• Gut microbiota
• Hypobaric hypoxia
• Inflammatory response
• L. rhamnosus GG
• Oxidative stress
• Stachyose

• Animals
• Mice
• Antioxidants/pharmacology
• Antioxidants/metabolism
• Lacticaseibacillus rhamnosus
• Cytokines/metabolism
• Intestinal Diseases
• Oxidative Stress
• Hypoxia
• Anti-Inflammatory Agents
• Oligosaccharides

• Acute kidney injury
• HIF-1α
• Hypoxia
• Ischemia/reperfusion
• Ischemic kidney
• Oxygen sensing

• Humans
• Oxygen/metabolism
• Ischemia/metabolism
• Kidney/metabolism
• Hypoxia/genetics
• Hypoxia/metabolism
• Acute Kidney Injury/metabolism

• 71526 Tabriz University of Medical Sciences

Renal ischemia–reperfusion injury (IRI) is a common prerequisite of acute renal injury (AKI) that involves the entire system and induces critical illness. The C domain of insulin-like growth factor-1 (IGF-1C) plays an important role in promoting angiogenesis and enhancing the inflammatory response. However, given the shortcomings of its short half-life and poor stability, the application of IGF-1C is restricted. In the present study, IGF-1C nanoparticles (NP-IGF-1C) were constructed by combining 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[maleimide (polye thyleneglycol)](DSPE-PEG-MAL) and IGF-1C through a Michael addition reaction to evaluate the effects of NP-IGF-1C on preventing IRI. In vitro studies have shown that NP-IGF-1C is not cytotoxic and protects cells from oxidative damage. The renal enrichment and biocompatibility of NP-IGF-1C were determined in vivo by connecting fluorescent molecules to NP-IGF-1C for in vivo imaging and pathological staining of important organs. After IRI, renal function decreased, and inflammatory cell infiltration, oxidative stress and apoptosis increased. As expected, NP-IGF-1C reversed these changes, indicating that NP-IGF-1C played a protective role in the process of IRI, which may be mediated by its antioxidant, anti-inflammatory and antiapoptotic activities.

• C domain of insulin-like growth factor
• NP-IGF-1C
• Renal ischemia–reperfusion
• acute kidney injury
• antioxidant

Radiation-induced rectal injury is a common side effect of radiotherapy. Hypoxia often occurs after radiotherapy. This study aimed to explore the bystander effect of hypoxia on radiation-induced rectal injury. In vivo, apoptosis increased nearby the highly hypoxic area in the rectal tissues in the mouse models of radiation-induced rectal injury, indicating the potential involvement of hypoxia. In vitro, flow cytometry and Western blotting showed that both hypoxia and hypoxic human intestinal epithelial crypt (HIEC) cell supernatant promoted apoptosis in normoxic HIEC cells. The pro-apoptotic effect of extracellular vesicles (EVs) derived from hypoxic HIEC cell to normoxic HIEC cells was then determined. MiR-122-5p was chosen for further studies through a microRNA (miRNA) microarray assay and apoptosis was alleviated in cells receiving miR-122-5p inhibiting hypoxic EVs. Together, our study demonstrated that the miR-122-5p containing-EVs derived from hypoxic HIEC cells promoted apoptosis in normoxic HIEC cells. Hypoxic EV-derived miR-122-5p plays a critical pathologic role in radiation-induced rectal injury and may be a potential therapeutic target.

• BH3-only protein
• apoptosis
• lncRNA Neat1
• membranous nephropathy

Ischemia-reperfusion injury refers to the exacerbated and irreversible tissue damage caused by blood flow restoration after a period of ischemia. The hypoxia-reoxygenation (H/R) model in vitro is ideal for studying ischemia-reperfusion injury at the cellular level. We employed this model and investigated the effects of cobalt chloride- (CoCl₂-) induced H/R in cells derived from mouse digital flexor tendons.

Various H/R conditions were simulated via treatment of tendon-derived cells with different concentrations of CoCl₂ for 24 h, followed by removal of CoCl₂ to restore a normal oxygen state for up to 96 h. Cell viability was measured using the Cell Counting Kit-8 (CCK-8) assay. Cell growth was determined via observation of cell morphology and proliferation. Oxidative stress markers and mitochondrial activity were detected. The expression levels of hypoxia-inducible factor- (HIF-) 1α, vascular endothelial growth factor-A (VEGF-A), collagen I, and collagen III were determined using Western blot (WB), real-time PCR, and immunofluorescence staining. Cellular apoptosis was analyzed via flow cytometry, and the expression of apoptosis-related proteins Bax and bcl-2 was examined using WB.

The cells treated with low concentrations of CoCl₂ showed significantly increased cell viability after reoxygenation. The increase in cell viability was even more pronounced in cells that had been treated with high concentrations of CoCl₂. Under H/R conditions, cell morphology and growth were unchanged, while oxidative stress reaction was induced and mitochondrial activity was increased. H/R exerted opposite effects on the expression of HIF-1α mRNA and protein. Meanwhile, the expression of VEGF-A was upregulated, whereas collagen type I and type III were significantly downregulated. The level of cellular apoptosis did not show significant changes during H/R, despite the significantly increased Bax protein and reduced bcl-2 protein levels that led to an increase in the Bax/bcl-2 ratio during reoxygenation.

Tendon-derived cells were highly tolerant to the hypoxic environments induced by CoCl₂. Reoxygenation after hypoxia preconditioning promoted cell viability, especially in cells treated with high concentrations of CoCl₂. H/R conditions caused oxidative stress responses but did not affect cell growth. The H/R process had a notable impact on collagen production and expression of apoptosis-related proteins by tendon-derived cells, while the level of cellular apoptosis remained unchanged.

• Adiponectin
• Apoptosis
• Fibrogenic factor
• Human renal tubular epithelial cell
• Ischemic renal disease

The present study aimed to investigate the molecular mechanism of quercitrin, a major constituent of Hottuynia cordata extract, for its hair growth stimulating activities in cultured human dermal papilla cells (hDPCs). Quercitrin enhanced the cell viability and cellular energy metabolism in cultured hDPCs by stimulating the production of NAD(P)H and mitochondrial membrane potential (ΔΨ). The expression of Bcl2, an essential marker for anagen hair follicle and cell survival, was increased by quercitrin treatment. Quercitrin also increased the cell proliferation marker Ki67. The expression of growth factors—such as bFGF, KGF, PDGF-AA, and VEGF—were increased by quercitrin both in mRNA and protein levels. In addition, quercitrin was found to increase the phosphorylation of Akt, Erk, and CREB in cultured hDPCs, while inhibitors of MAPKs reversed the effects of quercitrin. Finally, quercitrin stimulated hair shaft growth in cultured human hair follicles. Our data obtained from present study are in line with those previously reported and demonstrate that quercitrin is (one of) the active compound(s) of Hottuynia cordata extract which showed hair growth promoting effects. It is strongly suggested that the hair growth stimulating activity of quercitrin was exerted by enhancing the cellular energy metabolism, increasing the production of growth factors via activation of MAPK/CREB signaling pathway.

• CREB
• MAPK
• growth factors
• hair growth
• human DPCs
• quercitrin

• Apoptosis/drug effects
• Butadienes/pharmacology
• Cell Proliferation/drug effects
• Cell Survival/drug effects
• Cells, Cultured
• Cyclic AMP Response Element-Binding Protein/metabolism
• Dermis/cytology
• Energy Metabolism/drug effects
• Extracellular Signal-Regulated MAP Kinases/metabolism
• Gene Expression Regulation/drug effects
• Hair/drug effects
• Hair/growth & development
• Humans
• Intercellular Signaling Peptides and Proteins/genetics
• Intercellular Signaling Peptides and Proteins/metabolism
• MAP Kinase Signaling System/drug effects
• Nitriles/pharmacology
• Phosphorylation/drug effects
• Proto-Oncogene Proteins c-akt/metabolism
• Proto-Oncogene Proteins c-bcl-2/genetics
• Proto-Oncogene Proteins c-bcl-2/metabolism
• Quercetin/analogs & derivatives
• Quercetin/chemistry
• Quercetin/pharmacology
• RNA, Messenger/genetics
• RNA, Messenger/metabolism
• Receptors, Cell Surface/genetics
• Receptors, Cell Surface/metabolism

Background and Objectives: Several studies have reported that some conditions such as exercise and hypoxia induce DNA damage and dysfunction and apoptosis. Some plant foods contain numerous bioactive compounds and anti-inflammatory properties that can help fight DNA damage. Therefore, the current study evaluated the effect of supplementation of Adiantum capillus-veneris (ACV) extract on Bax/B-cell lymphoma 2 (Bcl-2) ratio apoptotic index and remodeling of pulmonary alveolar epithelial cells in lung tissue of healthy Wistar rats during stressful conditions (hypoxia). Materials and Methods: Twenty-seven Wistar male rats (four-week old, 72 ± 9 g) were randomly assigned into three groups: normoxic, sedentary, and not-supplemented (NG, n = 9); exercise and hypoxia and not-supplemented (HE, n = 9); and exercise and hypoxia and supplemented group (HS, n = 9). The NG remained sedentary in the normoxia environment for nine weeks. The HE group participated in a high-intensity (IT) program for six weeks, then remained sedentary in the hypoxia environment for three weeks. The low-pressure chamber simulated a ~2800 M altitude 24 h/d. HS participated in IT, then entered and remained sedentary in the hypoxia environment for three weeks, and they consumed 500 mg per kg of body weight ACV extract. Results: The Bax/Bcl-2 ratio of the HE group increased significantly (+50.27%, p ≤ 0.05), the average number of type I pneumocytes was reduced significantly (−18.85%, p ≤ 0.05), and the average number of type II pneumocytes was increased significantly (+14.69%, p ≤ 0.05). Also, after three weeks of consuming the ACV extract, the HS group in comparison with the HE group had their Bax/Bcl-2 ratio reduced significantly (−24.27%, p ≤ 0.05), the average number of type I pneumocytes increased significantly (+10.15%, p ≤ 0.05), and the average number of type II pneumocytes reduced significantly (−7.18%, p ≤ 0.05). Conclusion: The findings show that after three weeks of hypoxia following six weeks of high-intensity interval training in Wistar rats, the Bax/Bcl-2 ratio and the number of type II pneumocytes were increased and the number of type I pneumocytes was reduced significantly. These results strongly suggest that an apoptosis state was induced in the lung parenchyma, and consuming ACV extract modulated this state.

• Bax/Bcl-2 ratio
• exercise training
• pathological apoptosis
• pneumocytes
• respiratory disease

• Adiantum/metabolism
• Animals
• Apoptosis/drug effects
• Disease Models, Animal
• Exercise Therapy/methods
• Exercise Therapy/standards
• Hypoxia/drug therapy
• Hypoxia/physiopathology
• Plant Extracts/pharmacology
• Plant Extracts/therapeutic use
• Pulmonary Alveoli/drug effects
• Pulmonary Alveoli/physiopathology
• Rats
• Rats, Wistar

Hypoxia is an important cause of acute kidney injury (AKI) in various conditions because kidneys are one of the most susceptible organs to hypoxia. In this study, we investigated whether nicotinamide adenine dinucleotide 3-phosphate (NADPH) oxidase 4 (Nox4) plays a role in hypoxia induced AKI in a cellular and animal model. Expression of Nox4 in cultured human renal proximal tubular epithelial cells (HK-2) was significantly increased by hypoxic stimulation. TGF-β1 was endogenously secreted by hypoxic HK-2 cells. SB4315432 (a TGF-β1 receptor I inhibitor) significantly inhibited Nox4 expression in HK-2 cells through the Smad-dependent cell signaling pathway. Silencing of Nox4 using Nox4 siRNA and pharmacologic inhibition with GKT137831 (a specific Nox1/4 inhibitor) reduced the production of ROS and attenuated the apoptotic pathway. In addition, knockdown of Nox4 increased cell survival in hypoxic HK-2 cells and pretreatment with GKT137831 reproduce these results. This study demonstrates that hypoxia induces HK-2 cell apoptosis through a signaling pathway involving TGF-β1 via Smad pathway induction of Nox4-dependent ROS generation. In an ischemia/reperfusion rat model, pretreatment of GKT137831 attenuated ischemia/reperfusion induced acute kidney injury as indicated by preserved kidney function, attenuated renal structural damage and reduced apoptotic cells. Therapies targeting Nox4 may be effective against hypoxia-induced AKI.

• Acute Kidney Injury/metabolism
• Acute Kidney Injury/pathology
• Acute Kidney Injury/physiopathology
• Animals
• Apoptosis/drug effects
• Cell Hypoxia/drug effects
• Cell Line
• Cell Survival/drug effects
• Female
• Humans
• Kidney Function Tests
• MAP Kinase Signaling System/drug effects
• Mitochondria/drug effects
• Mitochondria/metabolism
• Models, Biological
• NADPH Oxidase 4/antagonists & inhibitors
• NADPH Oxidase 4/metabolism
• Oxidation-Reduction
• Oxidative Stress/drug effects
• Pyrazoles/pharmacology
• Pyrazolones
• Pyridines/pharmacology
• Pyridones
• Rats, Sprague-Dawley
• Reactive Oxygen Species/metabolism
• Signal Transduction
• Smad Proteins/metabolism
• Transforming Growth Factor beta1/metabolism
• Transforming Growth Factor beta1/pharmacology

• the Konyang University Myunggok Research Fund of 20
• Te Basic Science Research Program of the National Research Foundation of Korea (NRF) funded by the Ministry of Education
• Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education

• Heart failure
• Hypobaric hypoxia
• Nitronyl nitroxide radical
• Oxidant stress

Fatty acid synthase (FAS), as a key enzyme involved in de novo lipogenesis, is highly expressed in many cancers. FAS inhibition induces cell death in vivo and in vitro, rendering FAS as an attractive target for cancer therapy, but the defined mechanism is still not well understood. Herein, we confirmed that FAS was highly expressed in breast cancers and FAS inhibition by its inhibitors or knockdown induced apoptosis in breast cancer cells. Our results showed that a significantly high level of reactive oxygen species was induced but not responsible for apoptosis in breast cancer cells by FAS inhibition. Instead, NADPH accumulation resulting from FAS inhibition was found to stimulate NADPH oxidase to generate reactive oxygen species and highly associated with apoptosis induction. Suppression of NADPH oxidase almost totally blocked reactive oxygen species generation while significantly potentiated the in vitro and in vivo killing of breast cancers by FAS inhibition. Taken together, these data suggest that FAS plays a critical role in maintaining cellular redox homeostasis and its inhibition leads to NADPH accumulation-mediated apoptosis. Our finding may provide new insights into cancer metabolism and aid in designing effective anticancer treatments.

• apoptosis
• breast cancer
• fatty acid synthase
• redox homeostasis

• Berberine
• H/R-reduced apoptosis
• HK-2 cells
• SPHK1

• Antidepressant-like
• CUMS
• GDNF/ERK1/2/ROS
• PI3K/AKT/NOX
• Schisandrin

Kinin B1 receptor (B1R) enhanced superoxide anion (O2•-) production in the vasculature of diabetic rats. This study investigates the induction and distribution of B1R in diabetic blood vessels and addresses the hypothesis that B1R is co-localized with NADPH oxidase (NOX1 and NOX2) and produces its activation via protein kinase C (PKC). Diabetes was induced in rats with streptozotocin (STZ 65 mg.kg⁻¹, i.p.). Two weeks later, the production of O2•- was measured in aorta rings in response to the B1R agonist (Sar[D-Phe⁸]-des-Arg⁹-BK, 20 μM) by the method of lucigenin-enhanced chemiluminescence. Various inhibitors were added (10 μM) to block PKC_total (Ro-31-8220), PKCβ1/2 (LY333531), or NADPH oxidase (Diphenyleneiodonium). The cellular localization of B1R was studied in the aorta, popliteal artery, and renal glomerulus/arteries by immunofluorescence and confocal microscopy with markers of endothelial cells (anti-RECA-1), macrophages (anti-CD11), vascular smooth muscle cells (anti-SMA), and NADPH oxidase (anti-NOX1 and NOX2). Although B1R was largely distributed in resistant vessels, it was sparsely expressed in the aorta's endothelium. The greater basal production of O2•- in STZ-diabetic aorta was significantly enhanced by the B1R agonist (15–45 min). The peak response to the agonist (30 min) was inhibited by all inhibitors. Immunofluorescent staining for B1R, NOX1, and NOX2 was significantly increased in endothelial cells, vascular smooth muscle cells, and macrophages of STZ-diabetic aorta on which they were found co-localized. Data showed that B1R enhanced O2•- by activating vascular NADPH oxidase through PKCβ1/2. This was substantiated by the cellular co-localization of B1R with NOX1 and NOX2 and opens the possibility that B1R-enhanced oxidative stress is derived from vascular and infiltrating immune cells in diabetes.

• NOX1
• NOX2
• VSMC
• bradykinin B1 receptor
• diabetes mellitus
• endothelium
• macrophages

• AMP-activated protein kinase (AMPK)
• autophagy
• fat-1 transgenic mice
• ischemia-reperfusion injury (IRI)

Retinal ischemia/reperfusion injury is a common feature of various retinal diseases such as glaucoma and diabetic retinopathy. Lutein, a potent anti-oxidant, is used to improve visual function in patients with age-related macular degeneration (AMD). Lutein attenuates apoptosis, oxidative stress and inflammation in animal models of acute retinal ischemia/hypoxia. Here, we further show that lutein improved Műller cell viability and enhanced cell survival upon hypoxia-induced cell death through regulation of intrinsic apoptotic pathway. Moreover, autophagy was activated upon treatment of cobalt (II) chloride, indicating that hypoxic injury not only triggered apoptosis but also autophagy in our in vitro model. Most importantly, we report for the first time that lutein treatment suppressed autophagosome formation after hypoxic insult and lutein administration could inhibit autophagic event after activation of autophagy by a pharmacological approach (rapamycin). Taken together, lutein may have a beneficial role in enhancing glial cell survival after hypoxic injury through regulating both apoptosis and autophagy.

• Animals
• Apoptosis/drug effects
• Autophagy/drug effects
• Cell Hypoxia
• Cell Line, Transformed
• Cobalt/pharmacology
• Lutein/pharmacology
• Rats
• Retina/cytology
• Retina/drug effects

• Hong Kong Research Grants Council
• FDCT grant from the Science and Technology Development Fund of Macao

Dapagliflozin, a new type of drug used to treat diabetes mellitus (DM), is a sodium/glucose cotransporter 2 (SGLT2) inhibitor. Although some studies showed that SGLT2 inhibition attenuated reactive oxygen generation in diabetic kidney the role of SGLT2 inhibition is unknown. We evaluated whether SLT2 inhibition has renoprotective effects in ischemia-reperfusion (IR) models. We evaluated whether dapagliflozin reduces renal damage in IR mice model. In addition, hypoxic HK2 cells were treated with or without SGLT2 inhibitor to investigate cell survival, the apoptosis signal pathway, and the induction of hypoxia-inducible factor 1 (HIF1) and associated proteins. Dapagliflozin improved renal function. Dapagliflozin reduced renal expression of Bax, renal tubule injury and TUNEL-positive cells and increased renal expression of HIF1 in IR-injured mice. HIF1 inhibition by albendazole negated the renoprotective effects of dapagliflozin treatment in IR-injured mice. In vitro, dapagliflozin increased the expression of HIF1, AMP-activated protein kinase (AMPK), and ERK and increased cell survival of hypoxic HK2 cells in a dose-dependent manner. In conclusion, dapagliflozin attenuates renal IR injury. HIF1 induction by dapagliflozin may play a role in renoprotection against renal IR injury.

• AMP-Activated Protein Kinases/metabolism
• Animals
• Apoptosis/drug effects
• Benzhydryl Compounds/pharmacology
• Cell Hypoxia/drug effects
• Cell Line
• Diabetic Nephropathies/drug therapy
• Diabetic Nephropathies/metabolism
• Diabetic Nephropathies/pathology
• Dose-Response Relationship, Drug
• Extracellular Signal-Regulated MAP Kinases/metabolism
• Glucosides/pharmacology
• Hypoxia-Inducible Factor 1/metabolism
• Kidney Diseases/drug therapy
• Kidney Diseases/metabolism
• Kidney Diseases/pathology
• Kidney Tubules, Proximal/metabolism
• Kidney Tubules, Proximal/pathology
• Male
• Mice
• Reperfusion Injury/drug therapy
• Reperfusion Injury/metabolism
• Reperfusion Injury/pathology
• Sodium-Glucose Transporter 2
• Sodium-Glucose Transporter 2 Inhibitors
• bcl-2-Associated X Protein/metabolism

• Catholic University of Korea
• Yonsei University college of medicine

• Apoptosis
• Diabetic nephropathy
• Glucose
• Podocytes

• AMP-Activated Protein Kinases/metabolism
• Apoptosis/drug effects
• Cell Line
• Cell Survival/drug effects
• Cytoprotection
• Diabetic Nephropathies/genetics
• Diabetic Nephropathies/metabolism
• Diabetic Nephropathies/pathology
• Diabetic Nephropathies/prevention & control
• Dose-Response Relationship, Drug
• Glucose/toxicity
• Humans
• Hypoglycemic Agents/metabolism
• Hypoglycemic Agents/pharmacology
• Metformin/metabolism
• Metformin/pharmacology
• Organic Cation Transporter 1/genetics
• Organic Cation Transporter 1/metabolism
• Phosphorylation
• Podocytes/drug effects
• Podocytes/metabolism
• Podocytes/pathology
• Signal Transduction/drug effects
• TOR Serine-Threonine Kinases/metabolism

• Apoptosis
• Colon cancer
• Hypoxia
• PI3K/AKT
• PLD2

Ganoderma lucidum polysaccharide peptide (GLPP) scavenges oxygen free radicals that are a key factor in the pathogenesis of renal ischemia reperfusion injury (RIRI). The aim of this study was to determine whether GLPP could attenuate RIRI by counteracting the oxidative stress. The mechanism involved was assessed by an in vivo mouse RIRI model and an in vitro hypoxia/reoxygenation model, and tunicamycin-stimulated NRK-52E cells were used to explore the GLPP-mediated alleviation of ER stress. Experimental results showed that renal dysfunction and morphological damage were reduced in GLPP-treated group. The imbalance of redox status was reversed and production of ROS was reduced by GLPP. RIRI-induced mitochondrial- and ER stress-dependent apoptosis were dramatically inhibited in GLPP-treated group. Intriguingly, JNK activation in the kidney with RIRI or hypoxia/reoxygenation was inhibited by GLPP. These results suggest that the protective effect of GLPP against RIRI may be due to reducing oxidative stress, alleviating the mitochondrial and ER stress-dependent apoptosis caused by excessive ROS.

• Apoptosis
• Pancreatic carcinoma
• Yin Chen Hao Decoction

• Antineoplastic Agents, Phytogenic/pharmacology
• Apoptosis/drug effects
• Carcinoma/drug therapy
• Carcinoma/genetics
• Carcinoma/metabolism
• Carcinoma/pathology
• Cell Line, Tumor
• Drugs, Chinese Herbal/pharmacology
• Gene Expression Regulation, Neoplastic
• Humans
• Immunohistochemistry
• In Situ Nick-End Labeling
• Pancreatic Neoplasms/drug therapy
• Pancreatic Neoplasms/genetics
• Pancreatic Neoplasms/metabolism
• Pancreatic Neoplasms/pathology
• Proto-Oncogene Proteins c-bcl-2/genetics
• Proto-Oncogene Proteins c-bcl-2/metabolism
• RNA, Messenger/metabolism
• Reverse Transcriptase Polymerase Chain Reaction
• Time Factors
• bcl-2-Associated X Protein/genetics
• bcl-2-Associated X Protein/metabolism