The clinical application of poly(ADP-ribose) polymerase 1 (PARP1) inhibitors is frequently constrained by drug resistance and clinical efficacy. Suppression of the extracellular signal-regulated kinase (ERK) pathway can impair homologous recombination (HR) repair and sensitize cancer cells to PARP1 inhibition. Capitalizing on this synthetic lethal interaction, we designed and developed a novel dual PARP1/ERK inhibitor, I-16, which exhibits potent and selective inhibition against both PARP1 (IC50 = 0.9 nM) and ERK2 (IC50 = 1.8 nM). Remarkably, I-16 displayed strong antiproliferative activity across a panel of cancer cell lines, including both breast cancer susceptibility genes (BRCA) mutant and BRCA-wild-type models. In an HCT116 xenograft model, I-16 (20 mg/kg) elicited significant tumor growth suppression, outperforming Olaparib (50 mg/kg) or BVD-523 (5 mg/kg) monotherapy and achieving efficacy comparable to their combination. These findings suggest that I-16, as the first potent dual PARP1/ERK inhibitor, represents a promising candidate for cancer therapy.

Background Alcohol-associated liver disease (ALD) is a major public health concern due to its increasing prevalence and lack of effective therapies. Pien Tze Huang (PTH) is a traditional Chinese medicinal formula commonly used for viral hepatitis and liver fibrosis. However, whether it also has a robust therapeutic effect on ALD remains unclear. Purpose This study aimed to verify the effect of PTH on ALD, identify the active components, and explore the underlying mechanisms. Methods HPLC-Q-TOF-MS and GC-MS were performed for chemical constitution analysis, quality control, and bioactive components identification. An ALD mouse model was established via gavage of 50% ethanol, while oxidative stress and ferroptosis in HepG2 cells were induced using ethanol or tert-Butyl hydroperoxide. Biochemical indicators and pathological analysis were conducted to evaluate the effects. Transcriptome, polymerase chain reaction, western blotting, and siRNA/plasmids transfection were performed to explore and verify the mechanism. Results PTH significantly attenuated ALD in mice. It had marginal effects on alcohol metabolism but strongly suppressed oxidative stress and ferroptosis. Mechanistically, PTH restored Keap1-Nrf2 signaling and inhibited ferric iron import. Calculus Bovis (from Bos taurus domesticus) and Musk (Moschus, from Moschus berezovskii, M. sifanicus, or M. moschiferus) were bioactive ingredients. Bovinic acid and taurine (1.3 and 2.3 mg/g in PTH, respectively) were bioactive components. They directly bound SIRT1 at different amino acid residues to suppress oxidative stress and ferroptosis via SIRT1/Keap1/Nrf2 axis and SIRT1/transferrin receptor signal. Conclusions Bovinic acid and taurine in PTH suppress SIRT1/Keap1/Nrf2 axis-mediated oxidative stress and SIRT1/ transferrin receptor-mediated ferroptosis to ameliorate ALD.

Dry eye (DE) is a multifactorial ocular surface disease characterized primarily by tear film instability and ocular discomfort. Nearly all forms of DE exhibit elevated inflammatory markers in tear fluid, accompanied by clinical signs of tear dysfunction including reduced secretion and shortened breakup time. Although the pathophysiology of dry eye disease remains incompletely understood, accumulating evidence implicates neutrophil extracellular traps (NETs) as key pathogenic drivers. Robust clinical associations and mechanistic studies have established causal links between NETs and ocular surface pathology. This review summarizes current research on the role of NETs in the development of dry eye, aiming to identify potential therapeutic targets.

The pathogenesis and progression of liver diseases are characterized by marked zonal heterogeneity, yet conventional research paradigms have long overlooked this intrinsic spatial logic. Ferroptosis and cuproptosis have been widely implicated in liver disease; however, their precise intralobular distribution and zonal susceptibility patterns remain poorly defined. We present a narrative synthesis of the literature on the spatial zonation of hepatic metabolism, redox homeostasis, and metal handling, and assess their potential roles as determinants of region-specific cell death vulnerability. We propose the novel “spatial redox–metalloptosis axis” hypothesis. The pericentral zone (Zone 3), characterized by hypoxia, high cytochrome P450 activity, and a redox environment that may favor lipid peroxidation under specific pathological conditions, is hypothesized to form a ferroptosis-susceptible niche under metabolic stress. Conversely, the periportal zone (Zone 1), characterized by active copper handling and oxidative phosphorylation-dependent metabolism, is hypothesized to be preferentially vulnerable to cuproptosis (proposed hypothesis; direct zone-resolved evidence of cuproptosis execution in Zone 1 is currently absent). Ceruloplasmin is proposed as a candidate molecular link between copper and iron metabolism. We further identify shared molecular hubs and a hypothesized spatial redox–metalloptosis axis linking these two regulated cell death modalities, while direct biological crosstalk remains to be demonstrated. We also highlight critical technological, mechanistic, and translational gaps. This review aims to shift liver disease research from viewing the liver as a homogeneous organ to a functionally compartmentalized zoned ecosystem, providing a testable theoretical framework for deciphering region-specific liver injury and developing spatially informed therapeutic strategies.

Background Immunosuppressive phenotype compromised immunotherapy efficacy of hepatocellular carcinoma. Tumor cells intrinsic mitochondria dynamics could pass effects on the extracellular microenvironment through mtDNA stress. PGAM5 anchors at mitochondria and regulates mitochondria functions. We aim to explore whether the regulation of tumor-intrinsic PGAM5 on mitochondria affects tumor-infiltrating immune cells in the microenvironment and whether tumor-intrinsic PGAM5 can be a therapeutic target to enhance the immunotherapy efficacy of hepatocellular carcinoma (HCC).Methods We analyzed the correlation of PGAM5 expression and immune cells infiltration using Gene Expression Omnibus (GEO) and The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) data sets based on cibersort algorithm and tumor-tissue arrays from two independent cohorts. To further validate our findings, we established subcutaneous and orthotopic mouse HCC models with tumor-intrinsic Pgam5 deficiency and analyzed tumor-infiltrating immune cells by flow cytometry and single-cell RNA sequencing. Mechanistically, we established an in vitro co-culture system and analyzed proteomics data to find out the bridge between tumor cell PGAM5 and tumor-associated macrophages (TAMs) in the microenvironment. Immunofluorescence, chromatin-immunoprecipitation, ELISA, mass spectrometry were conducted to explore the molecular pathway. Macrophages were depleted to investigate whether the effects of tumor-intrinsic PGAM5 on TAMs could affect immunotherapy efficacy in HCC orthotopic and subcutaneous mouse models.Results PGAM5 expression in tumor was positively correlated with M2-phenotype TAM infiltration in patients with both HCC and mouse HCC tumor models. High tumor-intrinsic PGAM5 expression promoting M2 TAMs infiltration correlated with poor clinical-pathological characteristics and prognosis in patients with HCC. Disruption of tumor-intrinsic Pgam5 reduced TAM M2 polarization and inhibited HCC tumor growth in tumor-bearing mice. Mechanistically, in HCC cells PGAM5 deficiency inhibited mitochondria fission by promoting TRIM28 binding with DRP1, which increased ubiquitination and degradation of DRP1. Tumor-intrinsic PGAM5 deficiency mediated mitochondria fusion and reduced cytosolic mtDNA stress which attenuated TLR9 activation and downstream NF-κB-regulated CCL2 secretion. Furthermore, disruption of tumor-intrinsic Pgam5 significantly facilitated CD8+ T cells activation and improved anti-programmed cell death protein-1 therapeutic efficacy with macrophages depletion compromising synergistic antitumor immune response.Conclusion Our results shed light on the effect of tumor mitochondria dynamics on TAMs in tumor microenvironment. Tumor-intrinsic PGAM5 can be a therapeutic target to improve immunotherapy efficacy in patients with HCC.

ETHNOPHARMACOLOGICAL RELEVANCE:Cattle bile Arisaema (CBA) and Pig bile Arisaema (PBA) are both processed products fermented from Arisaema erubescens (Wall.) Schott and animal bile, which are recorded in China Pharmacopoeia. Traditionally, bile Arisaema was often used for clearing heat and eliminating phlegm, calming wind and calming panic. Modern pharmacological researches suggest that both two drugs exert an antipyretic effect, while there is lack of the systematical and comparative evidence on underlying mechanism. AIM OF THE STUDY:To comprehensively clarify the differences and underlying mechanisms of antipyretic effect of the two drugs. METHODS:In this study, an accurate and reliable detection method based on ultra-performance liquid chromatography coupled with triple quadrupole mass spectrometry (UPLC-TQ MS) for comparing the content difference of bile acids from the two drugs was successfully established and applied. Besides, a dry yeast-induced fever rat model was established, and rectal temperature and content of pyrogenic cytokines were conducted to evaluate the antipyretic effect of CBA and PBA. Serum and hypothalamus untargeted metabolomics analysis based on ultra-performance liquid chromatography coupled with quadrupole-time of flight-mass spectrometry (UPLC-Q-TOF-MS/MS) technology were performed for elucidating the changes of metabolic profile. RESULTS:The results indicated that CBA and PBA both exerted a significantly antipyretic effect, but CBA showed the characteristic of quicker onset and longer duration than that of PBA. The ELISA and western blotting analysis exhibited that the underlying antipyretic mechanism of the two drugs was closely associated with inhibiting inflammation through regulating TLR4/NF-κB signaling pathway. Moreover, the metabolism pathway analysis revealed that lipid metabolism and amino acid metabolism were greatly disturbed, which showed a certain correlation with antipyretic effect of two drugs. CONCLUSION:Collectively, our results delineate a potential mechanism of two different bile Arisaemas against febrile via regulating metabolic disorders and targeting inhibition of inflammation for the improvement of fever symptom of the body. Notably, our current study suggested that CBA might be a better choice for suppressing fever clinically.

Enzymatic methods have been demonstrated to effectively enhance the gel properties of soybean protein. Current research primarily focuses on modifying commercially available soybean protein isolate (SPI) products, which involves complex modification processes and poses challenges for industrialization. This study aimed to investigate the impact of enzyme-assisted extraction on structural, physicochemical and gelation properties of the derived SPI. Limited hydrolysis was achieved by subjecting defatted soy flour to hydrolysis using Flavorzyme, Neutrase and Protamex for varying durations while controlling the degree of hydrolysis (DH) below 10 %. The enzyme-assisted extracted SPI (ESPI) prepared using Flavorzyme exhibited smaller particle sizes compared to those treated with Protamex and Neutrase, facilitating aggregation through hydrophobic interactions, hydrogen bonds, and disulfide bonds to form a denser and more uniform gel network structure. Minimal hydrolysis with Protamex exposed more active groups on protein molecules leading to improved formation of a gel network structure. On the other hand, Nuetrase leads to a reduced enhancement in protein surface's hydrophobicity, indicating limited impact on the gelation properties of the protein. This research work provides novel insights into effectively improving the gelation properties of derived enzyme-assisted extracted SPI.

Colorectal cancer(CRC)is the third most common cancer worldwide and the second leading cause of cancer-related mortality.While early-stage CRC patients generally exhibit favorable overall survival(OS)rates,the prognosis for meta-static CRC(mCRC)remains poor,with a survival rate<15％.

Introduction In the era of functional intraocular lens (IOL) implantation, it is crucial to investigate the influence of different capsulorhexis sizes (including the diameter of the capsulorhexis, area of the anterior capsule opening, anterior capsule coverage, centration and circularity of the capsulorhexis) on the postoperative outcomes (eg, visual acuity, capsule shrinkage, IOL stability and intraocular pressure) in patients undergoing cataract surgery. This is particularly important in patients with high myopia or diabetes mellitus. The proposed protocol aims to enhance the transparency of our research and offer references for future studies.Methods and analysis A comprehensive search of PubMed, Embase, Cochrane Library, Web of Science, SinoMed, China National Knowledge Infrastructure, Wanfang Data Knowledge Service Platform and China Science and Technology Journal Database is performed from inception to 4 July 2024. Data of individual participants will be collected from relevant clinical trials, both completed and ongoing. The collected data will be analysed using multilevel regression models to examine the association between capsulorhexis size and surgical outcomes. Potential demographic and clinical factors that may influence the results of cataract surgery, including postoperative visual acuity and IOL rotational stability, will also be explored. Any future modification to this protocol will include the date and rationale for the change.Ethics and dissemination Ethical approval is not required because the study does not involve individual patients. The study results are to be disseminated via professional journals as well as academic media.Trial registration number CRD42023459903.

Vertebrate life begins with fertilization, and then the zygote genome is activated after transient silencing, a process termed zygotic genome activation (ZGA). Despite its fundamental role in totipotency and the initiation of life, the precise mechanism underlying ZGA initiation remains unclear. The existence of minor ZGA implies the possible critical role of noncoding RNAs in the initiation of ZGA. Here, we delineate the expression profile of long noncoding RNAs (lncRNAs) in early mouse embryonic development and elucidate their critical role in minor ZGA. Compared with protein-coding genes (PCGs), lncRNAs exhibit a stronger correlation with minor ZGA. Distinct H3K9me3 profiles can be observed between lncRNA genes and PCGs, and the enrichment of H3K9me3 before ZGA might explain the suspended expression of major ZGA-related PCGs despite possessing PolII pre-configuration. Furthermore, we identified the presence of PolII-enriched MuERV-L around the transcriptional start site of minor ZGA-related lncRNAs, and these repeats are responsible for the activation of minor ZGA-related lncRNAs and subsequent embryo development. Our study suggests that MuERV-L mediates minor ZGA lncRNA activation as a critical driver between epigenetic reprogramming triggered by fertilization and the embryo developmental program, thus providing clues for understanding the regulatory mechanism of totipotency and establishing bona fide totipotent stem cells.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease globally, with only one Food and Drug Administration (FDA)-approved drug for its treatment. Given MASLD's complex pathophysiology, therapies that simultaneously target multiple pathways are highly desirable. One promising approach is dual-modulation of the farnesoid X receptor (FXR), which regulates lipid and bile acid metabolism. However, FXR agonists alone are insufficient due to their limited anti-inflammatory effects. This study aimed to dto identify natural products capable of both FXR activation and inflammation inhibition to provide a comprehensive therapeutic approach for MASLD. Potential FXR ligands from the Natural Product Library were predicted via virtual screening using the Protein Preparation Wizard module in Schrodinger (2018) for molecular docking. Direct binding and regulation of candidate compounds on FXR were analyzed using surface plasmon resonance (SPR) binding assay, reporter gene analysis, and reverse transcription-polymerase chain reaction (RT-PCR). The anti-inflammatory properties of these compounds were evaluated in AML12 cells treated with tumor necrosis factor-alpha (TNF-α). Dual-function compounds with FXR agonism and inflammation inhibition were further identified in cells transfected with Fxr siRNA and treated with TNF-α. The effects of these dual-function compounds on lipid accumulation and inflammation were evaluated in cells treated with palmitic acid. Results revealed that 17 natural products were predicted via computational molecular docking as potential FXR agonists, with 15 exhibiting a strong affinity for FXR recombinant protein. Nine isoflavone compounds significantly enhanced FXR reporter luciferase activity and the mRNA expressions of Shp and Ostb. Structure-activity relationship analysis indicated that introducing isopropyl or methoxy groups at the C7 position or a methoxy group at the C6 position could enhance the agonistic efficacy of isoflavones. Three compounds (2, 6, and 8) were identified as dual-function natural products functioning as FXR agonists and inflammatory inhibitors, while one compound (12) acted as an FXR agonist to inhibit inflammation. These natural products protected hepatocytes against palmitic acid-induced lipid accumulation and inflammation. In conclusion, compounds 2, 6, and 8 (genistein, biochanin A, and 7-methoxyisoflavone, respectively) were identified as dual-function bioactive products that transactivate FXR and inhibit inflammation, serving as potential candidates or lead compounds for MASLD therapy.

SummaryIn the development of diabetic retinopathy (DR), neutrophil infiltration hastens the adhesion between neutrophils and endothelial cells, leading to inflammation. Meanwhile, neutrophil extracellular traps (NETs) produced by neutrophils could clear aging blood vessels, setting the stage for retinal vascular regeneration. To explore the mechanism of NETs-related genes in DR, the transcriptome of NETs from normal and DR individuals were analyzed with gene sequencing and mendelian randomization (MR) analysis. Five NETs-related genes were identified as key genes. Among these genes, CLIC3, GBP2, and P2RY12 were found to be risk factors for Proliferative DR(PDR), whereas HOXA1 and PSAP were protective factors. Further verification by qRT-PCR recognized GBP2, P2RY12 and PSAP as NETs-associated biomarkers in PDR.PurposeTo investigate neutrophil extracellular traps (NETs) related genes as biomarkers in the progression of diabetic retinopathy (DR).MethodsWe collected whole blood samples from 10 individuals with DR and 10 normal controls (NCs) for transcriptome sequencing. Following quality control and preprocessing of the sequencing data, differential expression analysis was conducted to identify differentially expressed genes (DEGs) between the DR and NC groups. Candidate genes were then selected by intersecting these DEGs with key module genes identified through weighted gene co-expression network analysis. These candidate genes were subjected to mendelian randomization (MR) analysis, then least absolute shrinkage and selection operator analysis to pinpoint key genes. The diagnostic utility of these key genes was evaluated using receiver operating characteristic curve analysis, and their expression levels were examined. Additional analysis, including nomogram construction, gene set enrichment analysis, drug prediction and molecular docking, were performed to investigate the functions and molecular mechanisms of the key genes. Finally, the expression of key genes was verified by qRT-PCR and biomarkers were identified.ResultsIntersection of 1,004 DEGs with 1,038 key module genes yielded 291 candidate genes. Five key genes were identified: HOXA1, GBP2, P2RY12, CLIC3 and PSAP. Among them, CLIC3, GBP2, and P2RY12 were identified as risk factors for DR, while HOXA1 and PSAP were protective. These key genes demonstrated strong diagnostic performance for DR. With the exception of P2RY12, all other key genes exhibited down-regulation in the DR group. Furthermore, the nomogram incorporating multiple key genes demonstrated superior predictive capacity for DR compared to a single key genes. The identified key genes are involved in oxidative phosphorylation and ribosome functions. Drug predictions targeting P2RY12 suggested prasugrel, ticagrelor, and ticlopidine as potential options owing to their high binding affinity with this key genes. The qRT-PCR results revealed that the results of GBP2, PSAP and P2RY12 exhibited consistent expression patterns with the dataset.ConclusionThis study identified GBP2, P2RY12 and PSAP as NETs-associated biomarkers in the development of PDR, offering new insights for clinical diagnosis and potential treatment strategies for DR.

Background: Hemophagocytic lymphohistiocytosis (HLH) is a severe inflammatory reaction syndrome caused by genetic or acquired immune dysregulation. The majority of adult HLH cases are caused by tumors, rheumatic immune disorders, and infections. However, drug-induced HLH is rarely reported. Methods: We report a case of HLH in an adult caused by the administration of lamotrigine, to our knowledge, only nine other cases of lamotrigine-associated HLH have been reported in adult patients. Results: After discontinuing lamotrigine and using steroid hormones for the HLH, the patient's condition has been brought under control. Conclusions: This case confirms that dexamethasone is also effective for drug-induced HLH. Usually, after discontinuing the relevant medications, there is no need for further maintenance treatment. (Clin. Lab. 2024;70:417-420. DOI: 10.7754/Clin.Lab.2023.230730)

PARP7, a polyadenosine diphosphate-ribose polymerase, has been identified as a negative regulator in type I interferon (IFN) signaling. An overexpression of PARP7 is typically found in a wide range of cancers and can lead to the suppression of type I IFN signaling and innate immune response. Herein, we describe the discovery of compound I-1, a novel PARP7 inhibitor with high inhibitory potency (IC50 = 7.6 nM) and selectivity for PARP7 over other PARPs. Especially, I-1 has excellent pharmacokinetic properties and low toxicity in mice and exhibits significantly stronger in vivo antitumor potency (TGI: 67%) than RBN-2397 (TGI: 30%) without the addition of 1-aminobenzotriazole (a nonselective and irreversible inhibitor of cytochrome P450) in CT26 syngeneic mouse models. Our findings reveal that I-1 mainly acts as an immune activator through PARP7 inhibition in the tumor microenvironment, which highlights the potential advantages of I-1 as a tumor immunotherapeutic agent.

We aimed to characterize the clinical significance of epigenetic loss of death-associated protein kinase (DAPK) gene function through promoter methylation in the development and prognosis of lymphoma. PubMed, Web of Science and ProQuest databases were searched for relevant studies. Twelve studies involving 709 patients with lymphoma were identified. The prognostic value of DAPK methylation was expressed as risk ratio (RR) and its corresponding 95% confidence interval (CI), while the associations between DAPK methylation and the clinical characteristics of patients with lymphoma were expressed as odd ratios (ORs) and their corresponding 95% CIs. Meta-analysis showed that the 5-year survival rate was significantly lower in lymphoma patients with hypermethylated DAPK (RR = 0.85, 95% CI (0.73, 0.98), P = 0.025). Sensitivity analysis demonstrated consistent result. However, no associations were found between DAPK methylation and clinicopathological features of lymphoma, in relation to gender (OR = 1.07, 95% CI (0.72, 1.59), P = 0.751), age (OR = 1.01, 95% CI (0.66, 1.55), P = 0.974), international prognostic index (OR = 1.20, 95% CI (0.63, 2.27), P = 0.575), B symptoms (OR = 0.76, 95% CI (0.38, 1.51), P = 0.452), serum lactate dehydrogenase (OR = 1.13, 95% CI (0.62, 2.05), P = 0.683), and BCL-2 expression (OR = 1.55, 95% CI (0.91, 2.66), P = 0.106). Lymphoma patients with hypermethylated DAPK are at risk for poorer 5-year survival rate. DAPK methylation may serve as a negative prognostic biomarker among lymphoma patients, although it may not be associated with the progression of lymphoma.

Pien Tze Huang (PTH) was documented as an imperial prescription composed of Notoginseng Radix, Calculus Bovis, Snake Gallbladder, and Musk. It is famous in China and Asian countries due to its excellent effects in heat clearing, detoxifying, swelling reduction, and pain relieving. Modern pharmacological studies demonstrate that PTH shows excellent effects against various inflammatory diseases, liver diseases, and cancers. This review summaries the pharmacological effects, clinical applications, and mainchemical components of PTH. More importantly, its potential quality markers (Q-markers) were then analyzed based on the "five principles" of Q-markers under the guidance of Traditional Chinese Medicine theory, including transfer and traceability, specificity, efficacy, compatibility, and measurability. As a result, ginsenosides Rb1, ginsenoside Rg1, ginsenoside Rd, ginsenoside Re, notoginsenoside R1, dencichine, bilirubin, biliverdin, taurocholic acid, and muscone are considered as the Q-markers of PTH. These findings will provide guidance and assistance for the construction of a quality control system for PTH.

Reprogramming of metabolism is a hallmark of tumors, which has been explored for therapeutic purposes. Prostate cancer (PCa), particularly advanced and therapy-resistant PCa, displays unique metabolic properties. Targeting metabolic vulnerabilities in PCa may benefit patients who have exhausted currently available treatment options and improve clinical outcomes. Among the many nutrients, glutamine has been shown to play a central role in the metabolic reprogramming of advanced PCa. In addition to amino acid metabolism, glutamine is also widely involved in the synthesis of other macromolecules and biomasses. Targeting glutamine metabolic network by maximally inhibiting glutamine utilization in tumor cells may significantly add to treatment options for many patients. This review summarizes the metabolic landscape of PCa, with a particular focus on recent studies of how glutamine metabolism alterations affect therapeutic resistance and disease progression of PCa, and suggests novel therapeutic strategies.

Background Renal injury is one of the common microvascular complications of diabetes, known as diabetic kidney disease (DKD) seriously threatening human health. Previous research has reported that the Chinese Medicine Fufang-Zhenzhu-Tiaozhi (FTZ) capsule protected myocardia from injury in diabetic minipigs with coronary heart disease (DM-CHD). And we found significant renal injury in the minipigs. Therefore, we further investigated whether FTZ prevents renal injury of DM-CHD minipig and H 2 O 2 -induced oxidative injury of HK-2 cells. Methods DM-CHD model was established by streptozotocin injection, high fat/high-sucrose/high-cholesterol diet combined with balloon injury in the coronary artery. Blood lipid profile, fasting blood glucose (FBG), and SOD were measured with kits. The levels of blood urea nitrogen (BUN), serum creatinine (Scr), urine trace albumin (UALB), urine creatinine (UCR) (calculate UACR), cystatin (Cys-C), and β-microglobulin (β-MG) were measured by ELISA kits to evaluate renal function. TUNEL assay was performed to observe the apoptosis. qPCR was used to detect the mRNA expression levels of HO-1, NQO1, and SOD in kidney tissue. The protein expressions of Nrf2, HO-1, NQO1, Bax, Bcl-2, and Caspase 3 in the kidney tissue and HK-2 cells were detected by western blot. Meanwhile, HK-2 cells were induced by H 2 O 2 to establish an oxidative stress injury model to verify the protective effect and mechanisms of FTZ. Results In DM-CHD minipigs, blood lipid profile and FBG were elevated significantly, and the renal function was decreased with the increase of BUN, Scr, UACR, Cys-c, and β-MG. A large number of inflammatory and apoptotic cells in the kidney were observed accompanied with lower levels of SOD, Bcl-2, Nrf2, HO-1, and NQO1, but high levels of Bax and Cleaved-caspase 3. FTZ alleviated glucose-lipid metabolic disorders and the pathological morphology of the kidney. The renal function was improved and the apoptotic cells were reduced by FTZ administration. FTZ could also enhance the levels of SOD, Nrf2, HO-1, and NQO1 proteins to promote antioxidant effect, down-regulate the expression of Bax and Caspase3, as well as up-regulate the expression of Bcl-2 to inhibit cell apoptosis in the kidney tissue and HK-2 cells. Conclusions We concluded that FTZ prevents renal injury of DM-CHD through activating anti-oxidative capacity to reduce apoptosis and inhibiting inflammation, which may be a new candidate for DKD treatment. Graphical Abstract

Cycloastragenol (CAG) is a sapogenin of Astragaloside IV (AG-IV), isolated from the dried roots of legumes Astragalus mongolica or Astragalus membranaceus. Cycloastragenol has a steroidal skeleton of tetracyclic triterpene and possess diverse pharmacological activities such as anti-aging, anti-inflammatory, anti-fibrosis, pro-wound healing, liver protection and endothelial protection. In addition, cycloastragenol is the only telomerase activator reported in natural products, which is closely related to MAPK and PI3K/Akt signaling pathways. This review provides a theoretical basis for the development of cycloastragenol into the candidate for the treatment of multi-factorial diseases in clinic, focusing on the extensively biological activities as well as the mechanism of action and structural modification and aiming to attract researchers to conduct in-depth studies on cycloastragenol. Meanwhile, the pharmacokinetics and toxicology studies of CAG are also described for further druggability exploration to provides valuable reference.

To investigate the Th1/Th2 cytokine profile in patients with lymphoma during the myelosuppression stage of infection. 52 patients with gram-negative bacterial infection (G- group), 49 patients with gram-positive bacterial infection (G+ group), 51 uninfected patients with lymphoma (uninfected group) and 20 healthy controls (healthy group) were enrolled in this study. We evaluated the quantification of Th1/Th2 cytokines with flow cytometry bead assay (CBA) in the sera to explore a rapid diagnostic method to determine the type of infection and anti-infective effect. The levels of procalcitonin (PCT) were also detected simultaneously. The four groups did not differ with regard to IL-2 and IL-4 (P>0.05). The IFN-γ and TNF-α levels of patients with lymphoma were higher than those of healthy controls (P<0.05). There was significantly upregulated IL-6 and IL-10 expression in the G- group (P<0.001). A similar trend was reflected in the IL-6 of the G+ group, which was significantly increased (P<0.001). However, no significant upregulation was observed for IL-10 in the G+ group. According to the different degrees of increased IL-6 and IL-10 levels, We proposed to use the G- Bacterial Infection Cytokine Profile (G- BICP) and the G+ Bacterial Infection Cytokine Profile (G+ BICP) for the first time to differentiate between Gram-negative and Gram-positive (G-/G+) bacterial infection in adults with lymphoma in the myelosuppression stage after chemotherapy. The IL-6, IL-10 and PCT in the G- group and the IL-6, PCT in the G+ group were significantly decreased at day 4 and day 8 compared with those at day 1. IL-6 and IL-10 are closely associated with the severity and treatment efficacy in adults with lymphomas who develop infections after chemotherapy and can help distinguish between G- and G+ bacterial infections at an early stage.