Quality and production enhancement of fish mint, Houttuynia cordata Thunb., cultivated in a hydroponic planting system with designed plant growth-promoting additives.

Fish mint, Houttuynia cordata Thunb. (HCT) is an edible vegetable that has also been used in traditional folk medicines. As both a medicinal herb and a dietary source, HCT has been clinically proven to be a pivotal ingredient in formulas administered to alleviate COVID-19 symptoms. With the increasing market demand for imported materials, ensuring the quality consistency of HCT becomes a significant concern. In this study, the growing time for hydroponically-cultivated HCT with seaweed extract and amino acids added (HCTW) reduced by half compared to conventional soil-cultivated HCT (HCTS). Key quantified components in HCTW, flavonoid glycosides and caffeoylquinic acid derivatives, exhibited a 143% increase over HCTS. These crucial constituents were responsible for possessing antioxidant activity (IC50 < 25 µg/mL) and anti-nitrite oxide production (IC50 < 20 µg/mL). An economically-designed hydroponic system with appropriate additives is proposed to replace HCTS with improvements of growth time, overall production yields, and bioactive qualities.

In vitro antimicrobial susceptibility data of global meropenem-resistant Acinetobacter baumannii isolates causing pneumonia: Data from the Antimicrobial Testing Leadership and Surveillance Program, 2014-2021, and re-estimations of susceptibility breakpoints and appropriate dosages of important antibiotics for pneumonia treatment.

OBJECTIVES: To evaluate the susceptibility of globally pneumonia-causing meropenem-resistant (MEM-R) Acinetobacter baumannii isolates against important antibiotics and estimate appropriate dosages of indicated antibiotics. METHODS: We extracted the 2014-2021 Antimicrobial Testing of Leadership Surveillance database regarding the susceptibility of MEM-R A. baumannii isolates causing pneumonia against important antibiotics. The susceptibility and carbapenemase-encoding gene (CPEG) data of pneumonia-causing MEM-R A. baumannii isolates from patients hospitalized in intensive care units of five major regions were analyzed. The susceptibility breakpoints (SBP) recommended by the Clinical and Laboratory Standards Institute (CLSI) in 2022, other necessary criteria [SBP of MIC for colistin, 2 mg/L, in the CLSI 2018; and cefoperazone-sulbactam (CFP-SUL), 16 mg/L], and the pharmacokinetic and pharmacodynamic data of indicated antibiotics were employed. RESULTS: Applying the aforementioned criteria, we observed the susceptible rates of colistin, minocycline, and CFP-SUL against the pneumonia-causing MEM-R A. baumannii isolates globally (n = 2905) were 93.2%, 69.1%, and 26.3%, respectively. Minocycline was significantly more active in vitro (MIC ≤4 mg/L) against the pneumonia-causing MEM-R A. baumannii isolates collected from North and South America compared to those from other regions (>90% vs. 58-72%). Additionally, blaOXA-23 and blaOXA-72 were the predominant CPEG in pneumonia-causing MEM-R A. baumannii isolates. CONCLUSIONS: After deliberative estimations, dosages of 200 mg minocycline intravenously every 12 h (SBP, 8 mg/L), 100 mg tigecycline intravenously every 12 h (SBP, 1 mg/L), and 160 mg nebulized colistin methanesulphonate every 8 h (SBP, 2 mg/L) are needed for the effective treatment of pneumonia-causing MEM-R A. baumannii isolates.

Minimum inhibitory concentrations of antifungals against invasive isolates of Cryptococcus species worldwide: Global antifungal antimicrobial testing leadership and surveillance program, 2010-2020.

This study examined the geographic distribution of minimum inhibitory concentrations (MICs) of antifungals against Cryptococcus isolates. Data were collected on the MICs of specific antifungals (amphotericin B, 5-flucytosine, fluconazole, voriconazole, posaconazole, and isavuconazole) against various Cryptococcus species for the period 2010 to 2020 from the Antimicrobial Testing Leadership and Surveillance database. Cryptococcus isolates were collected from samples of blood and cerebrospinal fluid (CSF) from patients hospitalized in different regions worldwide. We applied the epidemiological cutoff values (ECVs) of antifungals against various Cryptococcus species to distinguish wild-type (WT) from non-WT Cryptococcus isolates. A total of 395 isolates of Cryptococcus species cultured from blood (n = 201) or CSF (n = 194) were analyzed. C. grubii (n = 270), C. neoformans (n = 111), and C. gattii (n = 11) were the three predominant species causing bloodstream infections (BSI) or meningitis/meningoencephalitis (MME). The proportion of MICs above the ECV (1 mg/L) for amphotericin B among C. neoformans isolates was significantly lower than that among C. gattii isolates (MICs >0.5 mg/L; P < 0.001), as evaluated using the chi-square test. For most isolates of the three predominant Cryptococcus species, the MICs of new triazoles were ≤0.25 mg/L. The MICs of fluconazole and amphotericin B in the BSI/MME-causing Cryptococcus isolates collected from patients hospitalized in the Asia-Western Pacific region and Europe were significantly lower (i.e., the distributions were more leftward) than those in North America and Latin America. Ongoing monitoring of MIC data for important antifungals against cryptococcosis is crucial.

Identification of Andrographolide as an Agonist of Bile Acid TGR5 Receptor in a Cell Line to Demonstrate the Reduction in Hyperglycemia in Type-1 Diabetic Rats.

Andrographolide (ADG) is contained in bitter plants, and its effects are widely thought to be associated with taste receptors. The current study used animal studies and cell lines to investigate the role of ADG in diabetic models. The Takeda G-protein-coupled receptor (TGR5) was directly influenced by ADG, and this boosted GLP-1 synthesis in CHO-K1 cells transfected with the TGR5 gene. However, this was not seen in TGR5-mutant cells. The human intestinal L-cell line NCI-H716 showed an increase in GLP-1 production in response to ADG. In NCI-H716 cells, the TGR5 inhibitor triamterene reduced the effects of ADG, including the rise in TGR5 mRNA levels that ADG caused. Additionally, as with the antihyperglycemic impact in type-1 diabetic rats, the increase in plasma-active GLP-1 level caused by ADG was enhanced by a DPP-4 inhibitor. The recovery of the hypoglycemic effect in diabetic rats and the increase in plasma GLP-1 caused by ADG were both suppressed by TGR5 blockers. As a result, after activating TGR5, ADG may boost GLP-1 synthesis in diabetic rats, enhancing glucose homeostasis. In Min-6 cells, a pancreatic cell line grown in culture, ADG-induced insulin secretion was also examined. Blocking GLP-1 receptors had little impact, suggesting that ADG directly affects TGR5 activity in Min-6 cells. A TGR5 mRNA level experiment in Min-6 cells further confirmed that TGR5 is activated by ADG. The current study revealed a novel finding suggesting that ADG may activate TGR5 in diabetic rats in a way that results in enhanced insulin and GLP-1 production, which may be helpful for future research and therapies.

Use of Multiple Doses of Intravenous Infusion of Umbilical Cord-Mesenchymal Stem Cells for the Treatment of Adult Patients with Severe COVID-19-Related Acute Respiratory Distress Syndrome: Literature Review.

Objectives: Acute respiratory distress syndrome (ARDS) is a critical complication in severe COVID-19 patients. The intravenous infusion (IVF) of umbilical cord- (UC-) mesenchymal stem cells (MSCs), validated to substantially reduce the release of several inflammatory cytokines in vivo, was also shown to exhibit benefits in improving hypoxemia among severe COVID-19 patients. A single dose of IVF-UC-MSCs therapy for severe COVID-19 patients was shown to alleviate the initial ARDS severity, but have 50%-67% case-fatality rates. In Taiwan, few adult patients with severe COVID-19-induced ARDS receiving compassionate adjuvant treatment consisting of either a single dose (1-10 × 106 cells/kg body weight (kg BW)) or three doses (5 × 106 cells/kg BW in each dose) of IVF-UC-MSCs had good outcomes. However, the optimal dosage and rounds of IVF-UC-MSCs administration for the treatment of severe COVID-19 patients with ARDS are undetermined. Methods: We reviewed the 2020-2022 PubMed literature database concerning the clinical efficacy of IVF-UC-MSCs among severe COVID-19 patients. Results: The data of COVID-19 case series in the PubMed literature revealed a notable heterogeneity in the therapeutic dosage (a single dose: 1-10 × 106 cells/kg BW; and three doses: 50-200 × 106 cells/kg BW in each dose) and the post-ARDS days of IVF-UC-MSCs administration (a single dose: 1-12; and multiple doses: 5-14) for the treatment of severe COVID-19-associated ARDS. The survival rates among these severe COVID-19 patients ranged from 50% to 76%. However, an overall rate of 93.1% of significant improvement in hypoxemia was observed for the COVID-19 survivors receiving IVF-UC-MSCs at the initial ARDS stage. Conclusions: According to our analysis, the ideal treatment dosage of IVF-UC-MSCs for severe COVID-19-induced ARDS is likely 5 × 106 cells/kg BW for three cycles within 5 days of ARDS onset in severe COVID-19 patients.

Off-label use versus formal recommendations of conventional and novel antibiotics for the treatment of infections caused by multidrug-resistant bacteria.

The infections caused by multidrug- and extensively drug-resistant (MDR, XDR) bacteria, including Gram-positive cocci (GPC, including methicillin-resistant Staphylococcus aureus, MDR-Streptococcus pneumoniae and vancomycin-resistant enterococci) and Gram-negative bacilli (GNB, including carbapenem-resistant [CR] Enterobacterales, CR-Pseudomonas aeruginosa and XDR/CR-Acinetobacter baumannii complex) can be quite challenging for physicians with respect to treatment decisions. Apart from complicated urinary tract and intra-abdominal infections (cUTIs, cIAIs), bloodstream infections and pneumonia, these difficult-to-treat bacteria also cause infections at miscellaneous sites (bones, joints, native/prosthetic valves and skin structures, etc.). Antibiotics like dalbavancin, oritavancin, telavancin and daptomycin are currently approved for the treatment of acute bacterial skin and skin structural infections (ABSSSIs) caused by GPC. Additionally, ceftaroline, linezolid and tigecycline have been formally approved for the treatment of community-acquired pneumonia and ABSSSI. Cefiderocol and meropenem-vaborbactam are currently approved for the treatment of cUTIs caused by XDR-GNB. The spectra of ceftazidime-avibactam and imipenem/cilastatin-relebactam are broader than that of ceftolozane-tazobactam, but these three antibiotics are currently approved for the treatment of hospital-acquired pneumonia, cIAIs and cUTIs caused by MDR-GNB. Clinical investigations of other novel antibiotics (including cefepime-zidebactam, aztreonam-avibactam and sulbactam-durlobactam) for the treatment of various infections are ongoing. Nevertheless, evidence for adequate antibiotic regimens against osteomyelitis, arthritis and infective endocarditis due to several GPC and MDR-GNB is still mostly lacking. A comprehensive review of PubMed publications was undertaken and the formal indications and off-label use of important conventional and novel antibiotics against MDR/XDR-GPC and GNB isolates cultured from miscellaneous sites are presented in this paper.

Hispidin in the Medicinal Fungus Protects Dopaminergic Neurons from JNK Activation-Regulated Mitochondrial-Dependent Apoptosis in an MPP+-Induced In Vitro Model of Parkinson's Disease.

Degenerative diseases of the brain include Parkinson's disease (PD), which is associated with moveable signs and is still incurable. Hispidin belongs to polyphenol and originates primarily from the medicinal fungi Inonotus and Phellinus, with distinct biological effects. In the study, MES23.5 cells were induced by 1-methyl-4-phenylpyridinium (MPP+) to build a cell model of PD in order to detect the protective effect of hispdin and to specify the underlying mechanism. Pretreatment of MES23.5 cells with 1 h of hispdin at appropriate concentrations, followed by incubation of 24 h with 2 µmol/L MPP+ to induce cell damage. MPP+ resulted in reactive oxygen species production that diminished cell viability and dopamine content. Mitochondrial dysfunction in MS23.5 cells exposed to MPP+ was observed, indicated by inhibition of activity in the mitochondrial respiratory chain complex I, the collapse of potential in mitochondrial transmembrane, and the liberation of mitochondrial cytochrome c. Enabling C-Jun N-terminal kinase (JNK), reducing Bcl-2/Bax, and enhancing caspase-9/caspase-3/PARP cleavage were also seen by MPP+ induction associated with increased DNA fragmentation. All of the events mentioned above associated with MPP+-mediated mitochondrial-dependent caspases cascades were attenuated under cells pretreatment with hispidin (20 µmol/L); similar results were obtained during cell pretreatment with pan-JNK inhibitor JNK-IN-8 (1 µmol/L) or JNK3 inhibitor SR3576 (25 µmol/L). The findings show that hispidin has neuroprotection against MPP+-induced mitochondrial dysfunction and cellular apoptosis and suggest that hispidin can be seen as an assist in preventing PD.

p-Hydroxybenzyl Alcohol Antagonized the ROS-Dependent JNK/Jun/Caspase-3 Pathway to Produce Neuroprotection in a Cellular Model of Parkinson's Disease.

Parkinson's disease (PD) is a progressive disorder that affects brain nerve cells responsible for body motion and remains incurable. p-Hydroxybenzyl alcohol (HBA) is the primary phenolic compound in Gastrodiae Rhizoma, known for its therapeutic benefits against neurodegeneration. However, the protective effect of HBA against Parkinson's disease (PD) remains unclear. The objective of this study was to evaluate the neuroprotective effects of HBA in vitro 6-hydroxydopamine (6-OHDA)-induced PD model in SH-SY5Y cells. SH-SY5Y cells were pretreated with various concentrations of HBA for 1 h and incubated with 100 µmol/L 6-OHDA for 24 h to induce cellular lesions. 2,5-Diphenyl-2H-tetrazolium bromide was used to detect cellular viability. 2',7'-dichlorofluorescin oxidation detects reactive oxygen species (ROS). The enzyme-linked immunosorbent assay was used to determine the activities of superoxide dismutase, catalase, and glutathione peroxidase. The cellular mitochondrial function was identified through the collapse of the mitochondrial membrane potential, the release of cytochrome c, and the synthesis of mitochondrial ATP. Expression of pro-and anti-apoptotic factors was measured by Western blot. HBA enhanced cell viability, blocked ROS overproduction, and reduced antioxidant activities induced by 6-OHDA. HBA also reduced mitochondrial dysfunction and cell death caused by 6-OHDA. Moreover, HBA reversed the 6-OHDA-mediated activation of c-Jun N-terminal kinase, the downregulation of the Bcl-2/Bax ratio, the Apaf-1 upregulation and the induction of caspase-9, caspase-3, and PARP cleavage. This study shows that the protective effects of HBA against 6-OHDA-induced cell injury provide the potential preventive effects of HBA, making it a promising preventive agent for PD.

Plant Therapeutics.

Plants for therapeutics and the phytotherapy for disorders are the same thing in practice [...].

Diosmetin Targeted at Peroxisome Proliferator-Activated Receptor Gamma Alleviates Advanced Glycation End Products Induced Neuronal Injury.

The present study aimed to evaluate the role of diosmetin in alleviating advanced glycation end products (AGEs)-induced Alzheimer's disease (AD)-like pathology and to clarify the action mechanisms. Before stimulation with AGEs (200 µg/mL), SH-SY5Y cells were treated with diosmetin (10 µmol/L), increasing cell viability. The induction of AGEs on the reactive oxygen species overproduction and downregulation of antioxidant enzyme activities, including superoxide dismutase, glutathione peroxidase, and catalase, were ameliorated by diosmetin. Amyloid precursor protein upregulation, accompanied by increased production of amyloid-ß, caused by AGEs, was reversed by diosmetin. In the presence of diosmetin, not only ß-site amyloid precursor protein cleaving enzyme1 expression was lowered, but the protein levels of insulin-degrading enzyme and neprilysin were elevated. Diosmetin protects SH-SY5Y cells from endoplasmic reticulum (ER) stress response to AGEs by suppressing ER stress-induced glucose regulated protein 78, thereby downregulating protein kinase R-like endoplasmic reticulum kinase, eukaryotic initiation factor 2 α, activating transcription factor 4, and C/EBP homologous protein. Diosmetin-pretreated cells had a lower degree of apoptotic DNA fragmentation; this effect may be associated with B-cell lymphoma (Bcl) 2 protein upregulation, Bcl-2-associated X protein downregulation, and decreased activities of caspase-12/-9/-3. The reversion of diosmetin on the AGEs-induced harmful effects was similar to that produced by pioglitazone. The peroxisome proliferator-activated receptor (PPAR)γ antagonist T0070907 (5 µmol/L) abolished the beneficial effects of diosmetin on AGEs-treated SH-SY5Y cells, indicating the involvement of PPARγ. We conclude that diosmetin protects neuroblastoma cells against AGEs-induced ER injury via multiple mechanisms and may be a potential option for AD.

Myricetin Increases Circulating Adropin Level after Activation of Glucagon-like Peptide 1 (GLP-1) Receptor in Type-1 Diabetic Rats.

Myricetin is a common plant-derived flavonoid, considered an agonist of glucagon-like peptide 1 (GLP-1) receptor. It improves glycemic control and helps reduce body weight in diabetic subjects. The potential mechanisms of action of myricetin in this context might be enhancing the secretion of ß-endorphin (BER) to activate peripheral µ-opioid receptors. Moreover, adropin is a nutritionally regulated peptide hormone, which regulates energy metabolism, and plays a role in ameliorating diabetes. Because their mechanisms of insulin sensitivity are closely related, we hypothesized that myricetin may interact with adropin and plasma BER. The present study investigated the glucose-lowering effect of acute and chronic treatments of myricetin in type-1 diabetic rats. Plasma BER and adropin levels were determined by enzyme-linked immunosorbent assay (ELISA). The secretion of BER was measured in rats who received adrenalectomy. The changes in adropin gene (Enho) or mRNA level of GLP-1 receptor were measured using qPCR analysis. The results showed that myricetin dose-dependently increased plasma BER and adropin levels like the reduction of hyperglycemia after bolus injection as acute treatment. In addition, these effects of myricetin were inhibited by the antagonist of GLP-1 receptor. Moreover, in HepG2 cell line, myricetin induced GLP-1 receptor activation, which modulated the expression of adropin. In diabetic rats, the plasma adropin increased by myricetin is mainly through endogenous ß-endorphin after activation of GLP-1 receptor via bolus injection as acute treatment. Additionally, chronic treatment with myricetin increased adropin secretion in diabetic rats. In conclusion, our results provide a new finding that activation of opioid µ-receptor in the liver may enhance circulating adropin in animals.

The Citrus Flavonoid Hesperetin Encounters Diabetes-Mediated Alzheimer-Type Neuropathologic Changes through Relieving Advanced Glycation End-Products Inducing Endoplasmic Reticulum Stress.

The present study investigates whether hesperetin, a citrus flavonoid, can encounter advanced glycation end-product (AGE)-induced Alzheimer's disease-like pathophysiological changes with the underlying mechanisms. SH-SY5Y cells pretreated with hesperetin before stimulation with AGEs (200 µg/mL) were assessed in the following experiments. Hesperetin (40 µmol/L) elevated the reduced cell viability induced by AGEs. Hesperetin ameliorated reactive oxygen species overproduction and the downregulation of superoxide dismutase, glutathione peroxidase, and catalase, triggered by AGEs. Amyloid precursor protein upregulation, accompanied by the increased production of Aß, caused by AGEs, was reversed by hesperetin. However, hesperetin lowered ß-site APP-cleaving enzyme 1 expression, inducing insulin-degrading and neprilysin expression. In addition, hesperetin downregulated the expressions of the AGEs-induced endoplasmic reticulum (ER) stress proteins, including 78-kDa glucose-regulated protein and C/EBP homologous protein, and lowered the phosphorylation of protein kinase R-like ER kinase and activating transcription factor 4. Hesperetin-pretreated cells had a minor apoptotic DNA fragmentation. Hesperetin is able to upregulate Bcl-2 protein expression, downregulate Bax expression, and decrease caspase-12/-9/-3 activity as well, indicating that it inhibits ER stress-mediated neuronal apoptosis. There is a similar effect between hesperetin and positive rosiglitazone control against Aß aggravation of SH-SY5Y cell injury induced by AGEs. Thus, hesperetin might be a potential agent for treating glycation-induced Aß neurotoxicity.

A Bibenzyl Component Moscatilin Mitigates Glycation-Mediated Damages in an SH-SY5Y Cell Model of Neurodegenerative Diseases through AMPK Activation and RAGE/NF-κB Pathway Suppression.

Moscatilin can protect rat pheochromocytoma cells against methylglyoxal-induced damage. Elimination of the effect of advanced glycation end-products (AGEs) but activation of AMP-activated protein kinase (AMPK) are the potential therapeutic targets for the neurodegenerative diseases. Our study aimed to clarify AMPK signaling's role in the beneficial effects of moscatilin on the diabetic/hyperglycemia-associated neurodegenerative disorders. AGEs-induced injury in SH-SY5Y cells was used as an in vitro neurodegenerative model. AGEs stimulation resulted in cellular viability loss and reactive oxygen species production, and mitochondrial membrane potential collapse. It was observed that the cleaved forms of caspase-9, caspase-3, and poly (ADP-ribose) polymerase increased in SH-SY5Y cells following AGEs exposure. AGEs decreased Bcl-2 but increased Bax and p53 expression and nuclear factor kappa-B activation in SH-SY5Y cells. AGEs also attenuated the phosphorylation level of AMPK. These AGEs-induced detrimental effects were ameliorated by moscatilin, which was similar to the actions of metformin. Compound C, an inhibitor of AMPK, abolished the beneficial effects of moscatilin on the regulation of SH-SY5Y cells' function, indicating the involvement of AMPK. In conclusion, moscatilin offers a promising therapeutic strategy to reduce the neurotoxicity or AMPK dysfunction of AGEs. It provides a potential beneficial effect with AGEs-related neurodegenerative diseases.

The protective effects of moscatilin against methylglyoxal-induced neurotoxicity via the regulation of p38/JNK MAPK pathways in PC12 neuron-like cells.

Methylglyoxal (MGO) is an endogenous toxic compound that plays a vital role in diabetic complications such as diabetic neuropathy. Moscatilin is a bibenzyl component from Dendrobium species, has been shown to possess a wide range of pharmacological activities. To clarify whether moscatilin prevents rat pheochromocytoma cells (PC12 cells) from damage induced by MGO, cells were pre-treated with moscatilin and then stimulated with MGO. Moscatilin inhibited MGO associated cytotoxicity in a concentration (0.1, 0.5, or 1.0 µmol/L)-dependent manner and downregulated the formation of advanced glycation end products and reactive oxygen species. Moscatilin attenuated MGO-induced mitochondrial dysfunction involving the loss of mitochondrial membrane potential and depletion of adenosine triphosphate. MGO induced cell apoptosis via the upregulation of p53, caspases 3 and poly(ADP-ribose)polymerase, enhancement of cytochrome c release, and interruption of the Bax/Bcl-2 balance; these detrimental effects were ameliorated by moscatilin. Furthermore, moscatilin inhibited MGO-induced activation of MAP kinase (MAPK) superfamily, including p38 and c-Jun N-terminal kinases (JNKs). In conclusion, we found that the neuroprotective effect of moscatilin is due to a reduction of MGO-induced damage to mitochondria function through modulating the p38 and JNK stress-activated MAPK cascades pathway. Thus, it might be a potent compound for preventing/counteracting diabetic neuropathy.

Erianin protects against high glucose-induced oxidative injury in renal tubular epithelial cells.

Erianin is the major bibenzyl compound found in Dendrobium chrysotoxum Lindl. The current study was designed to investigate the protective effects of erianin on high glucose-induced injury in cultured renal tubular epithelial cells (NRK-52E cells) and determine the possible mechanisms for its effects. NRK-52E cells were pretreated with erianin (5, 10, 25 or 50 nmol/L) for 1 h followed by further exposure to high glucose (30 mmol/L, HG) for 48 h. Erianin concentration dependently enhanced cell viability followed by HG treatment in NRK-52E cells. HG induced reactive oxygen species (ROS) generation, malondialdehyde production, and glutathione deficiency were recovered in NRK-52E cells pretreated with erianin. HG triggered cell apoptosis via the loss of mitochondrial membrane potential, depletion of adenosine triphosphate, upregulation of caspases 9 and 3, enhancement of cytochrome c release, and subsequent interruption of the Bax/Bcl-2 balance. These detrimental effects were ameliorated by erianin. HG also induced activation of p53, JNK, p38 mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) in NRK-52E cells, which were blocked by erianin. The results suggest that treatment NRK-52E cells with erianin halts HG-induced renal dysfunction through the suppression of the ROS/MAPK/NF-κB signaling pathways. Our findings provide novel therapeutic targets for diabetic nephropathy.

Gigantol has Protective Effects against High Glucose-Evoked Nephrotoxicity in Mouse Glomerulus Mesangial Cells by Suppressing ROS/MAPK/NF-κB Signaling Pathways.

Gigantol is a bibenzyl compound derived from several medicinal orchids. This biologically active compound has shown promising therapeutic potential against diabetic cataracts, but whether this compound exerts beneficial effects on the other diabetic microvascular complications remains unclear. This study was carried out to examine effects of gigantol on high glucose-induced renal cell injury in cultured mouse kidney mesangial cells (MES-13). MES-13 cells were pretreated with gigantol (1, 5, 10 or 20 µmol/L) for 1 h followed by further exposure to high (33.3 mmol/L) glucose for 48 h. Gigantol concentration dependently enhanced cell viability followed by high glucose treatment in MES-13 cells. High glucose induced reactive oxygen species (ROS) generation, malondialdehyde production and glutathione deficiency were recoved in MES-13 cells pretreated with gigantol. High glucose triggered cell apoptosis via the the loss of mitochondrial membrane potential, depletion of adenosine triphosphate, upregulation of caspases 9 and 3, enhancement of cytochrome c release, and subsequent interruption of the Bax/Bcl-2 balance. These detrimental effects were ameliorated by gigantol. High glucose also induced activation of JNK, p38 mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) in MES-13 cells, which were blocked by gigantol. The results suggest that treatment MES-13 cells with gigantol halts high glucose-induced renal dysfunction through the suppression of the ROS/MAPK/NF-κB signaling pathways. Our data are of value to the understanding the mechanism for gigantol, and would benefit the study of drug development or food supplement for diabetes and nephropathy.

Hesperidin Prevents High Glucose-Induced Damage of Retinal Pigment Epithelial Cells.

The present study aimed to determine whether hesperidin, a plant-based active flavanone found in citrus fruits, can prevent high glucose-induced retinal pigment epithelial (RPE) cell impairment. Cultured human RPE cells (ARPE-19) were exposed to a normal glucose concentration (5.5 mM) for 4 d and then soaked in either normal (5.5 mM) or high (33.3 mM) concentrations of D-glucose with or without different concentrations of hesperidin (10, 20, or 40 µM) for another 48 h. The survival rates of the cells were measured using a 3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide reduction assay. With the help of a fluorescent probe, the intracellular production of reactive oxygen species (ROS) was evaluated. Colorimetric assay kits were used to assess the antioxidant enzyme activities, and western blotting was used to measure the expression of apoptosis-related protein. Hesperidin was effective in inhibiting high glucose-induced ROS production, preventing loss of cell viability, and promoting the endogenous antioxidant defense components, including glutathione peroxidase, superoxide dismutase, catalase, and glutathione, in a concentration-dependent manner. Furthermore, high glucose triggered cell apoptosis via the upregulation of caspase-9/3, enhancement of cytochrome c release into the cytosol, and subsequent interruption of the Bax/Bcl-2 balance. These detrimental effects were ameliorated by hesperidin in a concentration-dependent manner. We conclude that through the scavenging of ROS and modulation of the mitochondria-mediated apoptotic pathway, hesperidin may protect RPE cells from high glucose-induced injury and thus may be a candidate in preventing the visual impairment caused by diabetic retinopathy.

The Benefits of the Citrus Flavonoid Diosmin on Human Retinal Pigment Epithelial Cells under High-Glucose Conditions.

We investigate diosmin for its effect on the ARPE-19 human retinal pigment epithelial cells exposed to high glucose, a model of diabetic retinopathy (DR). After incubation for 4 days with a normal (5 mmol/L) concentration of D-glucose, ARPE-19 cells were exposed separately to normal or high concentrations of D-glucose (30 mmol/L) with or without diosmin at different concentrations (0.1, 1, 10 µg/mL) for another 48 h. Next, we assessed cell viability, reactive oxygen species (ROS) generation and antioxidant enzyme activities. In order to examine the underlying molecular mechanisms, we meanwhile analyzed the expressions of Bax, Bcl-2, total and phosphorylated JNK and p38 mitogen-activated protein kinase (MAPK). Diosmin dose dependently enhanced cell viability following high glucose treatment in ARPE-19 cells. The activities of superoxide dismutase and glutathione peroxidase, as well as the levels of reduced glutathione were decreased, while it was observed that levels of ROS in high glucose cultured ARPE-19 cells increased. High glucose also disturbed Bax and Bcl-2 expression, interrupted Bcl-2/Bax balance, and triggered subsequent cytochrome c release into the cytosol and activation of caspase-3. These detrimental effects were ameliorated dose dependently by diosmin. Furthermore, diosmin could abrogate high glucose-induced apoptosis as well as JNK and P38 MAPK phosphorylation in ARPE-19 cells. Our results suggest that treatment ARPE-19 cells with diosmin halts hyperglycemia-mediated oxidative damage and thus this compound may be a candidate for preventing the visual impairment caused by DR.

Protective Effects of Hesperidin (Citrus Flavonone) on High Glucose Induced Oxidative Stress and Apoptosis in a Cellular Model for Diabetic Retinopathy.

The aim of this study was to investigate the protective effects and mechanisms of hesperidin, a plant based active flavanone found in citrus fruits, under the oxidative stress and apoptosis induced by high levels of glucose in retinal ganglial cells (RGCs). RGC-5 cells were pretreated with hesperidin (12.5, 25, or 50 µmol/L) for 6 h followed by exposure to high (33.3 mmol/L) d-glucose for 48 h. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was adopted to evaluate cell viability. Mitochondrial function was estimated by measuring the mitochondrial membrane potential (ΔΨm). A fluorescent probe was employed to evaluate the intercellular production of reactive oxygen species (ROS). Colorimetric assay kits were used to evaluate lipid peroxidation, antioxidant enzyme activities, and protein carbonyls formation. The expression of apoptosis-related proteins and mitogen-activated protein kinase (MAPK) were measured with Western blotting. Hesperidin inhibited high glucose-mediated cell loss and restored mitochondrial function including a reversion of ΔΨm loss and cytochrome c release. Treated with hesperidin, high glucose-induced increase in ROS, malondialdehyde, and protein carbonyl levels were blocked in RGC-5 cells. Hesperidin was found to elevate the activities of superoxide dismutase, catalase, glutathione peroxidase, and to recover glutathione levels. Hesperidin inhibited high glucose-induced cell apoptosis by attenuating the downregulation of caspase-9, caspase-3, and Bax/Bcl-2. Furthermore, the phosphorylation of c-Jun N-terminal kinases (JNK) and p38 MAPK triggered by high glucose were attenuated in RGC-5 cells after their incubation with hesperdin. We concluded that hesperidin may protect RGC-5 cells from high glucose-induced injury since it owns the properties of antioxidant action and blocks mitochondria-mediated apoptosis.

Healing potential of zerumbone ointment on experimental full-thickness excision cutaneous wounds in rat.

Zerumbone is a monocyclic sesquiterpene compound. Based on report, it is the predominant bioactive compound from the rhizomes of Zingiber zerumbet. The study was undertaken to evaluate the therapeutic effects of topical zerumbone on excision wounds in rats. A 1% (w/w) simple ointment containing zerumbone was applied topically (100 mg ointment per rat) once a day on full-thickness excision wounds created on rats. The wound tissue was removed and used for estimation of antioxidant activity and to observe histopathological changes. Immunohistochemical staining was performed to study the expression pattern of vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-ß1 and collagen IV. Zerumbone exhibited antimicrobial activity against Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, Candida albicans and Candida tropicali. Zerumbone ointment has potent wound healing capacity as evident from the wound contraction on 15th post wounding day. The histopathological examinations of healed wound sections showed greater tissue regeneration, more fibroblasts and angiogenesis in zerumbone ointment-treated group. VEGF, TGF-ß1 and collagen IV expression were also correlative with the healing pattern observed. Zerumbone possesses potent antioxidant activity by increasing superoxide dismutase, catalase, glutathione and decreased lipid peroxidation. The synergistic effects of both antimicrobial and antioxidant activities in zerumbone are deduced to have accelerated the wound repair. The results demonstrate that zerumbone possessed strong wound healing potential and can be exploited to accelerate excision wound healing.