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1.
Front Cell Infect Microbiol ; 14: 1397724, 2024.
Article in English | MEDLINE | ID: mdl-38966251

ABSTRACT

Cryptococcus neoformans is at the top of the list of "most wanted" human pathogens. Only three classes of antifungal drugs are available for the treatment of cryptococcosis. Studies on antifungal resistance mechanisms are limited to the investigation of how a particular antifungal drug induces resistance to a particular drug, and the impact of stresses other than antifungals on the development of antifungal resistance and even cross-resistance is largely unexplored. The endoplasmic reticulum (ER) is a ubiquitous subcellular organelle of eukaryotic cells. Brefeldin A (BFA) is a widely used chemical inducer of ER stress. Here, we found that both weak and strong selection by BFA caused aneuploidy formation in C. neoformans, mainly disomy of chromosome 1, chromosome 3, and chromosome 7. Disomy of chromosome 1 conferred cross-resistance to two classes of antifungal drugs: fluconazole and 5-flucytosine, as well as hypersensitivity to amphotericin B. However, drug resistance was unstable, due to the intrinsic instability of aneuploidy. We found overexpression of AFR1 on Chr1 and GEA2 on Chr3 phenocopied BFA resistance conferred by chromosome disomy. Overexpression of AFR1 also caused resistance to fluconazole and hypersensitivity to amphotericin B. Furthermore, a strain with a deletion of AFR1 failed to form chromosome 1 disomy upon BFA treatment. Transcriptome analysis indicated that chromosome 1 disomy simultaneously upregulated AFR1, ERG11, and other efflux and ERG genes. Thus, we posit that BFA has the potential to drive the rapid development of drug resistance and even cross-resistance in C. neoformans, with genome plasticity as the accomplice.


Subject(s)
Aneuploidy , Antifungal Agents , Brefeldin A , Cryptococcus neoformans , Drug Resistance, Fungal , Cryptococcus neoformans/drug effects , Cryptococcus neoformans/genetics , Brefeldin A/pharmacology , Antifungal Agents/pharmacology , Drug Resistance, Fungal/genetics , Fluconazole/pharmacology , Amphotericin B/pharmacology , Fungal Proteins/genetics , Fungal Proteins/metabolism , Microbial Sensitivity Tests , Flucytosine/pharmacology , Humans , Endoplasmic Reticulum Stress/drug effects
2.
Diabetes Metab Syndr Obes ; 17: 1511-1521, 2024.
Article in English | MEDLINE | ID: mdl-38586542

ABSTRACT

Alcoholic fatty liver disease (FALD) and non-alcoholic fatty liver disease (NAFLD) have similar pathological spectra, both of which are associated with a series of symptoms, including steatosis, inflammation, and fibrosis. These clinical manifestations are caused by hepatic lipid synthesis and metabolism dysregulation and affect human health. Despite having been studied extensively, targeted therapies remain elusive. The Cytochrome P450 (CYP450) family is the most important drug-metabolising enzyme in the body, primarily in the liver. It is responsible for the metabolism of endogenous and exogenous compounds, completing biological transformation. This process is relevant to the occurrence and development of AFLD and NAFLD. In this review, the correlation between CYP450 and liver lipid metabolic diseases is summarised, providing new insights for the treatment of AFLD and NAFLD.

3.
Int J Biol Macromol ; 256(Pt 1): 128270, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38000586

ABSTRACT

Sirtuins (SIRT1-SIRT7), as a family of NAD+-dependent protein modifying enzymes, have various catalytic functions, such as deacetylases, dealkalylases, and deribonucleases. The Sirtuins family is directly or indirectly involved in pathophysiological processes such as glucolipid metabolism, oxidative stress, DNA repair and inflammatory response through various pathways and assumes an important role in several cardiovascular diseases such as atherosclerosis, myocardial infarction, hypertension and heart failure. A growing number of studies supports that metabolic and bioenergetic reprogramming directs the sequential process of inflammation. Failure of homeostatic restoration leads to many inflammatory diseases, and that macrophages are the central cells involving the inflammatory response and are the main source of inflammatory cytokines. Regulation of cellular metabolism has emerged as a fundamental process controlling macrophage function, but its exact signaling mechanisms remain to be revealed. Understanding the precise molecular basis of metabolic control of macrophage inflammatory processes may provide new approaches for targeting immune metabolism and inflammation. Here, we provide an update of studies in cardiovascular disease on the function and role of sirtuins in macrophage inflammation and metabolism, as well as drug candidates that may interfere with sirtuins, pointing to future prospects in this field.


Subject(s)
Cardiovascular Diseases , Sirtuins , Humans , Sirtuins/genetics , Cardiovascular Diseases/genetics , Oxidative Stress/genetics , Macrophages/metabolism , Inflammation/metabolism
4.
Pancreas ; 52(2): e151-e162, 2023 Feb 01.
Article in English | MEDLINE | ID: mdl-37523607

ABSTRACT

OBJECTIVES: This study aimed to develop a liver metastasis-related gene prognostic index (LMPI) for pancreatic ductal adenocarcinoma prognosis and therapy. METHODS: The Cancer Genome Atlas data set was used to identify liver metastasis-related hub genes via weighted gene coexpression network analysis. The core genes were identified to construct an LMPI by using the Cox regression method. An immune cell abundance identifier was applied to determine the immune cell abundance. RESULTS: A total of 78 hub liver metastasis-related genes in the black module were significantly enriched in complement and coagulation cascades, fat digestion and absorption, and the PPAR signaling pathway. Then, an LMPI was constructed on the basis of the 5 prognostic genes (MOGAT3, ASGR1, TRPM8, SGSM1, and LOC101927851). Patients with higher LMPI scores had poor overall survival, more co-occurring or mutually exclusive pairs of driver gene mutations, and less benefit from immunotherapy than patients with lower LMPI scores. In addition, a high correlation was also found between LMPI scores and immune infiltration, such as CD4 naive, CD8 T, cytotoxic T, T helper 2, follicular helper T, and natural killer cells. CONCLUSIONS: The core genes of the LMPI developed may be independent factors for predicting prognosis, immune characteristics, and immunotherapy efficacy in pancreatic ductal adenocarcinoma.


Subject(s)
Carcinoma, Pancreatic Ductal , Liver Neoplasms , Pancreatic Neoplasms , Humans , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/therapy , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/therapy , Liver Neoplasms/genetics , Liver Neoplasms/therapy , Prognosis , Asialoglycoprotein Receptor , Pancreatic Neoplasms
5.
Front Microbiol ; 14: 1137083, 2023.
Article in English | MEDLINE | ID: mdl-37113223

ABSTRACT

Candida parapsilosis is an emerging major human fungal pathogen. Echinocandins are first-line antifungal drugs for the treatment of invasive Candida infections. In clinical isolates, tolerance to echinocandins in Candida species is mostly due to point mutations of FKS genes, which encode the target protein of echinocandins. However, here, we found chromosome 5 trisomy was the major mechanism of adaptation to the echinocandin drug caspofungin, and FKS mutations were rare events. Chromosome 5 trisomy conferred tolerance to echinocandin drugs caspofungin and micafungin and cross-tolerance to 5-flucytosine, another class of antifungal drugs. The inherent instability of aneuploidy caused unstable drug tolerance. Tolerance to echinocandins might be due to increased copy number and expression of CHS7, which encodes chitin synthase. Although copy number of chitinase genes CHT3 and CHT4 was also increased to the trisomic level, the expression was buffered to the disomic level. Tolerance to 5-flucytosine might be due to the decreased expression of FUR1. Therefore, the pleiotropic effect of aneuploidy on antifungal tolerance was due to the simultaneous regulation of genes on the aneuploid chromosome and genes on euploid chromosomes. In summary, aneuploidy provides a rapid and reversible mechanism of drug tolerance and cross-tolerance in C. parapsilosis.

6.
mBio ; 14(2): e0022723, 2023 04 25.
Article in English | MEDLINE | ID: mdl-36877011

ABSTRACT

Antifungal drug tolerance is a response distinct from resistance, in which cells grow slowly above the MIC. Here, we found that the majority (69.2%) of 133 Candida albicans clinical isolates, including standard lab strain SC5314, exhibited temperature-enhanced tolerance at 37°C and 39°C, and were not tolerant at 30°C. Other isolates were either always tolerant (23.3%) or never tolerant (7.5%) at these three temperatures, suggesting that tolerance requires different physiological processes in different isolates. At supra-MIC fluconazole concentrations (8 to 128 µg/mL), tolerant colonies emerged rapidly at a frequency of ~10-3. In liquid passages over a broader range of fluconazole concentrations (0.25 to 128 µg/mL), tolerance emerged rapidly (within one passage) at supra-MICs. In contrast, resistance appeared at sub-MICs after 5 or more passages. Of 155 adaptors that evolved higher tolerance, all carried one of several recurrent aneuploid chromosomes, often including chromosome R, alone or in combination with other chromosomes. Furthermore, loss of these recurrent aneuploidies was associated with a loss of acquired tolerance, indicating that specific aneuploidies confer fluconazole tolerance. Thus, genetic background and physiology and the degree of drug stress (above or below the MIC) influence the evolutionary trajectories and dynamics with which antifungal drug resistance or tolerance emerges. IMPORTANCE Antifungal drug tolerance differs from drug resistance: tolerant cells grow slowly in drug, while resistant cells usually grow well, due to mutations in a few known genes. More than half of Candida albicans clinical isolates have higher tolerance at body temperature than they do at the lower temperatures used for most lab experiments. This implies that different isolates achieve drug tolerance via several cellular processes. When we evolved different strains at a range of high drug concentrations above inhibitory levels, tolerance emerged rapidly and at high frequency (one in 1,000 cells) while resistance appeared only later at very low drug concentrations. An extra copy of all or part of chromosome R was associated with tolerance, while point mutations or different aneuploidies were seen with resistance. Thus, genetic background and physiology, temperature, and drug concentration all influence how drug tolerance or resistance evolves.


Subject(s)
Antifungal Agents , Fluconazole , Antifungal Agents/pharmacology , Antifungal Agents/therapeutic use , Fluconazole/pharmacology , Candida albicans/genetics , Drug Resistance, Fungal/genetics , Microbial Sensitivity Tests , Drug Tolerance , Aneuploidy , Mitomycin/pharmacology , Chromosomes
7.
Microbiol Spectr ; : e0301622, 2023 Feb 28.
Article in English | MEDLINE | ID: mdl-36853047

ABSTRACT

Candida albicans is a prevalent, opportunistic, human fungal pathogen. Antifungal drug resistance and tolerance are two distinct mechanisms of adaptation to drugs. Studies of mechanisms of drug resistance are limited to the applications of high doses of drugs. Few studies have investigated the effects of subinhibitory amounts of drugs on the development of drug resistance or tolerance. In this study, we found that growth in a subinhibitory amount of fluconazole (FLC), a widely used antifungal drug, for just a short time was sufficient to induce aneuploidy in C. albicans. Surprisingly, the aneuploids displayed fitness loss in the presence of subinhibitory FLC, but a subpopulation of cells could tolerate up to 128 µg/mL FLC. Particular aneuploidy (ChrR trisomy) caused tolerance, not resistance, to FLC. In the absence of FLC, the aneuploids were unstable. Depending on the karyotype, aneuploids might become completely euploid or maintain particular aneuploidy, and, accordingly, the tolerance would be lost or maintained. Mechanistically, subinhibitory FLC was sufficient to induce the expression of several ERG genes and as well as the drug efflux gene MDR1. Aneuploids had a constitutive high-level expression of genes on and outside the aneuploid chromosomes, including most of the ERG genes as well as the drug efflux genes MDR1 and CDR2. Therefore, aneuploids were prepared for FLC challenges. In summary, aneuploidy provides a rapid and reversible strategy of adaptation when C. albicans is challenged with subinhibitory concentrations of FLC. IMPORTANCE Genome instability is a hallmark of C. albicans. Aneuploidy usually causes fitness loss in the absence of stress but confers better fitness under particular stress conditions. Therefore, aneuploidy is considered to be a double-edged sword. Here, we extend the understanding of aneuploidy. We found that aneuploidy arose under weak stress conditions but that it did not confer better fitness to the stress. Instead, it was less fit than its euploid counterparts. If the stress was withdrawn, aneuploidy spontaneously reverted to euploidy. If the stress became stronger, aneuploidy enabled subpopulation growth in a dose-independent manner of the stress. Therefore, we posit that aneuploidy enables the rapid and reversible development of drug tolerance in C. albicans. Further studies are required to investigate whether this is a general mechanism in human fungal pathogens.

8.
Cancer Med ; 12(10): 11073-11096, 2023 05.
Article in English | MEDLINE | ID: mdl-36645225

ABSTRACT

Colorectal cancer (CRC) is a common gastrointestinal malignancy with high morbidity and fatality. Chemotherapy, as traditional therapy for CRC, has exerted well antitumor effect and greatly improved the survival of CRC patients. Nevertheless, chemoresistance is one of the major problems during chemotherapy for CRC and significantly limits the efficacy of the treatment and influences the prognosis of patients. To overcome chemoresistance in CRC, many strategies are being investigated. Here, we review the common and novel measures to combat the resistance, including drug repurposing (nonsteroidal anti-inflammatory drugs, metformin, dichloroacetate, enalapril, ivermectin, bazedoxifene, melatonin, and S-adenosylmethionine), gene therapy (ribozymes, RNAi, CRISPR/Cas9, epigenetic therapy, antisense oligonucleotides, and noncoding RNAs), protein inhibitor (EFGR inhibitor, S1PR2 inhibitor, and DNA methyltransferase inhibitor), natural herbal compounds (polyphenols, terpenoids, quinones, alkaloids, and sterols), new drug delivery system (nanocarriers, liposomes, exosomes, and hydrogels), and combination therapy. These common or novel strategies for the reversal of chemoresistance promise to improve the treatment of CRC.


Subject(s)
Colorectal Neoplasms , MicroRNAs , Humans , MicroRNAs/genetics , Drug Resistance, Neoplasm/genetics , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , RNA Interference , Prognosis , Cell Line, Tumor
9.
Front Microbiol ; 13: 930495, 2022.
Article in English | MEDLINE | ID: mdl-36204612

ABSTRACT

Candida albicans is a prevalent, opportunistic human fungal pathogen. It usually dwells in the human body as a commensal, however, once in its pathogenic state, it causes diseases ranging from debilitating superficial to life-threatening systemic infections. The switch from harmless colonizer to virulent pathogen is, in most cases, due to perturbation of the fungus-host-microbiota interplay. In this review, we focused on the interactions between C. albicans and the host microbiota in the mouth, gut, blood, and vagina. We also highlighted important future research directions. We expect that the evaluation of these interplays will help better our understanding of the etiology of fungal infections and shed new light on the therapeutic approaches.

11.
Article in English | MEDLINE | ID: mdl-35770417

ABSTRACT

OBJECTIVE: Chemotherapy induced phlebitis (CIP) is a side product of chemotherapy treatment for malignant tumors, which affects the therapeutic effect and quality of life of cancer patients, and still lacks a clear therapeutic means. In this study, we investigated the therapeutic effects of QLTMP on CIP using network pharmacology and verified the anti-inflammatory mechanism of QLTMP in mice model induced by vinorelbine. METHODS: Network pharmacology analysis was performed to identify bioactive compounds in QLTMP. The protein-protein interaction network was used to identify the core therapeutic targets of QLTMP against CIP. Analyzed biological function and pathway enrichment based on the identified core therapeutic targets. Evaluate the therapeutic effect of QLTMP in a model of CIP induced by vinorelbine to confirm the reliability of the network pharmacological analysis. MATERIALS AND METHODS: The 165 bioactive compounds of QLTMP matched the screening criteria and identified 19 core therapeutic targets of QLTMP against CIP. Biofunctional analysis showed that the therapeutic effect of QLTMP on CIP was mainly related to the inhibition of inflammation; while pathway enrichment analysis showed that TNF signaling pathway was involved in the inflammatory process. Experimental confirmation in mice model showed that QLTMP exerts anti-inflammatory effects through modulation of PI3K/AKT/TNF signaling pathway, a discovery consistent with the network pharmacological analysis. DISCUSSION AND CONCLUSIONS: The network pharmacological analysis of the anti-inflammatory mechanism of QLTMP on CIP and its exploration of in vivo experiments provide a theoretical basis for the design of agents that can mitigate or cure CIP.

12.
Transl Res ; 247: 39-57, 2022 09.
Article in English | MEDLINE | ID: mdl-35452875

ABSTRACT

Fungal infection threatens human health worldwide due to the limited arsenal of antifungals and the rapid emergence of resistance. Epidermal growth factor receptor (EGFR) is demonstrated to mediate epithelial cell endocytosis of the leading human fungal pathogen, Candida albicans. However, whether EGFR inhibitors act on fungal cells remains unknown. Here, we discovered that the specific EGFR inhibitor osimertinib mesylate (OSI) potentiates azole efficacy against diverse fungal pathogens and overcomes azole resistance. Mechanistic investigation revealed a conserved activity of OSI by promoting intracellular fluconazole accumulation via inhibiting Pdr5 and disrupting V-ATPase function via targeting Vma1 at serine 274, eventually leading to inactivation of the global regulator TOR. Evaluation of the in vivo efficacy and toxicity of OSI demonstrated its potential clinical application in impeding fluconazole resistance. Thus, the identification of OSI as a dual action antifungal with co-targeting activity proposes a potentially effective therapeutic strategy to treat life-threatening fungal infection and overcome antifungal resistance.


Subject(s)
Azoles , Mycoses , Antifungal Agents/pharmacology , Azoles/pharmacology , Azoles/therapeutic use , ErbB Receptors , Fluconazole/pharmacology , Humans , Microbial Sensitivity Tests , Mycoses/drug therapy , Mycoses/microbiology
13.
Cell Death Discov ; 7(1): 344, 2021 Nov 10.
Article in English | MEDLINE | ID: mdl-34759279

ABSTRACT

Macrophages play a vital role in the development of atherosclerosis. Previously, we have found that swiprosin-1 was abundantly expressed in macrophages. Here, we investigated the role of swiprosin-1 expressed in macrophages in atherogenesis. Bone marrow transplantation was performed from swiprosin-1-knockout (Swp-/-) mice and age-matched ApoE-/- mice. Atherosclerotic lesion, serum lipid, and interleukin-ß (IL-ß) levels were detected. In vitro, the peritoneal macrophages isolated from Swp-/- and wild-type mice were stimulated with oxidized low-density lipoprotein (ox-LDL) and the macrophage of foam degree, cellular lipid content, apoptosis, inflammatory factor, migration, and autophagy were determined. Our results showed that swiprosin-1 was mainly expressed in macrophages of atherosclerotic plaques in aorta from ApoE-/- mice fed with high-cholesterol diet (HCD). The expression of swiprosin-1 in the foaming of RAW264.7 macrophages gradually increased with the increase of the concentration and time stimulated with ox-LDL. Atherosclerotic plaques, accumulation of macrophages, collagen content, serum total cholesterol, LDL, and IL-ß levels were decreased in Swp-/- → ApoE-/- mice compared with Swp+/+ → ApoE-/- mice fed with HCD for 16 weeks. The macrophage foam cell formation and cellular cholesterol accumulation were reduced, while the lipid uptake and efflux increased in macrophages isolated from Swp-/- compared to wild-type mice treated with ox-LDL. Swiprosin-1 deficiency in macrophages could inhibit apoptosis, inflammation, migration, and promote autophagy. Taken together, our results demonstrated that swiprosin-1 deficiency in macrophages could alleviate the development and progression of AS. The role of swiprosin-1 may provide a promising new target for ameliorating AS.

14.
Genetics ; 218(2)2021 06 24.
Article in English | MEDLINE | ID: mdl-33837402

ABSTRACT

Candida albicans is a prevalent human fungal pathogen. Rapid genomic change, due to aneuploidy, is a common mechanism that facilitates survival from multiple types of stresses including the few classes of available antifungal drugs. The stress survival of aneuploids occurs despite the fitness costs attributed to most aneuploids growing under idealized lab conditions. Systematic study of the aneuploid state in C. albicans has been hindered by the lack of a comprehensive collection of aneuploid strains. Here, we describe a collection of diploid C. albicans aneuploid strains, each carrying one extra copy of each chromosome, all from the same genetic background. We tested the fitness of this collection under several physiological conditions including shifts in pH, low glucose, oxidative stress, temperature, high osmolarity, membrane stress, and cell wall stress. We found that most aneuploids, under most conditions, were less fit than their euploid parent, yet there were specific conditions under which specific aneuploid isolates provided a fitness benefit relative to the euploid parent strain. Importantly, this fitness benefit was attributable to the change in the copy number of specific chromosomes. Thus, C. albicans can tolerate aneuploidy of each chromosome and some aneuploids confer improved growth under conditions that the yeast encounters in its host niches.


Subject(s)
Candida albicans/genetics , Chromosomes, Fungal/genetics , Genetic Fitness , Trisomy , Antifungal Agents/pharmacology , Antifungal Agents/therapeutic use , Candidiasis/drug therapy , Candidiasis/microbiology , Drug Resistance, Fungal/genetics , Genome, Fungal , Host Microbial Interactions/genetics , Humans
15.
Biotechnol Appl Biochem ; 68(2): 366-380, 2021 Apr.
Article in English | MEDLINE | ID: mdl-32374895

ABSTRACT

Ruan Jian Qing Mai formula (RJQM), a multicomponent herbal formula, has been widely used to treat peripheral arterial disease (PAD) in China. However, its active compounds and mechanisms of action are still unknown. First, RNA sequencing analysis of 15 healthy and 16 PAD samples showed that 524 PAD differential genes were significantly enriched in Go Ontology (ribonucleotide metabolic process, oxidoreductase complex, and electron transfer activity), Kyoto Encyclopedia of Genes and Genomes (KEGG) and GSEA pathways (OXPHOS and TCA cycle), miRNA (MIR183), and kinase (PAK6). Fifty-three active ingredients in RJQM had similar structures to the seven drug molecules in CLUE. Then, network topology analysis of the 53 components-target-pathway-disease network yielded 10 active ingredients. Finally, computational toxicity estimations showed that the median lethal dose (LD50) of the 10 active ingredients was above 1000 mg/kg, and eight of them did not cause hepatotoxicity, mutagenicity, carcinogenicity, cytotoxicity, and immunotoxicity nor activate 12 toxic pathways. In conclusion, RJQM has a protection effect on PAD by regulating a complex molecular network. Part of the mechanism is associated with the regulation of OXPHOS by 10 active components, which may alleviate mitochondrial dysfunction and pathological metabolic programming.


Subject(s)
Drugs, Chinese Herbal/pharmacology , Gene Expression Regulation/drug effects , Peripheral Arterial Disease/prevention & control , Humans , Peripheral Arterial Disease/genetics , Peripheral Arterial Disease/metabolism
16.
Anal Methods ; 13(1): 64-68, 2021 01 07.
Article in English | MEDLINE | ID: mdl-33305762

ABSTRACT

Owing to the growing interest in the application of Raman spectroscopy for quantitative purposes in solid pharmaceutical preparations, an article on the identification of compositions in excipient dominated drugs based on Raman spectra is presented. We proposed label-free Raman spectroscopy in conjunction with deep learning (DL) and non-negative least squares (NNLS) as a solution to overcome the drug fast screening bottleneck, which is not only a great challenge to drug administration, but also a major scientific challenge linked to falsified and/or substandard medicines. The result showed that Raman spectroscopy remains a cost effective, rapid, and user-friendly method, which if combined with DL and NNLS leads to fast implantation in the identification of lactose dominated drug (LDD) formulations. Meanwhile, Raman spectroscopy with the peak matching method allows a visual interpretation of the spectral signature (presence or absence of active pharmaceutical ingredients (APIs) and low content APIs).


Subject(s)
Deep Learning , Pharmaceutical Preparations , Drug Compounding , Excipients , Spectrum Analysis, Raman
17.
Biomed Pharmacother ; 129: 110281, 2020 Sep.
Article in English | MEDLINE | ID: mdl-32554251

ABSTRACT

Qingfei Paidu decoction (QFPD), a multi-component herbal formula, has been widely used to treat COVID-19 in China. However, its active compounds and mechanisms of action are still unknown. Firstly, we divided QFPD into five functional units (FUs) according to the compatibility theory of traditional Chinese medicine. The corresponding common targets of the five FUs were all significantly enriched in Go Ontology (oxidoreductase activity, lipid metabolic process, homeostatic process, etc.), KEGG pathways (steroid biosynthesis, PPAR signaling pathway, adipocytokine signaling pathway, etc.), TTD diseases (chronic inflammatory diseases, asthma, chronic obstructive pulmonary Disease, etc.), miRNA (MIR183), kinase (CDK7) and TF (LXR). QFPD contained 257 specific targets in addition to HCoV, pneumonia and ACE2 co-expression proteins. Then, network topology analysis of the five components-target-pathway-disease networks yielded 67 active ingredients. In addition, ADMET estimations showed that 20 compounds passed the stringent lead-like criteria and in silico drug-likeness test with high gastrointestinal absorption and the median lethal dose (LD50 > 1600 mg/kg). Moreover, 4 specific ingredients (M3, S1, X2 and O2) and 5 common ingredients (MS1, MX16, SX1, WO1 and XO1) of QFPD presented good molecular docking score for 2019-nCov structure and non-structure proteins. Finally, drug perturbation of COVID-19 network robustness showed that all five FUs may protect COVID-19 independently, and target 8 specifically expressed drug-attacked nodes which were related to the bacterial and viral responses, immune system, signaling transduction, etc. In conclusion, our new FUNP analysis showed that QFPD had a protection effect on COVID-19 by regulating a complex molecular network with safety and efficacy. Part of the mechanism was associated with the regulation of anti-viral, anti-inflammatory activity and metabolic programming.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Antiviral Agents/pharmacology , Coronavirus Infections/drug therapy , Drugs, Chinese Herbal/pharmacology , Pneumonia, Viral/drug therapy , Anti-Inflammatory Agents/administration & dosage , Antiviral Agents/administration & dosage , COVID-19 , Computer Simulation , Coronavirus Infections/virology , Drugs, Chinese Herbal/administration & dosage , Humans , Lethal Dose 50 , Molecular Docking Simulation , Pandemics , Pneumonia, Viral/virology , COVID-19 Drug Treatment
18.
Cell Physiol Biochem ; 45(3): 899-916, 2018.
Article in English | MEDLINE | ID: mdl-29421811

ABSTRACT

BACKGROUND/AIMS: Podocyte injury, especially podocyte apoptosis, plays a major role in early-stage diabetic nephropathy (DN). Swiprosin-1, also known as EF hand domain containing 2 (EFhd2), is a Ca2+-binding protein in different cell types. However, the function of swiprosin-1 in podocytes remains unknown. METHODS: The expression and distribution of swiprosin-1 were investigated in the mouse renal glomerulus and conditionally immortalized mouse podocyte cell line MPC-5. The expression of swiprosin-1 was also detected in streptozotocin (STZ)-treated mice and MPC-5 cells treated with high glucose (HG). Nephrin and podocin were detected by immunohistochemistry and immunofluroscence. Collagen IV, transforming growth factor-ß (TGF-ß) and fibronectin mRNA expressions were assayed by real-time PCR. Apoptotic proteins and phosphorylation of p38 mitogen-activated protein kinase (MAPK) were detected by immunoblotting. RESULTS: Swiprosin-1 was found to be expressed in podocytes of the mouse glomerulus and MPC-5 cells. Swiprosin-1 expression was increased in STZ-treated mice and MPC-5 cells treated with HG. In Swiprosin-1-/- diabetic mice, kidney/ body weight, urinary albumin, podocyte foot process effacement and glomerular basement membrane thickening were attenuated; the downregulation of nephrin and podocin expression in the glomerulus was inhibited; and the upregulation of collagen IV, TGF-ß and fibronectin mRNA expression in the renal cortex was ameliorated as compared with those in diabetic swiprosin-1+/+ mice. In addition, the increased apoptosis of podocytes, proapoptotic protein expression and p38 phosphorylation in Swiprosin-1-/- diabetic mice were inhibited as compared with those in diabetic swiprosin-1+/+ mice. Knockdown of swiprosin-1 in MPC-5 cells reduced the apoptosis of podocytes, proapoptotic protein expression and p38 phosphorylation induced by HG. Targeted knockdown of p38 attenuated the increased apoptosis of MPC-5 cells over-expressing swiprosin-1. CONCLUSION: Swiprosin-1 expression in podocytes of the mouse glomerulus played a critical role in early-stage DN. Swiprosin-1 deficiency in early DN attenuated mitochondria-dependent podocyte apoptosis induced by hyperglycemia or HG via p38 MAPK signaling pathway.


Subject(s)
Apoptosis , Calcium-Binding Proteins/metabolism , Diabetes Mellitus, Experimental/pathology , p38 Mitogen-Activated Protein Kinases/metabolism , Animals , Apoptosis/drug effects , Calcium-Binding Proteins/antagonists & inhibitors , Calcium-Binding Proteins/genetics , Cell Line , Diabetes Mellitus, Experimental/chemically induced , Diabetes Mellitus, Experimental/metabolism , Down-Regulation/drug effects , Fibronectins/genetics , Fibronectins/metabolism , Glucose/pharmacology , Kidney Glomerulus/cytology , Male , Membrane Potential, Mitochondrial/drug effects , Mice , Mice, Inbred C57BL , Mice, Knockout , Mitochondria/drug effects , Mitochondria/metabolism , Podocytes/cytology , Podocytes/drug effects , Podocytes/metabolism , Signal Transduction/drug effects , Streptozocin/toxicity , Transforming Growth Factor beta/genetics , Transforming Growth Factor beta/metabolism , Up-Regulation/drug effects , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , p38 Mitogen-Activated Protein Kinases/genetics
19.
Virulence ; 9(1): 555-562, 2018 01 01.
Article in English | MEDLINE | ID: mdl-28795862

ABSTRACT

In vitro interaction of osthol (Ost) and fluconazole (FLC) was investigated against 11 fluconazole-resistant clinical isolates of Candida albicans. Synergistic activities were determined using the checkerboard microdilution assay. The results of agar diffusion test confirmed the synergistic interaction. We used an enteric material Eudragit S100 for preparation of Ost nanoparticle (Ost-NP) to improve the oral bioavailability, biological activity of Ost. The physicochemical characteristics of Ost-S100-NP revealed Ost-S100-NP with mean particle size of 55.4±0.4 nm, encapsulation efficiency of 98.95±0.06%, drug loading efficiency of 23.89±0.25%, yield of 98.5±0.1% and a polydispersity index (PDI) of 0.165. As the Ost concentration-time curve showed, Ost-S100-NP can increase the plasma concentration and relative bioavailability of Ost compared with Ost-suspension by oral administration. In vivo, Ost-S100-NP enhanced the therapeutic efficacy of Ost against FLC-resistant C. albicans in immunosuppressed candidiasis mice model. The available information strongly suggests that Ost-S100-NP may be used as a promising compound against drug-resistant fungi.


Subject(s)
Antifungal Agents/pharmacology , Candida albicans/drug effects , Coumarins/pharmacology , Drug Carriers/metabolism , Drug Synergism , Polymethacrylic Acids/metabolism , Administration, Oral , Animals , Antifungal Agents/administration & dosage , Antifungal Agents/pharmacokinetics , Candidiasis/drug therapy , Candidiasis/microbiology , Disease Models, Animal , Drug Carriers/administration & dosage , Drug Carriers/pharmacokinetics , Fluconazole/pharmacology , Mice , Plasma/chemistry , Polymethacrylic Acids/administration & dosage , Polymethacrylic Acids/pharmacokinetics , Treatment Outcome
20.
Microbiol Immunol ; 60(2): 82-92, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26891940

ABSTRACT

This study aimed to investigate the antifungal activity of Rubus chingii extract in combination with fluconazole (FLC) against FLC-resistant Candida albicans 100 in vitro. A R. chingii extract and FLC-resistant C. albicans fungus suspension were prepared. The minimum inhibitory concentration and fractional inhibitory concentration index of R. chingii extract combined with FLC against C. albicans were determined, after which growth curves for C. albicans treated with R. chingii extract, FLC alone and a combination of these preparations were constructed. Additionally, the mechanisms of drug combination against C. albicans were explored by flow cytometry, gas chromatographic mass spectrometry and drug efflux pump function detection. R. chingii extract combined with FLC showed significant synergy. Flow cytometry suggested that C. albicans cells mainly arrest in G1 and S phases when they have been treated with the drug combination. The drug combination resulted in a marked decrease in the ergosterol content of the cell membrane. Additionally, efflux of Rhodamine 6G decreased with increasing concentrations of R. chingii extract. R. chingii extract combined with FLC has antifungal activity against FLC-resistant C. albicans.


Subject(s)
Antifungal Agents/pharmacology , Candida albicans/drug effects , Fluconazole/pharmacology , Plant Extracts/pharmacology , Rubus/chemistry , Apoptosis/drug effects , Candida albicans/cytology , Candida albicans/growth & development , Candida albicans/metabolism , Cell Cycle/drug effects , Cell Membrane/drug effects , Cell Membrane/metabolism , Drug Resistance, Fungal , Drug Synergism , Ergosterol/metabolism , Microbial Sensitivity Tests , Microscopy, Electron, Transmission , Rhodamines/metabolism
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