Iodine Adsorption-Desorption-Induced Structural Transformation and Improved Ag+ Turn-On Luminescent Sensing Performance of a Nonporous Eu(III) Metal-Organic Framework.

Posttreatment of pristine metal-organic frameworks (MOFs) with suitable vapor may be an effective way to regulate their structures and properties but has been less explored. Herein, we report an interesting example in which a crystalline nonporous Eu(III)-MOF was transferred to a porous amorphous MOF (aMOF) via iodine vapor adsorption-desorption posttreatment, and the resulting aMOF showed improved turn-on sensing properties with respect to Ag+ ions. The crystalline Eu-MOF, namely, Eu-IPDA, was assembled from Eu(III) and 4,4'-{4-[4-(1H-imidazol-1-yl)phenyl]pyridine-2,6-diyl}dibenzoic acid (H2IPDA) and exhibited a two-dimensional (2D) coordination network based on one-dimensional secondary building blocks. The close packing of the 2D networks gives rise to a three-dimensional supramolecular framework without any significant pores. Interestingly, the nonporous Eu-IPDA could absorb iodine molecules when Eu-IPDA crystals were placed in iodine vapor at 85 °C, and the adsorption capacity was 1.90 g/g, which is comparable to those of many MOFs with large BET surfaces. The adsorption of iodine is attributed to the strong interactions among the iodine molecule, the carboxy group, and the N-containing group and leads to the amorphization of the framework. After immersion of the iodine-loaded Eu-IPDA in EtOH, approximately 89.7% of the iodine was removed, resulting in a porous amorphous MOF, denoted as a-Eu-IPDA. In addition, the remaining iodine in the a-Eu-IPDA framework causes strong luminescent quenching in the fluorescence emission region of the Eu(III) center when compared with that in Eu-IPDA. The luminescence intensity of a-Eu-IPDA in water suspensions was significantly enhanced when Ag+ ions were added, with a detection limit of 4.76 × 10-6 M, which is 1000 times that of pristine Eu-IPDA. It also showed strong anti-interference ability over many common competitive metal ions and has the potential to sense Ag+ in natural water bodies and traditional Chinese medicine preparations. A mechanistic study showed that the interactions between Ag+ and the absorbed iodine, the carboxylate group, and the N atoms all contribute to the sensing performance of a-Eu-IPDA.

Quercetin, Main Active Ingredient of Moutan Cortex, Alleviates Chronic Orofacial Pain via Block of Voltage-Gated Sodium Channel.

BACKGROUND: Chronic orofacial pain (COP) therapy is challenging, as current medical treatments are extremely lacking. Moutan Cortex (MC) is a traditional Chinese medicine herb widely used for chronic inflammatory diseases. However, the mechanism behind MC in COP therapy has not been well-established. The purpose of this study was to identify the active ingredients of MC and their specific underlying mechanisms in COP treatment. METHODS: In this study, the main active ingredients and compound-target network of MC in COP therapy were identified through network pharmacology and bioinformatics analysis. Adult male Sprague-Dawley rats received oral mucosa lipopolysaccharide (LPS) injection to induce COP. Pain behaviors were evaluated by orofacial mechanical nociceptive assessment after intraganglionar injection. In vitro inflammatory cytokines in LPS-pretreated human periodontal ligament stem cells (hPDLSCs) and rat primary cultural trigeminal ganglion (TG) neurons were quantified by real-time quantitative polymerase chain reaction (RT-qPCR). Schrödinger software was used to verify the molecular docking of quercetin and critical targets. Whole-cell recording electrophysiology was used to evaluate the effect of quercetin on voltage-gated sodium (Na v ) channel in rat TG neurons. RESULTS: The assembled compound-target network consisted of 4 compounds and 46 targets. As 1 of the active components of MC correlated with most related targets, quercetin alleviated mechanical allodynia in LPS-induced rat model of COP (mechanical allodynia threshold median [interquartile range (IQR) 0.5 hours after drug administration: vehicle 1.3 [0.6-2.0] g vs quercetin 7.0 [6.0-8.5] g, P = .002). Gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that immune response and membrane functions play essential roles in MC-COP therapy. Five of the related targets were identified as core targets by protein-protein interaction analysis. Quercetin exerted an analgesic effect, possibly through blocking Na v channel in TG sensory neurons (peak current density median [IQR]: LPS -850.2 [-983.6 to -660.7] mV vs LPS + quercetin -589.6 [-711.0 to -147.8] mV, P = .006) while downregulating the expression level of proinflammatory cytokines-FOS (normalized messenger RNA [mRNA] level mean ± standard error of mean [SEM]: LPS [2. 22 ± 0.33] vs LPS + quercetin [1. 33 ± 0.14], P = .034) and TNF-α (normalized mRNA level mean ± SEM: LPS [8. 93 ± 0.78] vs LPS + quercetin [3. 77 ± 0.49], P < .0001). CONCLUSIONS: Identifying Na v as the molecular target of quercetin clarifies the analgesic mechanism of MC, and provides ideas for the development of novel selective and efficient chronic pain relievers.

The natural product argentatin C attenuates postoperative pain via inhibition of voltage-gated sodium and T-type voltage-gated calcium channels.

BACKGROUND AND PURPOSE: Postoperative pain occurs in as many as 70% of surgeries performed worldwide. Postoperative pain management still relies on opioids despite their negative consequences, resulting in a public health crisis. Therefore, it is important to develop alternative therapies to treat chronic pain. Natural products derived from medicinal plants are potential sources of novel biologically active compounds for development of safe analgesics. In this study, we screened a library of natural products to identify small molecules that target the activity of voltage-gated sodium and calcium channels that have important roles in nociceptive sensory processing. EXPERIMENTAL APPROACH: Fractions derived from the Native American medicinal plant, Parthenium incanum, were assessed using depolarization-evoked calcium influx in rat dorsal root ganglion (DRG) neurons. Further separation of these fractions yielded a cycloartane-type triterpene identified as argentatin C, which was additionally evaluated using whole-cell voltage and current-clamp electrophysiology, and behavioural analysis in a mouse model of postsurgical pain. KEY RESULTS: Argentatin C blocked the activity of both voltage-gated sodium and low-voltage-activated (LVA) calcium channels in calcium imaging assays. Docking analysis predicted that argentatin C may bind to NaV 1.7-1.9 and CaV 3.1-3.3 channels. Furthermore, argentatin C decreased Na+ and T-type Ca2+ currents as well as excitability in rat and macaque DRG neurons, and reversed mechanical allodynia in a mouse model of postsurgical pain. CONCLUSION AND IMPLICATIONS: These results suggest that the dual effect of argentatin C on voltage-gated sodium and calcium channels supports its potential as a novel treatment for painful conditions.

1-O-Acetylgeopyxin A, a derivative of a fungal metabolite, blocks tetrodotoxin-sensitive voltage-gated sodium, calcium channels and neuronal excitability which correlates with inhibition of neuropathic pain.

Chronic pain can be the result of an underlying disease or condition, medical treatment, inflammation, or injury. The number of persons experiencing this type of pain is substantial, affecting upwards of 50 million adults in the United States. Pharmacotherapy of most of the severe chronic pain patients includes drugs such as gabapentinoids, re-uptake blockers and opioids. Unfortunately, gabapentinoids are not effective in up to two-thirds of this population and although opioids can be initially effective, their long-term use is associated with multiple side effects. Therefore, there is a great need to develop novel non-opioid alternative therapies to relieve chronic pain. For this purpose, we screened a small library of natural products and their derivatives in the search for pharmacological inhibitors of voltage-gated calcium and sodium channels, which are outstanding molecular targets due to their important roles in nociceptive pathways. We discovered that the acetylated derivative of the ent-kaurane diterpenoid, geopyxin A, 1-O-acetylgeopyxin A, blocks voltage-gated calcium and tetrodotoxin-sensitive voltage-gated sodium channels but not tetrodotoxin-resistant sodium channels in dorsal root ganglion (DRG) neurons. Consistent with inhibition of voltage-gated sodium and calcium channels, 1-O-acetylgeopyxin A reduced reduce action potential firing frequency and increased firing threshold (rheobase) in DRG neurons. Finally, we identified the potential of 1-O-acetylgeopyxin A to reverse mechanical allodynia in a preclinical rat model of HIV-induced sensory neuropathy. Dual targeting of both sodium and calcium channels may permit block of nociceptor excitability and of release of pro-nociceptive transmitters. Future studies will harness the core structure of geopyxins for the generation of antinociceptive drugs.

The Natural Flavonoid Naringenin Elicits Analgesia through Inhibition of NaV1.8 Voltage-Gated Sodium Channels.

Naringenin (2S)-5,7-dihydroxy-2-(4-hydroxyphenyl)-3,4-dihydro-2H-1-benzopyran-4-one is a natural flavonoid found in fruits from the citrus family. Because (2S)-naringenin is known to racemize, its bioactivity might be related to one or both enantiomers. Computational studies predicted that (2R)-naringenin may act on voltage-gated ion channels, particularly the N-type calcium channel (CaV2.2) and the NaV1.7 sodium channel-both of which are key for pain signaling. Here we set out to identify the possible mechanism of action of naringenin. Naringenin inhibited depolarization-evoked Ca2+ influx in acetylcholine-, ATP-, and capsaicin-responding rat dorsal root ganglion (DRG) neurons. This was corroborated in electrophysiological recordings from DRG neurons. Pharmacological dissection of each of the voltage-gated Ca2+ channels subtypes could not pinpoint any selectivity of naringenin. Instead, naringenin inhibited NaV1.8-dependent and tetrodotoxin (TTX)-resistant while sparing tetrodotoxin sensitive (TTX-S) voltage-gated Na+ channels as evidenced by the lack of further inhibition by the NaV1.8 blocker A-803467. The effects of the natural flavonoid were validated ex vivo in spinal cord slices where naringenin decreased both the frequency and amplitude of sEPSC recorded in neurons within the substantia gelatinosa. The antinociceptive potential of naringenin was evaluated in male and female mice. Naringenin had no effect on the nociceptive thresholds evoked by heat. Naringenin's reversed allodynia was in mouse models of postsurgical and neuropathic pain. Here, driven by a call by the National Center for Complementary and Integrative Health's strategic plan to advance fundamental research into basic biological mechanisms of the action of natural products, we advance the antinociceptive potential of the flavonoid naringenin.

Betulinic acid, derived from the desert lavender Hyptis emoryi, attenuates paclitaxel-, HIV-, and nerve injury-associated peripheral sensory neuropathy via block of N- and T-type calcium channels.

The Federal Pain Research Strategy recommended development of nonopioid analgesics as a top priority in its strategic plan to address the significant public health crisis and individual burden of chronic pain faced by >100 million Americans. Motivated by this challenge, a natural product extracts library was screened and identified a plant extract that targets activity of voltage-gated calcium channels. This profile is of interest as a potential treatment for neuropathic pain. The active extract derived from the desert lavender plant native to southwestern United States, when subjected to bioassay-guided fractionation, afforded 3 compounds identified as pentacyclic triterpenoids, betulinic acid (BA), oleanolic acid, and ursolic acid. Betulinic acid inhibited depolarization-evoked calcium influx in dorsal root ganglion (DRG) neurons predominantly through targeting low-voltage-gated (Cav3 or T-type) and CaV2.2 (N-type) calcium channels. Voltage-clamp electrophysiology experiments revealed a reduction of Ca, but not Na, currents in sensory neurons after BA exposure. Betulinic acid inhibited spontaneous excitatory postsynaptic currents and depolarization-evoked release of calcitonin gene-related peptide from lumbar spinal cord slices. Notably, BA did not engage human mu, delta, or kappa opioid receptors. Intrathecal administration of BA reversed mechanical allodynia in rat models of chemotherapy-induced peripheral neuropathy and HIV-associated peripheral sensory neuropathy as well as a mouse model of partial sciatic nerve ligation without effects on locomotion. The broad-spectrum biological and medicinal properties reported, including anti-HIV and anticancer activities of BA and its derivatives, position this plant-derived small molecule natural product as a potential nonopioid therapy for management of chronic pain.

Therapy of Dredging the Bowels Enhanced the Neuroprotective Effect of Nourishing Kidney Herbs on Hippocampal Cholinergic System in Alzheimer's Disease Model Rat Induced by Aß 1-42.

BACKGROUND: Therapy of nourishing kidney has been used for treating memory deficits of Alzheimer's disease (AD) for thousands of years based on traditional Chinese medicine. However, we found the therapy of dredging the bowels could alleviate both memory deficits and mental symptoms of AD in clinic. OBJECTIVE: To determine whether the therapy of dredging the bowels could enhance the neuroprotective effect of nourishing kidney herbs for treating AD rats, and to explore the underlying mechanism of the combination of nourishing kidney and dredging the bowels (NKDB) herbs. METHODS: 60 rats were randomly divided into sham-operated group (SOG), model group (MG), nourishing kidney group (NKG), dredging the bowels group (DBG), nourishing kidney and dredging the bowels group (NKDBG), and donepezil hydrochloride group (DHG). The model establishment was performed by injecting Aß 1-42 into the hippocampal CA1 region. Animals received aqueous solution of Chinese herbal medicine or western medicine while SOG received only distilled water. Ability of learning and memory were assessed by Morris water maze. Acetylcholinesterase(AChE) and choline acetyltransferase (ChAT) activity and positive cells in the hippocampus were detected by the biochemical and immunofluorescent assay. RESULTS: All rats were in the same baseline. While after model establishment, ability of learning and memory of MG, NKG, DBG, NKDBG, and DHG were significantly impaired compared with SOG. Whereas after treatment, ability of learning and memory of NKG, DBG, NKDBG, and DHG were significantly improved compared with MG. Additionally, AChE activity of NKG, DBG, and NKDBG was significantly decreased, meanwhile ChAT activity showed an increased tendency. The number of AChE-positive cells and ChAT-positive cells of both NKDBG and DHG were significantly decreased and increased respectively, superior to those when compared with NKG and DBG. What's more, there was no significant difference between NKDBG and DHG. CONCLUSION: Therapy of dredging the bowels could enhance the neuroprotective effect of nourishing kidney herbs by reversing morphological damage of hippocampal cholinergic system. Furthermore, treatment with NKDB herbs could be effectively against AD, providing a practical therapeutic strategy in clinic.

LC-UV-Guided Isolation and Structure Determination of Lancolide E: A Nortriterpenoid with a Tetracyclo[5.4.0.0(2,4).0(3,7)]undecane-Bridged System from a "Talented" Schisandra Plant.

Lancolide E (1) featuring a complex tetracyclo[5.4.0.0(2,4).0(3,7)]undecane-bridged system that is constructed by an eight-, a three-, and two five-membered carbon rings in a sterically congested region was obtained in trace amounts from a "talented" schinortriterpenoid producer Schisandra lancifolia. Its structure was fully characterized by combining 2D NMR spectroscopy, theoretical calculations, and X-ray diffraction analysis. The biogenetic pathway of 1 was proposed to involve a Prins cyclization.

[Medicated serum prepared with Chinese herbal medicine Zhizhen Recipe down-regulates activity of nuclear factor-κB and expression of P-glycoprotein in human colorectal cancer multidrug-resistant cell line HCT-8/VCR].

OBJECTIVE: To investigate the effects of medicated serum prepared with Chinese herbal medicine Zhizhen Recipe (ZZR) on activity of nuclear factor-κB (NF-κB) and expression and function of P-glycoprotein (P-gp) in human colorectal cancer multidrug-resistant cell line HCT-8/VCR. METHODS: The multidrug resistance of HCT-8/VCR cells was detected by cell counting kit-8 method, and the experimental concentrations of ZZR-medicated serum were determined by the same way. HCT-8 and HCT-8/VCR cells were treated with ZZR-medicated serum of medium dose for 24 h. The activity of NF-κB was determined by enzyme-linked immunosorbent assay. The intracellular distribution of P-gp was detected by laser scanning confocal microscopy, and the mean fluorescence intensity of rhodamine 123 was detected by flow cytometry. RESULTS: ZZR-medicated sera with volume fraction of 8%, 16% and 32% of medium dose were confirmed as the experimental sera. Compared with the untreated group, NF-κB activities of the ZZR-medicated serum groups (ZZR-medicated serum with volume fraction of 8%, 16% and 32% of medium dose) were obviously down-regulated (P<0.01), which had a negative correlation with the concentrations. After interfering HCT-8/VCR with ZZR-medicated serum of different concentrations for 24 h, P-gp in HCT-8/VCR transmitted gradually from cell membrane to cytoplasm and nuclei. Nuclei became pyknotic and cracking. Compared with the untreated group, the mean fluorescence intensities of ZZR-medicated serum groups declined with concentration gradients (P<0.01). The efflux of intracellular rhodamine 123 decreased, the wave crest shifted to right, and the intracellular fluorescence intensity strengthened (P<0.01). CONCLUSION: ZZR-medicated sera of experimental concentrations down-regulate activity of NF-κB and expression and function of P-gp in human colorectal cancer multidrug-resistant cell line HCT-8/VCR and the effect is related to the concentrations.

[A multi-center clinical trial of Qianlieantong tablets for chronic prostatitis].

OBJECTIVE: To observe the efficacy and safety of Qianlieantong Tablets in the treatment of chronic prostatitis. METHODS: A multi-center, self-controlled open clinical trial was conducted. A total of 280 subjects with chronic prostatitis were enrolled and treated by Qianlieantong Tablets, 3 times a day, 5 tablets each time. Before and after 2 and 4 weeks after the administration, NIH-CPSI scores and white blood cell counts in the prostate secretion were recorded. RESULTS: Of the 273 subjects evaluated, the rates of excellence, effectiveness and ineffectiveness were 35.2% (n = 96), 47.6% (n = 130) and 17.2% (n = 47), respectively, with a total effectiveness rate of 82.8%. After 4 weeks'medication, the scores of the subjects on NIH-CPSI pain, voiding and quality of life and white blood cell counts in prostate secretion were significantly decreased compared with pre-treatment (P < 0.01). No adverse events or laboratory abnormality related to the medication were observed. CONCLUSION: Qianlieantong Tablets has a significant effect on chronic prostatitis with high safety, particularly indicated in chronic prostatitis with pelvic pain.

[The effect of Yunnan Baiyao on reduction of intra-operative bleeding of the patients undergoing transurethral resection of prostate].

OBJECTIVE: To investigate the effect of Yunnan Baiyao on reduction of intra-operative bleeding of the patients undergoing transurethral resection of prostate (TURP). METHODS: A randomized placebo-control double-blind multi-center trial was conducted. 203 patients with benign prostate hyperplasia (BPH), aged 50 - 80, who were to undergo TURP were randomly divided into 2 groups: Yunnan Baiyao group, given 500 mg Yunnan Baiyao four times daily since the third day before the operation for 3 days, and placebo group, given empty capsules for 3 days. The amount of intra-operative bleeding, bleeding index and bleeding intensity were compared. The side effect of Yunnan Baiyao was also evaluated. RESULTS: The amount of intra-operative bleeding of the Yunnan Baiyao group was 147 ml +/- 144 ml, significantly less than that of the control group (182 ml +/- 157 ml, P < 0.05). The amount of intra-operative bleeding of the per protocol (PP) population in the Yunnan Baiyao group (n = 58) was 146 ml +/- 116 ml, significantly less than the PP population in the control group (n = 66) (220 ml +/- 207 ml, P = 0.0361). When the weight of the resected prostate tissue was more than 20 gram, the amount of intraoperative bleeding, bleeding index, and bleeding intensity of the ITT population in the Yunnan Baiyao group (n = 60) were all significantly lower than those of the ITT population in the control group (n = 68) (all P < 0.05); the bleeding intensity of the PP population in the Yunnan Baiyao group was 2.4 ml/min +/- 1.8 ml/min, significantly lower than that of the PP population in the control group (3.6 ml/min +/- 3.7 ml/min, P = 0.0072); the bleeding index of the PP population in the Yunnan Baiyao group was 4.7 ml/g +/- 4.6 ml/g, significantly lower than that of the PP population in the control group (7.1 ml/g +/- 8.3 ml/g, P = 0.025). No side effect was found in the 2 groups. CONCLUSION: Yunnan Baiyao is effective on reducing the amount of intraoperative bleeding of TURP without side effect.

[Predictive factors for conversion of transurethral resection of the prostate to open prostatectomy].

OBJECTIVE: To evaluate the factors for the conversion of transurethral resection of the prostate (TURP) to open prostatectomy and to provide clinical evidence for surgical options. METHODS: From January 1997 to March 2005, we performed 1 086 TURP and made retrospective analyses of 11 risk factors concerning the demographics, clinical history, laboratory data, ultrasound results, and intraoperative complications of the patients. In addition, multivariate logistic regression was used to determine those variables predicting the conversion of TURP. RESULTS: Thirty-nine (3.59%) of the TURP cases required conversion, mostly because of uncontrollable hemorrhage (71.79%). Multivariate analyses showed that a prostate volume > 85.2 ml (OR = 2.568, P < 0.01), intraoperative slit of capsula prostatic (OR = 1.916, P < 0.01) and a second midstream bladder specimen (VB2) white blood cell count of the urine > 13.5/HP (OR = 1.486, P < 0.01) predicted the conversion to open prostatectomy. CONCLUSION: Benign prostatic hyperplasia (BPH) patients with a huge prostate and those with intraoperative slit of capsula prostatic undergoing TURP are more likely to be converted. And uncontrollable hemorrhage, huge prostate and poor endoscopic vision are the major reasons for the conversion.

[A clinical study of prostat combined with an antibiotic for chronic nonbacterial prostatitis].

OBJECTIVE: To evaluate the efficacy and safety of Prostate in combination with an antibiotic for the treatment of chronic nonbacterial prostatitis. METHODS: A double-blind, parallel contrasted, multi-central method was applied in the study. After the Stamey test and expressed prostate secretion (EPS) examination, 160 patients with prostatitis were recruited and randomized into a trial group (80 cases with 1 case missing) and a control group (80 cases). In the trial group, the patients used the levofloxacin and Prostate during the first 4 weeks and Prostate only during the following 4 weeks. In the control group, the patients used the levofloxacin and placebo during the first 4 weeks, and placebo only during the following 4 weeks. Before and 4 and 8 weeks after the treatment, the patients were visited and evaluated by the national institute health-chronic prostatitis symptom index (NIH-CPSI), EPS, and asked about the side. RESULTS: After 4-week and 8-week treatment, the pain index dropped by 3.34 +/- 2.45 and 4.06 +/- 3.03 in the trial group, and effects. 2.28 +/- 2.42 and 3.30 +/- 3.29 in the control; the voiding index dropped by 2.22 +/- 1.79 and 2.77 +/- 2.04 in the trial group, and 1.24 +/- 1.67 and 1.83 +/- 2.25 in the control respectively. There was significant difference between pre-treatment and post-treatment in both the two groups (P < 0.01), while the difference was not significant between 4-week and 8-week post-treatment (P > 0.05). And there was significant difference between the two groups in the pain index and voiding index (P < 0.01), but not in the white blood cell count and lipid in the EPS (P > 0.05). No serious side effects were recorded, and the tolerance to Prostate and placebo showed no significant difference. CONCLUSION: Prostate in combination with an antibiotic can effectively relieve the pain and voiding symptoms and improve the life quality of the patients with nonbacterial prostatitis and well deserves to be recommended in clinical practice.

[Studies on the hypoglycemia and lipids regulating effects of Plantago depressa var. montata].

OBJECTIVE: To investigate the effects of Pantago depressa var. montata. Extract (PDM) on the metabolisms of glucose and lipids in mice as well as the underlined mechanism. METHOD: Fasting serum glucose (FSG) in normal mice was determined after oral administration of PDM. The effects of PDM on diabetic mice induced by alloxan were investigated by observing the changes of glucose tolerance, the contents of FSG, glycosylated serum protein (GSP), total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), superoxide dismutase (SOD), malondialdehyde (MDA), nitric oxide (NO) and the injured degree of pancreatic islet. Effects of PDM on the injured human umbilical vein endothelial cell lines (ECV304) induced by H2O2 were also investigated. RESULT: PDM showed no any significant effect on FSG in normal mice. However, in the mice with diabetes induced by alloxan PDM could remarkably decrease serum glucose tolerance, the contents of FSG, GSP, TC, TG and LDL-C and significantly increased the ratio of HDL-C/TC, the activity of SOD and the concentration of NO. The damage of pancreatic islet induced by alloxan was also significantly attenuated by PDM. Furthermore, PDM promoted the viability of injured ECV304, elevated SOD level and reduced the contents of MDA. CONCLUSION: The results in the present study suggest that PDM can significantly attenuate hyperlipidemia and hyperglycemia in diabetic mice, which are probably due to its effects of antioxidation and amelioration of damaged pancreatic islet induced by free radicals.