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International Journal of Molecular... Mar 2024The senolytics dasatinib and quercetin (DQ) alleviate age‑related disorders. However, limited information is available regarding the effects of DQ on diabetic kidney...
Senolytic combination of dasatinib and quercetin protects against diabetic kidney disease by activating autophagy to alleviate podocyte dedifferentiation via the Notch pathway.
The senolytics dasatinib and quercetin (DQ) alleviate age‑related disorders. However, limited information is available regarding the effects of DQ on diabetic kidney disease (DKD). The present study aimed to explore the effects of DQ on DKD and its potential molecular mechanism(s). Dasatinib (5 mg/kg) and quercetin (50 mg/kg) were administered to diabetic db/db mice by gavage for 20 weeks. Body weight, urine albumin‑creatinine ratio (ACR), serum creatinine (Scr), and blood urea nitrogen (BUN) were recorded at the indicated time periods. Periodic acid‑Schiff and Masson's staining were performed to assess the histopathological changes of kidney tissues. Immunohistochemical analysis, immunofluorescence and western blotting were performed to evaluate the expression levels of extracellular matrix (ECM) proteins, autophagic and podocyte differentiation‑related proteins. In addition, mouse podocytes were administered with high‑glucose, DQ and 3‑methyladenine (3‑MA), and the expression levels of autophagic and podocyte differentiation‑related proteins were measured. Moreover, following overexpression of the Notch intracellular domain (NICD), the expression levels of NICD, autophagic and podocyte differentiation‑related proteins were further assessed. DQ significantly reduced the body weight, blood glucose, ACR, Scr and BUN levels and improved the histopathological changes induced in diabetic db/db mice. In addition, DQ caused a significant downregulation of the expression levels of the ECM proteins, improved autophagy and induced an upregulation of the expression levels of podocyte differentiation‑related proteins. Administration of 3‑MA to mice significantly reduced podocyte differentiation, and overexpression of NICD could reverse the effects of DQ on autophagy and podocyte differentiation . The present study suggests that DQ protects against DKD by activation of autophagy to alleviate podocyte dedifferentiation via the Notch pathway.
Topics: Mice; Animals; Diabetic Nephropathies; Podocytes; Dasatinib; Quercetin; Senotherapeutics; Autophagy; Body Weight; Diabetes Mellitus
PubMed: 38240118
DOI: 10.3892/ijmm.2024.5350 -
Frontiers in Bioscience (Landmark... Sep 2023Previous studies have confirmed the anti-inflammation effect of bone marrow mesenchymal stem cell-derived exosomes (BMSC-Exo). We aimed to investigate the therapeutic...
BACKGROUND AND AIMS
Previous studies have confirmed the anti-inflammation effect of bone marrow mesenchymal stem cell-derived exosomes (BMSC-Exo). We aimed to investigate the therapeutic effect of BMSC-Exo on diabetic kidney disease (DKD), as well as the underlying mechanisms.
METHODS
SD rats were induced by streptozotocin combined with a high-fat diet to establish a diabetes disease model. BMSCs-Exo were injected via tail veins at a weekly dose of 100 µg for 12 weeks. Pathological changes in the rat kidneys were evaluated using HE, Masson, and Periodic Acid-Schiff and immunohistochemical staining. TUNEL staining and western blot were used to evaluate the expression levels of apoptosis-related proteins in the rat kidney cells. The TNF-α level was detected by PCR and NF-κB (p65) by western blotting to examine the inflammatory responses in the renal tissue.
RESULTS
BMSCs-Exo significantly alleviated the renal structural damage and the distribution of apoptotic cells in diabetic rats. Furthermore, BMSCs-Exo increased the expression of pro-apoptosis protein Bax and decreased the expression of apoptosis-executing protein Cleaved Caspase 9 and Cleaved caspase 3. In addition, the transcription level of TNF-α in kidney tissue and NF-κB (p65) expression was also decreased through BMSCs-Exo treatment. Besides, the levels of glucose (GLU), creatinine (Cr), and burea nitrogen (BUN) in diabetic rats were decreased by the BMSC-Exo treatment.
CONCLUSIONS
BMSCs-Exo may alleviate diabetic kidney damage by inhibiting apoptosis and inflammation.
Topics: Rats; Animals; Diabetic Nephropathies; Rats, Sprague-Dawley; NF-kappa B; Diabetes Mellitus, Experimental; Exosomes; Tumor Necrosis Factor-alpha; Mesenchymal Stem Cells; Apoptosis; Inflammation
PubMed: 37796685
DOI: 10.31083/j.fbl2809203 -
MSMR Oct 2023Malaria, caused by various species of the Plasmodium parasite, remains a significant health threat in most U.S. military regions-AFRICOM, CENT-COM, INDOPACOM, and... (Review)
Review
Malaria, caused by various species of the Plasmodium parasite, remains a significant health threat in most U.S. military regions-AFRICOM, CENT-COM, INDOPACOM, and SOUTHCOM-and although less prevalent, also poses periodic risks to military personnel in NORTHCOM through imported cases. Early diagnosis is crucial for effective malaria chemotherapy, and rapid diagnostic tests (RDTs) have proven valuable in resource-poor settings and operational environments. The BinaxNow Malaria RDT is currently the sole U.S. Food and Drug Administration (FDA)-approved test for use on U.S. military personnel. This simple RDT targets Plasmodium falciparum, the deadliest malaria species, by detecting the histidine-rich protein 2 (HRP2), as well as pan-Plasmodium species by detecting aldolase. The emergence of mutant P. falciparum parasites lacking pfhrp2/pfhrp3 genes and thus not expressing HRP2/HRP3 proteins poses a significant challenge in many malaria-endemic areas. This genetic variation has led to false-negative results in all HRP2-detecting RDTs including BinaxNow, undermining its utility. Current U.S. military force health protection (FHP) measures for preventing malaria, including chemoprophylaxis, permethrin-treated uniforms, and DEET application to exposed skin, are effective, but breakthrough infections still occur. The use of portable and user-friendly malaria diagnostics is necessary in remote locations that lack microscopy or nucleic acid-based diagnostic capabilities. The alarmingly high prevalence of mutant pfhrp2/3-deleted parasites poses a threat to malaria diagnosis in all Combatant Commands where point-of-care testing is vital. This review emphasizes the importance of ongoing monitoring to determine the frequency and distribution of mutant parasites. Urgent attention is needed to develop alternative RDTs that can effectively detect malaria infections caused by these mutant strains. These findings confirm that mutant pfhrp2/3-deleted parasites are highly prevalent in SOUTHCOM and parts of AFRICOM, rendering HRP2-based RDTs such as BinaxNow an unsuitable diagnostic tool for malaria in many of the SOUTHCOM and AFRICOM countries surveyed: Peru (14.3-62% between 2011-2018), Eritrea (62% in 2016 and 9.4% in 2020), Nigeria (13.3%), Sudan (11.2%), South Sudan (17.7%), and Uganda (3.3%). In INDOPACOM countries surveyed, no prevalence greater than 5% pfhrp2 deletions were observed. It is critical to continue surveillance on the frequency and distribution of these mutant parasites and develop alternative RDTs. WHO recommends that countries switch to non-HRP2-based RDTs when prevalence of pfhrp2/3 deletions that cause false-negative RDT results exceed 5%. Current prevalence of mutant pfhrp2/3-deleted parasites causing false-negative RDT results has exceeded this threshold in most parts of SOUTHCOM and several areas of AFRICOM. If alternative diagnostic tests are not utilized in areas affected, life-saving malaria treatment for U.S. military personnel could be delayed. Continuous mapping of the frequency and distribution of mutant parasites directly informs FHP protection policy decisions for alternative diagnostic tool utilization.
Topics: Humans; Protozoan Proteins; Antigens, Protozoan; Rapid Diagnostic Tests; Diagnostic Tests, Routine; Military Personnel; Malaria, Falciparum; Plasmodium falciparum
PubMed: 37963222
DOI: No ID Found -
Journal of Ethnopharmacology May 2024Wuji Wan (WJW) is a traditional Chinese medicine formula that can be found in the "Prescriptions of Taiping Benevolent Dispensary" that has been employed in treating...
The active components and potential mechanisms of Wuji Wan in the treatment of ethanol-induced gastric ulcer: An integrated metabolomics, network pharmacology and experimental validation.
ETHNOPHARMACOLOGICAL RELEVANCE
Wuji Wan (WJW) is a traditional Chinese medicine formula that can be found in the "Prescriptions of Taiping Benevolent Dispensary" that has been employed in treating gastric discomfort, burning epigastric pain, and gastric reflux for hundreds of years and has shown promise for treating gastric ulcers (GUs). However, the active components and mechanism of action against GUs remain unclear.
AIM OF THE STUDY
The aim of this study was to explore the active components of WJW and elucidate the underlying mechanism involved in treating GUs.
MATERIALS AND METHODS
Initially, cell viability was measured by a cell counting kit 8 (CCK-8) assay to evaluate the efficacy of WJW-containing serum in vitro. The gastric ulcer index, ulcer inhibition rate, hematoxylin and staining (H&E), and periodic acid-Schiff (PAS) staining were used to evaluate the therapeutic effect of WJW in vivo. Subsequently, the levels of inflammatory factors and oxidative stress factors were determined using an enzyme-linked immunosorbent assays (ELISA) on in vitro and in vivo samples. Additionally, UPLC-Q Exactive Plus Orbitrap HRMS was used to analyze the components that were absorbed into the blood of WJW and its metabolites. Network pharmacology and metabolomics were subsequently used to identify the targets and pathways. Real-time quantitative PCR (RT‒qPCR) and Western blotting were used to verify the mRNA and protein levels of the key targets and pathways. Finally, the active components were identified by molecular docking to verify the binding stability of the components and key targets.
RESULTS
WJW-containing serum ameliorated ethanol-induced damage in GES-1 cells and promoted cell healing. WJW-containing serum reduced IL-6, TNF-α, MDA, and LDH levels while increasing IL-10, SOD, and T-AOC levels in the cells. Moreover, WJW treatment resulted in decreased IL-6, TNF-α, and MDA levels and increased IL-10, SOD, PGE and NO levels in GUs rats. In addition, eight components of WJW were absorbed into the blood. The network pharmacology results revealed 192 common targets for blood entry components and GUs, and KEGG analysis revealed that apoptosis signaling pathways were the main pathways involved in WJW activity against GUs. Metabolomic screening was used to identify 13 differential metabolites. There were 23 common targets for blood entry components, GUs, and differential metabolites, with the key targets TNF (TNF-α), AKT1, PTGS2 (COX2) and MAPK1. WJW significantly inhibited the expression of Bax, Caspase-9, Caspase-3, cleaved Caspase-9, cleaved Caspase-3, TNF-α, COX2, and p-p44/42 MAPK while promoting the expression of Bcl-2 and p-AKT1. Molecular docking revealed that the active components of WJW for the treatment of GUs are berberine, palmatine, coptisine, evodiamine, rutaecarpine, evocarpine, and paeoniflorin.
CONCLUSIONS
WJW treatment reduces inflammation and oxidative stress injury and inhibits apoptosis signaling pathways. The main active components are berberine, palmatine, coptisine, evodiamine, rutaecarpine, evocarpine, and paeoniflorin. In this paper, we provide a new strategy for exploring the active components of traditional Chinese medicine formulas for the treatment of diseases based on target mechanisms.
Topics: Animals; Rats; Stomach Ulcer; Caspase 3; Caspase 9; Interleukin-10; Berberine; Cyclooxygenase 2; Interleukin-6; Molecular Docking Simulation; Network Pharmacology; Tumor Necrosis Factor-alpha; Superoxide Dismutase; Drugs, Chinese Herbal; Glucosides; Monoterpenes
PubMed: 38341112
DOI: 10.1016/j.jep.2024.117901 -
F1000Research 2022In routine histopathology, 10% neutral buffered formalin (NBF) is the choice fixative. However, formalin is a human carcinogen, so there is a necessity for a safer...
In routine histopathology, 10% neutral buffered formalin (NBF) is the choice fixative. However, formalin is a human carcinogen, so there is a necessity for a safer alternative. To the best of our knowledge, neutral honey, not natural or artificial honey, has not been tested to fix histological samples. This study determined the effectiveness of neutral buffered honey and other types of fixatives to fix histological tissues. The study was conducted between July 2019 and August 2020 at Sultan Qaboos University, Oman. Sections from three rat livers, kidneys, and stomach tissues were fixed with 10% NBF, neutral buffered Sumer honey, neutral buffered date honey, formalin, Sumer honey, date honey, alcoholic formalin, alcoholic Sumer honey, and alcoholic date honey for 24 hours. Samples were stained with hematoxylin and eosin (H&E), special stains, and vimentin methods. Three expert biomedical scientists then evaluated the fixed and stained samples for the quality of all sections. The fixation ability of the different honey solutions was then compared to 10% NBF and the utility was determined using nuclear and cytoplasmic criteria, specificity, and intensity. H&E showed adequate staining in all groups compared to 10% NBF. The specificity and intensity of all groups for the Periodic acid-Schiff method were identical to 10% NBF except for Sumer honey and alcoholic date honey. Vimentin showed comparable findings with 10% NBF as there were no significant differences. The findings of this study encourage the use of honey, including neutral, as a possible safe substitute fixative for formalin, however, further experiments on larger specimens should be conducted.
Topics: Animals; Rats; Humans; Fixatives; Vimentin; Honey; Formaldehyde; Carcinogens; Eosine Yellowish-(YS)
PubMed: 38433997
DOI: 10.12688/f1000research.122598.3 -
International Journal of Molecular... Sep 2023We designed 0D, 1D, and 2D supramolecular assemblies made of diaryliodonium salts (functioning as double σ-hole donors) and carboxylates (as σ-hole acceptors). The...
We designed 0D, 1D, and 2D supramolecular assemblies made of diaryliodonium salts (functioning as double σ-hole donors) and carboxylates (as σ-hole acceptors). The association was based on two charge-supported halogen bonds (XB), which occurred between I sites of the iodonium cations and the carboxylate anions. The sequential introduction of the carboxylic groups in the aryl ring of the benzoic acid added a dimension to the 0D supramolecular organization of the benzoate, which furnished 1D-chained and 2D-layered structures when terephthalate and trimesate anions, correspondingly, were applied as XB acceptors. The structure-directing XB were studied using DFT calculations under periodic boundary conditions and were followed by the one-electron-potential analysis and the Bader atoms-in-molecules topological analysis of electron density. These theoretical methods confirmed the existence of the XB and verified the philicities of the interaction partners in the designed solid-state structures.
Topics: Halogens; Carboxylic Acids; Anions; Density Functional Theory; Benzoic Acid
PubMed: 37834088
DOI: 10.3390/ijms241914642 -
Diagnostic Pathology Aug 2023Malakoplakia is a rare inflammatory disease of the urogenital tract. There have been no reports of malakoplakia expressing anaplastic lymphoma kinase (ALK) to date....
BACKGROUND
Malakoplakia is a rare inflammatory disease of the urogenital tract. There have been no reports of malakoplakia expressing anaplastic lymphoma kinase (ALK) to date. Here, we present one case of malakoplakia with aberrant ALK expression by immunohistochemistry and discuss the clinical significance.
CASE PRESENTATION
A 65-year-old Chinese woman with a history of diabetes presented with solid masses in the liver and kidney and elevated lesions on the mucosal surface of the colon. Right nephrectomy and partial liver resection were performed. Microscopically, sheets of histiocytes with poor intercellular adhesion were seen, with Michaelis-Gutmann bodies present in both the intracellular and extracellular interstitium. CD10-, CD68-, and CD163-positive cells were present, with Michaelis-Gutmann bodies confirmed by staining with Alcian blue, periodic acid-Schiff (PAS), periodic acid-Schiff with diastase, Von Kossa, and Prussian blue. Aberrant ALK1 and ALK (D5F3) expression was observed in the cytoplasm and nucleus of cells. However, ALK gene mutation was not detected by fluorescence in situ hybridization or whole exome next-generation sequencing. NGS revealed nine individual somatic gene mutations: GOT1L1, GLIS2, SPOUT1, TMEM97, MUC3A, NSD2, SFXN5, ADAD1 and RAD50. The significance of the somatic gene mutations detected in this study is not clear, and the relationship between them and malakoplakia cannot be clarified by existing scientific studies. The pathological diagnosis was malakoplakia with aberrant ALK expression by immunohistochemistry. The antibiotics imipenem and vancomycin were started based on the results of drug sensitivity analysis and the patient was subsequently discharged. She experienced no discomfort during 30 months of follow-up.
CONCLUSION
This is the first reported case of malakoplakia with aberrant ALK expression, it should be differentiated from ALK-positive histiocytosis to avoid misdiagnosis.
Topics: Female; Humans; Aged; Anaplastic Lymphoma Kinase; Immunohistochemistry; Malacoplakia; In Situ Hybridization, Fluorescence; Periodic Acid
PubMed: 37644531
DOI: 10.1186/s13000-023-01383-z -
Polymers Aug 2023Self-assembly of 3D interiors and iridescence properties of poly(β-hydroxybutyric acid-co-β-hydroxyvaleric acid) (PHBV) periodic crystals are examined using microcopy...
Self-assembly of 3D interiors and iridescence properties of poly(β-hydroxybutyric acid-co-β-hydroxyvaleric acid) (PHBV) periodic crystals are examined using microcopy techniques and microbeam X-ray diffraction. Morphology of PHBV can be tailored by crystallizing in presence of poly(vinyl acetate) (PVAc) or poly(trimethylene adipate) (PTA) for displaying desired periodicity patterns. The regular alternate-layered lamellae of banded PHBV crystal aggregates, resembling the structures the natural mineral moonstone or nacre, are examined to elaborate the origin of light interference and formation mechanisms of periodic lamellar aggregation of PHBV spherulites. By using PHBV as a convenient model and the crystal diffraction data, this continuing work demonstrates unique methodology for effectively studying the periodic assembly in widely varying polymers with similar aggregates. Grating structures in periodically assembled polymer crystals can be tailored for microstructure with orderly periodicity.
PubMed: 37631541
DOI: 10.3390/polym15163484 -
International Journal of Sports... Jul 2023To examine the effects of a high-carbohydrate diet (HCHO), periodized-carbohydrate (CHO) diet (PCHO), and ketogenic low-CHO high-fat diet (LCHF) on training capacity.
PURPOSE
To examine the effects of a high-carbohydrate diet (HCHO), periodized-carbohydrate (CHO) diet (PCHO), and ketogenic low-CHO high-fat diet (LCHF) on training capacity.
METHODS
Elite male racewalkers completed 3 weeks of periodic training while adhering to their dietary intervention. Twenty-nine data sets were collected from 21 athletes. Each week, 6 mandatory training sessions were completed, with additional sessions performed at the athlete's discretion. Mandatory sessions included an interval session (10 × 1-km efforts on a 6-min cycle), tempo session (14 km with a 450-m elevation gain), 2 long walks (25-40 km), and 2 easy walks (8-12 km) where "sleep-low" and "train-low" dietary strategies were employed for PCHO. Racewalking speed, heart rate, rating of perceived exhaustion, and blood metabolites were collected around key sessions.
RESULTS
LCHF covered less total distance than HCHO and PCHO (P < .001); however, no differences in training load between groups were evident (P = .285). During the interval sessions, walking speed was slower in LCHF (P = .001), equating to a 2.8% and 5.6% faster speed in HCHO and PCHO, respectively. LCHF was also 3.2% slower in completing the tempo session than HCHO and PCHO (P = .001). Heart rate was higher (P = .002) and lactate concentrations were lower (P < .001) in LCHF compared to other groups, despite slower walking speeds during the interval session. No between-groups differences in rating of perceived exhaustion were evident (P = .077).
CONCLUSION
Athletes adhering to an LCHF diet showed impaired training capacity relative to their high-CHO-supported counterparts, completing lower training volumes at slower speeds, with higher heart rates.
Topics: Humans; Male; Diet, High-Fat; Carbohydrates; Athletes; Lactic Acid; Dietary Carbohydrates
PubMed: 37263595
DOI: 10.1123/ijspp.2022-0351 -
Phytomedicine : International Journal... Jul 2024Bidirectional communication between the gut microbiota and the brain may play an essential role in the cognitive dysfunction associated with chronic sleep...
BACKGROUND
Bidirectional communication between the gut microbiota and the brain may play an essential role in the cognitive dysfunction associated with chronic sleep deprivation(CSD). Salvia miltiorrhiza Bunge (Danshen, DS), a famous Chinese medicine and functional tea, is extensively used to protect learning and memory capacities, although the mechanism of action remains unknown.
PURPOSE
The purpose of this research was to explore the efficacy and the underlying mechanism of DS in cognitive dysfunction caused by CSD.
METHODS
DS chemical composition was analyzed by UPLC-QTOF-MS/MS. Forty rats were randomly assigned to five groups (n = 8): control (CON), model (MOD), low- (1.35 g/kg, DSL), high-dose (2.70 g/kg, DSH) DS group, and Melatonin(100 mg/kg, MT) group. A CSD rat model was established over 21 days. DS's effects and the underlying mechanism were explored using the open-field test(OFT), Morris water-maze(MWM), tissue staining(Hematoxylin and Eosin Staining, Nissl staining, Alcian blue-periodic acid SCHIFF staining, and Immunofluorescence), enzyme-linked immunosorbent assay, Western blot, quantitative real-time polymerase chain reaction(qPCR), and 16S rRNA sequencing.
RESULTS
We demonstrated that CSD caused gut dysbiosis and cognitive dysfunction. Furthermore, 16S rRNA sequencing demonstrated that Firmicutes and Proteobacteria were more in fecal samples from model group rats, whereas Bacteroidota and Spirochaetota were less. DS therapy, on the contrary hand, greatly restored the gut microbial community, consequently alleviating cognitive impairment in rats. Further research revealed that DS administration reduced systemic inflammation via lowering intestinal inflammation and barrier disruption. Following that, DS therapy reduced Blood Brain Barrier(BBB) and neuronal damage, further decreasing neuroinflammation in the hippocampus(HP). Mechanistic studies revealed that DS therapy lowered lipopolysaccharide (LPS) levels in the HP, serum, and colon, consequently blocking the TLR4/MyD88/NF-κB signaling pathway and its downstream pro-inflammatory products(IL-1β, IL-6, TNF-α, iNOS, and COX2) in the HP and colon.
CONCLUSION
DS treatment dramatically improved spatial learning and memory impairments in rats with CSD by regulating the composition of the intestinal flora, preserving gut and brain barrier function, and reducing inflammation mediated by the LPS-TLR4 signaling pathway. Our findings provide novel insight into the mechanisms by which DS treats cognitive dysfunction caused by CSD.
Topics: Animals; Salvia miltiorrhiza; Sleep Deprivation; Cognitive Dysfunction; Male; Rats, Sprague-Dawley; Drugs, Chinese Herbal; Rats; Gastrointestinal Microbiome; Disease Models, Animal; Hippocampus; NF-kappa B; Morris Water Maze Test; Maze Learning
PubMed: 38772181
DOI: 10.1016/j.phymed.2024.155725