR-3689a-3p targeted the 3'UTR of the intracellular copper chaperone for superoxide dismutase (CCS) and suppressed its expression. As a result, miR-3689a-3p disrupted the intracellular copper trafficking and reduced SOD1-mediated scavenge of mitochondrial oxidative stress that eventually caused HCC cell death in response to sorafenib treatment. CCS overexpression blunted sorafenib response in HCC. Clinically, miR-3689a-3p was down-regulated in HCC and predicted favorable prognosis for HCC patients. CONCLUSION: Our findings provide comprehensive evidence for miR-3689a-3p as a positive regulator and potential druggable target for improving sorafenib treatment in HCC.

Efficacy and safety of herbal medicines intervention for cachexia associated with cancer: A systematic review and meta-analysis.

As a worldwide public health issue, cancer-induced cachexia can result in decreasing physical function and survival rate. However, the therapeutic effects of conventional approaches, including pharmacotherapy, exercise and nutritional intervention, are far from satisfactory. Herbal medicines (HMs), especially Traditional Chinese Medicine (TCM), are reported to effectively treat cachexia for centuries. The inclusion criteria of all participants in this study pointed to the diagnosis of cachexia, the trial group used herbal medicine (HM) in complementary and alternative medicine, etc. Twelve databases, including EMbase, PubMed, Web of science, Cochrane CENTRAL, CINAHL, CINAHLPlus, PsycINFO, AMED, China Biology Medicine disc (CBM), China National Knowledge Infrastructure (CNKI), Wanfang and Chongqing VIP (CQVIP) were retrieved from inception to March 28, 2022. We conducted the meta-analysis utilizing RevMan 5.3. A trial sequential analysis (TSA) was conducted to assess the adequacy of the sample size for the outcomes. We have registered the protocol and the registration number was CRD42022336446. A total of 66 studies were included, containing 3654 patients diagnosed with cancer cachexia, of which 1833 patients were assigned to the trial group and 1821 patients were treated in the control group. Outcomes cover the primary indicator KPS (RR = 1.84, 95%CI = [1.61, 2.09], p < 0.00001), and other outcomes including adverse events rate (RR = 0.37, 95%CI = [0.23, 0.58], p < 0.0001), albumin (MD = 2.14, 95%CI = [1.56, 2.71], p < 0.00001), haemoglobin (MD = 4.88, 95%CI = [3.26, 6.50], p < 0.00001), TCM syndrome effect (MD = 1.47, 95%CI = [1.31, 1.65], p < 0.00001), effect of weight (RR = 1.62, 95%CI = [1.34, 1.95], p < 0.00001), effect of appetite (RR = 1.23, 95%CI = [1.13, 1.34], p < 0.00001), FAACT (RR = 7.81, 95%CI = [6.12, 9.50], p < 0.00001), PG-SGA (MD = -2.16, 95%CI = [-2.65, -1.67], p < 0.00001) and QOL (MD = 5.76, 95%CI = [4.04, 7.48], p < 0.00001), suggesting that HMs or HMs combined with conventional treatment have an ameliorating effect on cachexia in each respect. Subgroup analysis showed that the five HMs with the best effect on improving KPS and their optimal doses were Coicis Semen (Yiyiren) in 10 g group, Citri Reticulatae Pericarpium (Chenpi) in 15 g group, Dioscoreae Rhizoma (Shanyao) in 10 g group, Ophiopogonis Radix (Maidong) in 10 g group and Ginseng Radix Et Rhizoma (Renshen) in 20 g group. In addition, there were HM combinations of levels 2-6. Egger's test showed publication bias for five outcomes. HMs have a significant effect on improving cancer cachexia on FAACT, TCM syndrome, KPS, QOL, appetite, nutritional status (evaluated by PG-SGA scale), weight, levels of albumin and haemoglobin. And the Adverse events rate is less than that of Western Medicine. The herbs with the best curative effect and their optimal dose were Dioscoreae R. (10 g), Citri R.P. (15 g), Coicis S. (10 g), Ophiopogonis R. (10 g) and Ginseng R.E.R. (20 g). Due to the quality of included studies is not high, further high-quality studies are needed to firmly establish the clinical efficacy of HM.

Advances of the small molecule drugs regulating fibroblast-like synovial proliferation for rheumatoid arthritis.

Rheumatoid arthritis (RA) is a type of chronic autoimmune and inflammatory disease. In the pathological process of RA, the alteration of fibroblast-like synoviocyte (FLS) and its related factors is the main influence in the clinic and fundamental research. In RA, FLS exhibits a uniquely aggressive phenotype, leading to synovial hyperplasia, destruction of the cartilage and bone, and a pro-inflammatory environment in the synovial tissue for perpetuation and progression. Evidently, it is a highly promising way to target the pathological function of FLS for new anti-RA drugs. Based on this, we summed up the pathological mechanism of RA-FLS and reviewed the recent progress of small molecule drugs, including the synthetic small molecule compounds and natural products targeting RA-FLS. In the end, there were some views for further action. Compared with MAPK and NF-κB signaling pathways, the JAK/STAT signaling pathway has great potential for research as targets. A small number of synthetic small molecule compounds have entered the clinic to treat RA and are often used in combination with other drugs. Meanwhile, most natural products are currently in the experimental stage, not the clinical trial stage, such as triptolide. There is an urgent need to unremittingly develop new agents for RA.

Panax notoginseng-microbiota interactions: From plant cultivation to medicinal application.

BACKGROUND: Microbiomes and their host plants are closely linked with each other; for example, the microbiome affects plant growth, fitness, nutrient uptake, stress tolerance and pathogen resistance, whereas the host plant supports the photosynthetically carbon-rich nutrition of the microbiome. The importance of the microbiome in plant‒soil ecosystems is unquestioned and has expanded to influence the medicinal application of some herbal plants via the gut microbiota. PURPOSE: Herbal plant-microbiome interactions may provide novel knowledge to enhance the robustness of herbal plant crop performance and medicinal applications, which requires a systematic review and preceding discussion. STUDY DESIGN AND METHODS: The interactions between Panax notoginseng and microorganisms (from soil to host) were reviewed from the literature. The terms "Panax notoginseng" and "microbiota" were used in combination with the keywords "microbiota/microbes", "bacteria/bacterium" or "fungi/fungus" or "endophyte", as well as our targeted bioactive phytochemicals, including saponins and ginsenosides. RESULT: Our study focuses on the famous medicinal herb Panax notoginseng F. H. Chen and proposes that the microbiota is a crucial participant not only in the cultivation of this herbal plant but also in its medicinal application. We also summarize and discuss how these plant‒microbe co-associations shape the assembly of plant-related microbiomes and produce bioactive phytochemicals, as well as influence beneficial herbal traits, such as herbal plant health and pharmacology. In addition, we also highlight future directions. CONCLUSION: The rhizosphere and endophytic microbiome of Panax notoginseng are indirectly or directly involved in plant health, biomass production, and the synthesis/biotransformation of plant secondary metabolites. Harnessing the microbiome to improve the quality of traditional Chinese medicine and improve the value of medicinal plants for human health is highly promising.

Add-on Rehmannia-6-Based Chinese Medicine in Type 2 Diabetes and CKD: A Multicenter Randomized Controlled Trial.

BACKGROUND: Diabetes is the leading cause of CKD and kidney failure. We assessed the real-world effectiveness of Rehmannia-6-based Chinese medicine treatment, the most used Chinese medicine formulation, on the change in eGFR and albuminuria in patients with diabetes and CKD with severely increased albuminuria. METHODS: In this randomized, assessor-blind, standard care-controlled, parallel, multicenter trial, 148 adult patients from outpatient clinics with type 2 diabetes, an eGFR of 30-90 ml/min per 1.73 m 2 , and a urine albumin-to-creatinine ratio (UACR) of 300-5000 mg/g were randomized 1:1 to a 48-week add-on protocolized Chinese medicine treatment program (using Rehmannia-6-based formulations in the granule form taken orally) or standard care alone. Primary outcomes were the slope of change in eGFR and UACR between baseline and end point (48 weeks after randomization) in the intention-to-treat population. Secondary outcomes included safety and the change in biochemistry, biomarkers, and concomitant drug use. RESULTS: The mean age, eGFR, and UACR were 65 years, 56.7 ml/min per 1.73 m 2 , and 753 mg/g, respectively. Ninety-five percent ( n =141) of end point primary outcome measures were retrievable. For eGFR, the estimated slope of change was -2.0 (95% confidence interval [CI], -0.1 to -3.9) and -4.7 (95% CI, -2.9 to -6.5) ml/min per 1.73 m 2 in participants treated with add-on Chinese medicine or standard care alone, resulting in a 2.7 ml/min per 1.73 m 2 per year (95% CI, 0.1 to 5.3; P = 0.04) less decline with Chinese medicine. For UACR, the estimated proportion in the slope of change was 0.88 (95% CI, 0.75 to 1.02) and 0.99 (95% CI, 0.85 to 1.14) in participants treated with add-on Chinese medicine or standard care alone, respectively. The intergroup proportional difference (0.89, 11% slower increment in add-on Chinese medicine, 95% CI, 0.72 to 1.10; P = 0.28) did not reach statistical significance. Eighty-five adverse events were recorded from 50 participants (add-on Chinese medicine versus control: 22 [31%] versus 28 [36%]). CONCLUSIONS: Rehmannia-6-based Chinese medicine treatment stabilized eGFR on top of standard care alone after 48 weeks in patients with type 2 diabetes, stage 2-3 CKD, and severely increased albuminuria. CLINICAL TRIAL REGISTRY: Semi-individualized Chinese Medicine Treatment as an Adjuvant Management for Diabetic Nephropathy (SCHEMATIC), NCT02488252 .

Characterization of cuproptosis in gastric cancer and relationship with clinical and drug reactions.

Gastric cancer (GC) is the fifth most common cancer worldwide. Cuproptosis is associated with cell growth and death as well as tumorigenesis. Aiming to lucubrate the potential influence of CRGs in gastric cancer, we acquired datasets of gastric cancer patients from TCGA and GEO. The identification of molecular subtypes with CRGs expression was achieved through unsupervised learning-cluster analysis. To evaluate the application value of subtypes, the K-M survival analysis was conducted to evaluate the clinical prognostic characteristics. Subsequently, we performed Gene Set Variation Analysis (GSVA) and utilized ssGSEA to quantify the extent of immune infiltration. Further, the K-M survival analysis was used to identify the prognosis-related CRGs. Next, signature genes of diagnostic predictive value were screened using the least absolute shrinkage and selection operator (LASSO) algorithm from the expression matrix for TCGA, as well as the signature gene-related subtype was clustered by the "ConsensusClusterPlus" package. Finally, the immunological and drug sensitivity assessments of the signature gene-related subtypes were conducted. A total of 173 CRGs were identified, most of the CRGs undergo copy number variation in gastric cancer. Under different patient subtypes, immune cell levels differed significantly, and the subtype exhibiting high expression of the CRGs had a better prognosis. Furthermore, we selected 34 CRGs that were highly correlated with the prognosis of gastric cancer. By constructing a multivariate Cox proportional-hazards model and a hazard scoring system, we were able to categorize patients into high- and low-risk groups based on their hazard score. K-M analysis demonstrated a significant survival disadvantage in the high-risk group. Based on Lasso regression analysis, we screened 16 signature genes, a multivariate logistic regression model [cutoff: 0.149 (0.000, 0.974), AUC:0.987] and a prognosis network diagram was constructed and their prediction efficiency for gastric cancer prognostic diagnosis was well validated. According to the signature genes, the patients were separated to two signature subtypes. We found that patients with higher CRGs expression and better prognosis had lower levels of immune infiltration. Finally, according to the results of drug susceptibility analysis, docetaxel, 5-Fluorouracil, gemcitabin, and paclitaxel were found to be more sensitive to gastric cancer.

Renal herb formula protects against hyperuricemic nephropathy by inhibiting apoptosis and inflammation.

BACKGROUND: Hyperuricemic nephropathy may be induced by the elevation and accumulation of uric acid in kidney after hyperuricemia, which leads to kidney residential cells apoptosis and inflammation. Renal herb formula (RHF) is a self-designed formula based on traditional Chinese medicine theory and clinical practice in kidney disease treatment. In the literature available currently, there is not yet research article reporting the reno-protective effect of RHF against hyperuricemic nephropathy. PURPOSE: This study was performed to analyze the bioactive compound profiles of RHF, evaluate its protective effects against hyperuricemic nephropathy, and investigate the mechanisms of actions regarding apoptosis and inflammation. METHODS: Ultra-performance liquid chromatography with a diode-array detector was applied to establish fingerprint and chemical composition of RHF. Potassium oxonate was used to induce hyperuricemic nephropathy in mice, and uric acid was used to stimulate apoptosis and inflammatory response in HK-2 cells, while the mice and cells were treated with RHF to explore its reno-protective effects and mechanisms. RESULTS: It was found that chlorogenic acid, neochlorogenic acid, cryptochlorogenic acid, and isochlorogenic acid A-C may be the characteristic components of RHF. RHF treatment could improve kidney functions in mice with hyperuricemic nephropathies, such as decreasing urine protein, uric acid, and creatinine and serum uric acid, creatinine, and urea nitrogen. Histopathological observations showed that RHF treatment ameliorated kidney glomerular hypotrophy, tubular damage, and inflammatory infiltration. Mechanism studies revealed that RHF inhibited kidney residential cell apoptosis and inflammatory response by targeting the p53-associated intrinsic apoptosis pathway and NF-κB-mediated inflammatory pathway. CONCLUSION: Taken together, it could be concluded that RHF exerted reno-protective effects against hyperuricemic nephropathy through reducing apoptosis and inflammation. RHF and the bioactive compounds chlorogenic acid analogs as promising candidates may be developed into novel and effective drugs for hyperuricemic nephropathy treatment and management.

Deciphering suppressive effects of Lianhua Qingwen Capsule on COVID-19 and synergistic effects of its major botanical drug pairs.

The COVID-19 pandemic has resulted in excess deaths worldwide. Conventional antiviral medicines have been used to relieve the symptoms, with limited therapeutic effect. In contrast, Lianhua Qingwen Capsule is reported to exert remarkable anti-COVID-19 effect. The current review aims to: 1) uncover the main pharmacological actions of Lianhua Qingwen Capsule for managing COVID-19; 2) verify the bioactive ingredients and pharmacological actions of Lianhua Qingwen Capsule by network analysis; 3) investigate the compatibility effect of major botanical drug pairs in Lianhua Qingwen Capsule; and 4) clarify the clinical evidence and safety of the combined therapy of Lianhua Qingwen Capsule and conventional drugs. Numerous bioactive ingredients in Lianhu Qingwen, such as quercetin, naringenin, ß-sitosterol, luteolin, and stigmasterol, were identified to target host cytokines, and to regulate the immune defence in response to COVID-19. Genes including androgen receptor (AR), myeloperoxidase (MPO), epidermal growth factor receptor (EGFR), insulin (INS), and aryl hydrocarbon receptor (AHR) were found to be significantly involved in the pharmacological actions of Lianhua Qingwen Capsule against COVID-19. Four botanical drug pairs in Lianhua Qingwen Capsule were shown to have synergistic effect for the treatment of COVID-19. Clinical studies demonstrated the medicinal effect of the combined use of Lianhua Qingwen Capsule and conventional drugs against COVID-19. In conclusion, the four main pharmacological mechanisms of Lianhua Qingwen Capsule for managing COVID-19 are revealed. Therapeutic effect has been noted against COVID-19 in Lianhua Qingwen Capsule.

Pancreatic melatonin enhances anti-tumor immunity in pancreatic adenocarcinoma through regulating tumor-associated neutrophils infiltration and NETosis.

Tumor microenvironment contributes to poor prognosis of pancreatic adenocarcinoma (PAAD) patients. Proper regulation could improve survival. Melatonin is an endogenous hormone that delivers multiple bioactivities. Here we showed that pancreatic melatonin level is associated with patients' survival. In PAAD mice models, melatonin supplementation suppressed tumor growth, while blockade of melatonin pathway exacerbated tumor progression. This anti-tumor effect was independent of cytotoxicity but associated with tumor-associated neutrophils (TANs), and TANs depletion reversed effects of melatonin. Melatonin induced TANs infiltration and activation, therefore induced cell apoptosis of PAAD cells. Cytokine arrays revealed that melatonin had minimal impact on neutrophils but induced secretion of Cxcl2 from tumor cells. Knockdown of Cxcl2 in tumor cells abolished neutrophil migration and activation. Melatonin-induced neutrophils presented an N1-like anti-tumor phenotype, with increased neutrophil extracellular traps (NETs) causing tumor cell apoptosis through cell-to-cell contact. Proteomics analysis revealed that this reactive oxygen species (ROS)-mediated inhibition was fueled by fatty acid oxidation (FAO) in neutrophils, while FAO inhibitor abolished the anti-tumor effect. Analysis of PAAD patient specimens revealed that CXCL2 expression was associated with neutrophil infiltration. CXCL2, or TANs, combined with NET marker, can better predict patients' prognosis. Collectively, we discovered an anti-tumor mechanism of melatonin through recruiting N1-neutrophils and beneficial NET formation.