Complete Restoration of Hearing Loss and Cochlear Synaptopathy via Minimally Invasive, Single-Dose, and Controllable Middle Ear Delivery of Brain-Derived Neurotrophic Factor-Poly(dl-lactic acid-co-glycolic acid)-Loaded Hydrogel.

Noise-induced hearing loss (NIHL) often accompanies cochlear synaptopathy, which can be potentially reversed to restore hearing. However, there has been little success in achieving complete recovery of sensorineural deafness using nearly noninvasive middle ear drug delivery before. Here, we present a study demonstrating the efficacy of a middle ear delivery system employing brain-derived neurotrophic factor (BDNF)-poly-(dl-lactic acid-co-glycolic acid) (PLGA)-loaded hydrogel in reversing synaptopathy and restoring hearing function in a mouse model with NIHL. The mouse model achieved using the single noise exposure (NE, 115 dBL, 4 h) exhibited an average 20 dBL elevation of hearing thresholds with intact cochlear hair cells but a loss of ribbon synapses as the primary cause of hearing impairment. We developed a BDNF-PLGA-loaded thermosensitive hydrogel, which was administered via a single controllable injection into the tympanic cavity of noise-exposed mice, allowing its presence in the middle ear for a duration of 2 weeks. This intervention resulted in complete restoration of NIHL at frequencies of click, 4, 8, 16, and 32 kHz. Moreover, the cochlear ribbon synapses exhibited significant recovery, whereas other cochlear components (hair cells and auditory nerves) remained unchanged. Additionally, the cochlea of NE treated mice revealed activation of tropomyosin receptor kinase B (TRKB) signaling upon exposure to BDNF. These findings demonstrate a controllable and minimally invasive therapeutic approach that utilizes a BDNF-PLGA-loaded hydrogel to restore NIHL by specifically repairing cochlear synaptopathy. This tailored middle ear delivery system holds great promise for achieving ideal clinical outcomes in the treatment of NIHL and cochlear synaptopathy.

Anaerobic purinolytic enzymes enable dietary purine clearance by engineered gut bacteria.

Uric acid, the end product of purine degradation, causes hyperuricemia and gout, afflicting hundreds of millions of people. The debilitating effects of gout are exacerbated by dietary purine intake, and thus a potential therapeutic strategy is to enhance purine degradation in the gut microbiome. Aerobic purine degradation involves oxidative dearomatization of uric acid catalyzed by the O2-dependent uricase. The enzymes involved in purine degradation in strictly anaerobic bacteria remain unknown. Here we report the identification and characterization of these enzymes, which include four hydrolases belonging to different enzyme families, and a prenyl-flavin mononucleotide-dependent decarboxylase. Introduction of the first two hydrolases to Escherichia coli Nissle 1917 enabled its anaerobic growth on xanthine as the sole nitrogen source. Oral supplementation of these engineered probiotics ameliorated hyperuricemia in a Drosophila melanogaster model, including the formation of renal uric acid stones and a shortened lifespan, providing a route toward the development of purinolytic probiotics.

Comparing the impact of comprehensive care with conventional care in children with congenital heart disease: a systematic review and meta-analysis.

Background: This study compares the impact of comprehensive care and conventional care on interventional therapy in children with congenital heart disease and to provide a reference basis for clinical care. Methods: Clinical randomized controlled trials (RCTs) examining care during interventional therapy in children with congenital heart disease were identified in the PubMed, Web of Science, Embase, China National Knowledge Infrastructure (CNKI), and Wanfang databases using a combination of subject terms and free terms. The retrieval time was from the establishment of the database to November 27th, 2022. The control group was given conventional care and the experimental group was given comprehensive care on the basis of conventional care. The outcome indicators included one or more of postoperative complications (number of cases), puncture time (minutes), pain score (points), surgical operation time (minutes), X-ray exposure time (minutes) and length of hospital stay (days). Meta-analysis was performed using Stata 14.0 software. The publication bias test was conducted using Harbor's test. Results: A total of 24 RCTs were eventually included, and a total of 2,028 study subjects were enrolled, including 1,025 in the test group and 1,003 in the control group. Meta-analysis showed that comprehensive care resulted in a lower risk of complications [risk ratio (RR) =0.27; 95% confidence interval (CI): 0.21 to 0.34]. Furthermore, subjects who received comprehensive care had lower puncture time [standardized mean difference (SMD) =-2.50; 95% CI: -3.23 to -1.77], lower operating time [SMD (95% CI): -2.50 (-3.31, -1.68)], lower X-ray exposition time [SMD (95% CI): -1.29 (-2.51, -0.07)], shorter length of hospital stay [SMD (95% CI): -1.57 (-2.04, -1.09)], and lower pain scores [SMD (95% CI): -2.43 (-3.20, -1.65)]. Conclusions: Comprehensive care has higher clinical utility, which is worthy of clinical application and popularization.

Analysis of the Anti-Tumour Effect of Xuefu Zhuyu Decoction Based on Network Pharmacology and Experimental Verification in Drosophila.

Background: Tumours are among the most lethal diseases that heavily endanger human health globally. Xuefu Zhuyu Decoction (XFZYD) is a prescription used to treat blood-activating stasis. Although XFZYD has been shown to suppress migration and invasion of tumour cells, the active ingredients, potential targets, and underlying mechanism remain largely elusive. Purpose: To identify the prospective ingredients and major targets of XFZYD against tumours, and evaluate the efficacy and potential molecular mechanisms of XFZYD extract on tumour growth and invasion. Methods: We predicted that XFZYD might act on 80 targets through 128 active components using the network pharmacology analysis method. In addition, we prepared an XFZYD aqueous extract and employed the RasV12/lgl -/- -induced Drosophila tumour model to carry out experimental verification. Results: XFZYD did not exhibit any side effects on development, viability, and fertility. Furthermore, XFZYD significantly impeded tumour size and invasion at moderate concentrations and suppressed the increased phosphorylation of JNK but strongly enhanced the expression of Caspase 3 in the RasV12/lgl -/- model. Finally, the mRNA level of the transcription complex AP-1 component c-FOS was remarkably reduced. In contrast, the transcription of three pro-apoptotic genes was significantly increased when XFZYD was used to treat the tumour model. Conclusion: The study findings suggest that XFZYD may promote tumour cell apoptosis by activating caspase signalling to control primary growth and hinder tumour cell invasion by suppressing JNK/AP-1 signalling activity, thus providing a potential therapeutic strategy for XFZYD in the clinical treatment of cancer and other related diseases.

LaCl3 treatment improves Agrobacterium-mediated immature embryo genetic transformation frequency of maize.

KEY MESSAGE: We report an optimized transformation system that uses a LaCl3 pretreatment (a Ca2+ channel blocker) for enhancing Agrobacterium-mediated infection of immature embryos and improving the genetic transformation frequency of maize. Agrobacterium-mediated genetic transformation of immature embryos is important for gene-function studies and molecular breeding of maize. However, the relatively low genetic transformation frequency remains a bottleneck for applicability of this method, especially on commercial scale. We report that pretreatment of immature embryos with LaCl3 (a Ca2+ channel blocker) improves the infection frequency of Agrobacterium tumefaciens, increases the proportion of positive callus, yields more positive regenerated plantlets, and increases the transformation frequency from 8.40 to 17.60% for maize. This optimization is a novel method for improving the frequency of plant genetic transformations mediated by Agrobacterium tumefaciens.

FDA-Approved Drug Screening for Compounds That Facilitate Hematopoietic Stem and Progenitor Cells (HSPCs) Expansion in Zebrafish.

Hematopoietic stem cells (HSCs) are a specialized subset of cells with self-renewal and multilineage differentiation potency, which are essential for their function in bone marrow or umbilical cord blood transplantation to treat blood disorders. Expanding the hematopoietic stem and progenitor cells (HSPCs) ex vivo is essential to understand the HSPCs-based therapies potency. Here, we established a screening system in zebrafish by adopting an FDA-approved drug library to identify candidates that could facilitate HSPC expansion. To date, we have screened 171 drugs of 7 categories, including antibacterial, antineoplastic, glucocorticoid, NSAIDS, vitamins, antidepressant, and antipsychotic drugs. We found 21 drugs that contributed to HSPCs expansion, 32 drugs' administration caused HSPCs diminishment and 118 drugs' treatment elicited no effect on HSPCs amplification. Among these drugs, we further investigated the vitamin drugs ergocalciferol and panthenol, taking advantage of their acceptability, limited side-effects, and easy delivery. These two drugs, in particular, efficiently expanded the HSPCs pool in a dose-dependent manner. Their application even mitigated the compromised hematopoiesis in an ikzf1-/- mutant. Taken together, our study implied that the larval zebrafish is a suitable model for drug repurposing of effective molecules (especially those already approved for clinical use) that can facilitate HSPCs expansion.

Dissolvable microneedles based on Panax notoginseng polysaccharide for transdermal drug delivery and skin dendritic cell activation.

This work explored the feasibility of using biological polysaccharide to fabricate dissolvable microneedles (MNs) for the purpose of transdermal drug delivery and skin dendritic cell (DC) activation. Panax notoginseng polysaccharide (PNPS), a naturally derived immunoactive macromolecule, was used to fabricate dissolvable MNs. The prepared PNPS MNs showed a satisfactory mechanical strength and a skin penetration depth. By Franz diffusion cell assay, the PNPS MNs demonstrated a high transdermal delivery amount of model drugs. Furthermore, with the assistance of MNs, PNPS easily penetrated across the stratum corneum and target ear skin DCs, activating the maturation and migration of immunocytes by increasing the expressions of CD40, CD80, CD86, and MHC II of skin DCs. Consequently, the matured DCs migrated to the auricular draining lymph nodes and increased the proportions of CD4+ T and CD8+ T cells. Thus, PNPS might be a promising biomaterial for transdermal drug delivery, with adjuvant potential.

A GLUT1 inhibitor-based fluorogenic probe for Warburg effect-targeted drug screening and diagnostic imaging of hyperglycolytic cancers.

Increased expression of glucose transporters, especially GLUT1 has been proven to be involved in the Warburg effect. Therefore, GLUT1-targeted oncological approaches are being successfully employed for clinical tumor diagnostic imaging (e.g. the 18F-FDG/PET), drug delivery and novel anticancer drug development. Despite the long history of the Warburg effect-targeted cancer diagnosis, other than antibody labeling, there have been no imaging tools developed for direct detection of the GLUT1 expression. Herein, we report the new strategy of using a non-antibody GLUT1 binding probe for Warburg effect-based tumor detection and diagnostic imaging. By specifically inhibits the transport function of GLUT1, the newly designed fluorescent probe, CUM-5, was found to be a useful tool not only for sensitive GLUT1-mediated cancer cell detection, but also for cell-based high-throughput GLUT inhibitor screening. In in vivo studies, CUM-5 shows clear advantages including desirable tumor-to-normal tissue contrast and excellent tumor selectivity (Tm/Bkg and Tm/Torg), as well as high fluorescence stability (long response time) and ideal physiological biocompatibility. In particular, the GLUT1 inhibitor probe offers the potential use for glycolysis-based diagnostic imaging in triple-negative breast cancer which is claimed to have unsatisfactory results with FDG/PET diagnosis, thus remaining a highly metastatic and lethal disease with a need for sensitive and precise identification.

Geniposide protects depression through BTK/JAK2/STAT1 signaling pathway in lipopolysaccharide-induced depressive mice.

The purpose of this study was to investigate the antidepressant mechanism of GEN (geniposide) on depression mice induced by LPS. The mice were intragastrically treated with GEN (10 mg/kg/d or 40 mg/kg/d) or ibrutinib for continuous 7 days prior to LPS injection. The anxiety- and depression-like behaviors of mice were assessed via behavioral tests (sucrose preference test (SPT), tail suspension test (TST), forced swimming test (FST), and open-field test (OFT)). Microglial BV2 cells were treated with GEN or/and ibrutinib and stimulated with LPS. The productions of pro-inflammatory cytokines IL-6 and TNF-α in hippocampus, serum, and supernatant were detected by ELISA. The correlative proteins BTK, p-BTK, JAK2, p-JAK2, STAT1, p-STAT1, BDNF, TrkB, and p-TrkB were assessed through western blot. As a result, GEN ameliorated the anxiety- and depression-like behaviors of mice in behavioral tests. GEN treatment also regulated microglia polarization towards anti-inflammatory phenotype M2 and inhibited the production of pro-inflammatory cytokines IL-6 and TNF-α. In addition, with the application of ibrutinib, the selective inhibitor of BTK, it was proclaimed that the administration of GEN restrained the activation of JAK2/STAT1 pathway via attenuating the hyperphosphorylation of BTK both in mice and BV2 cells. Furthermore, it was also found that GEN activated BDNF/TrkB neuroprotective signaling pathway through the reduction of BTK phosphorylation. From the overall results, we suggested that GEN exerted a beneficial effect on LPS-induced depression in mice possibly through the modulation of BTK/JAK2/STAT1 signaling.

The effect of geniposide on chronic unpredictable mild stress-induced depressive mice through BTK/TLR4/NF-κB and BDNF/TrkB signaling pathways.

The purpose of this study was to estimate the pharmacological effect of geniposide (GEN) on depression, caused by chronic unpredictable mild stress (CUMS), and explore its potential mechanism. During the 6 week CUMS procedure, the mice were treated with GEN (10, 40 mg/kg) by gavage once daily for 3 weeks. As a result, the GEN treatment remarkably improved the behavioral manifestations and suppressed the generations of inflammatory cytokines both in vivo and in vitro. The MDA level was significantly increased, while the activities of SOD, GSH-PX were decreased in CUMS-challenged mice and corticosterone-stimulated PC12 cells. GEN administration significantly inhibited those changes. Moreover, GEN treatment could downregulate the expressions of p-BTK, TLR4, MyD88, p-NF-κB proteins, and upregulate BDNF, p-TrkB generations in CUMS-induced mice. Moreover, GEN administration inhibited the protein levels of p-BTK, TLR4, MyD88, p-NF-κB in corticosterone-induced PC12 cell. In summary, the results suggested that GEN exerted a therapeutic effect on CUMS-induced depressive mice possibly through the regulation of BTK/TLR4/NF-κB and BDNF/TrkB signaling pathways.

Preliminary study on the electromagnetic field treatment of osteoporosis in rats.

OBJECTIVE: In our study, the influence of PEMF on skeleton morphology and bone metabolism on rats with disuse osteoporosis was investigated, and the possibility of using it for the treatment of disuse osteoporosis was explored. METHODS: The rats in the ALN group were treated with alendronate, and the rats in the PEMF group were exposed to pulsed electromagnetic fields (3.82 mT, 10 Hz) for 40 mind-1. Rats were sacrificed by the end of 2, 4, 8 and 12 weeks, and serum and right leg bones were collected. Serum BMP-2, BGP concentrations and bone metabolism and biomechanical parameters were measured. RESULTS: The bone structural mechanical indices and material mechanical indices of the right femur in all groups of mice during weeks 2 and 4 were decreased. At week 8 the bone structural mechanical index and maximum stress of the right femur in the ALN group were markedly raised compared with the CON group (P< 0.01). Only maximum stress and strain were improved in the ALN group and had a significant difference (P< 0.05) at week 12. The serum BGP and BMP-2 concentration in the PEMF and ALN groups was increased (P< 0.05) at week 2, but this increase was not synchronized. After 8 weeks, BGP and BMP-2 level in the PEMF group was observably elevated (P<0.01) in contrast to the ALN group. CONCLUSION: From the experimental time interval analysis, PEMF can improve the mechanical stability of bone structure more gently and permanently than alendronate.

A novel acidic polysaccharide from the residue of Panax notoginseng and its hepatoprotective effect on alcoholic liver damage in mice.

This study presented the first purification and characterization of a hepatoprotective polysaccharide (PNPS-0.5 M) from the residue of Panax notoginseng (Burk.) F.H. Chen. This polysaccharide included a backbone of (4 â†’ 1)-linked GalA and branches of (1→)-linked Araf, (1→)-linked Rhap, and (5 â†’ 1)-linked Araf and had an extremely high molecular weight (2600 kDa). We investigated the hepatoprotective effects of PNPS-0.5 M on mice with alcoholic liver damage (ALD). After administration of PNPS-0.5 M, the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG), and hepatic malondialdehyde (MDA) were reduced to normal. In contrast, hepatic levels of alcohol dehydrogenase (ADH) and the antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) were elevated to normal. Further investigations indicated that PNPS-0.5 M activated Nrf2 signaling as a protective mechanism against Cyp2e1 toxicity in ALD mice. Meanwhile, it strengthened the ADH pathway and suppressed the CAT pathway of alcohol metabolism to prevent peroxide accumulation, thereby ameliorating ALD. In the present study, we describe a novel acidic polysaccharide from P. notoginseng with hepatoprotective activity that facilitates the development and utilization of P. notoginseng resources.

Effect of rosemary extract on lipid oxidation of cooked pork during simulated gastric digestion.

BACKGROUND: Oxidation of food lipids occurs in the gastrointestinal tract, resulting in potential adverse health effects. Rosemary extract (RE), as one of the most popular naturally sourced antioxidants, is widely used in the food industry. However, the effect of RE on lipid oxidation during gastrointestinal digestion has not been well investigated. Therefore, this study aimed to evaluate the effect of RE on lipid oxidation of cooked pork during simulated gastric digestion. RESULTS: Results showed that RE at 12.5, 25, 50, and 100 mg kg-1 pork effectively decreased the formation of malondialdehyde during simulated gastric digestion of cooked pork. RE also effectively mitigated the decline of fatty acids during the simulated gastric digestion of pork. The total phenolic content in RE was calculated to be 170.67 mg gallic acid equivalent (GAE) g-1 . RE dissolved in distilled water (pH 6.5) or potassium hydrogen phthalate-hydrochloric acid buffer solution (0.2 mol L-1 , pH 3.0) both exhibited strong 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) and 1,1-diphenyl-2-picrylhydrazyl radical-scavenging activities as well as ferric reducing capacity. The inhibitory effects of RE on lipid oxidation of cooked pork during simulated gastric digestion may be attributed to the phenolic compounds with antioxidant properties. CONCLUSION: The results lend support to the possible application of rosemary or RE as a rich source of natural antioxidants to inhibit the oxidation of food lipids during gastrointestinal digestion. © 2019 Society of Chemical Industry.

MiR-421 promotes the development of osteosarcoma by regulating MCPIP1 expression.

Despite improvements in surgical resection and adjuvant chemotherapy, the prognosis and outcomes of patients with osteosarcoma remains poor due to the occurrence of metastasis or relapse. Monocyte chemoattractant protein-1-induced protein-1 (MCPIP1), a zinc-finger RNA-binding protein, is known to regulate inflammatory responses and repress breast cancer growth. However, the regulation of MCPIP1 by microRNAs has not been clearly elucidated in osteosarcoma. In this study, we found that miR-421 expression was upregulated and MCPIP1 expression was downregulated in the osteosarcoma specimens from patients. Moreover, MCPIP1 expression was inversely correlated with miR-421 expression in the clinical samples. Furthermore, the upregulation of miR-421 and downregulation of MCPIP1 resulted in poor overall survival and severe disease progression, respectively, in the patients with osteosarcoma. Bioinformatics analysis and luciferase reporter gene assays confirmed that miR-421 specifically targets and binds to the 3'-UTR of MCPIP1. The overexpression of miR-421 induced cell proliferation, invasion, and migration, and the release of pro-inflammatory IL-6 in cultured human osteosarcoma cells. Additionally, the administration of miR-421 to tumor-bearing mice facilitated osteosarcoma growth by downregulating MCPIP1 expression. Taken together, these findings indicate that miR-421 is able to promote the development of osteosarcoma by regulating MCPIP1 expression, and can be a potential therapeutic target for osteosarcoma.

Electrochemically triggered degradation of silicon membranes for smart on-demand transient electronic devices.

Transient electronics is an emerging technology that enables unique functional transformation or the physical disappearance of electronic devices, and is attracting increasing attention for potential applications in data secured hardware as an ultimate solution against data breaches. Developing smart triggered degradation modalities of silicon (Si) remain the key challenge to achieve advanced non-recoverable on-demand transient electronics. Here, we present a novel electrochemically triggered transience mechanism of Si by lithiation, allowing complete and controllable destruction of Si devices. The depth and microstructure of the lithiation-affected zone over time is investigated in detail and the results suggest a few hours of lithiation is sufficient to create microcracks and significantly promote lithium penetration. Finite element models are proposed to confirm the mechanism. Electrochemically triggered degradation of thin film Si ribbons and Si integrated circuit chips with metal-oxide-semiconductor field-effect transistors from a commercial 0.35 micrometer complementary metal-oxide-semiconductor technology node is performed to demonstrate the potential applications for commercial electronics. This work opens new opportunities for versatile triggered transience of Si-based devices for critical secured information systems and green consumer electronics.

Discovery of Nonpeptide, Reversible HER1/HER2 Dual-Targeting Small-Molecule Inhibitors as Near-Infrared Fluorescent Probes for Efficient Tumor Detection, Diagnostic Imaging, and Drug Screening.

The abnormal expression of epidermal growth factor receptors HER1(EGFR) and HER2 is strongly associated with cancer invasion, metastasis, and angiogenesis. Their molecular detection is mainly executed using genetically encoded or antibody-based diagnostic tracers, but no dual-targeting small-molecule bioprobe has been achieved. Here, we report the novel small-molecule fluorescent probes Cy3-AFTN and Cy5-AFTN as potent dual-targeting inhibitors for efficient detection of HER1/HER2 expression in cancer cells and in vivo tumor diagnostic imaging. Unlike the irreversible HER1/HER2 inhibitors, Cy3-AFTN and Cy5-AFTN were designed as reversible/noncovalent probes based on the clinical drug afatinib, by making the molecule structurally impossible for receptor-mediated Michael additions. The synthesized probes were validated with live cell fluorescence imaging, flow cytometry and confocal-mediated competitive binding inhibition, molecular docking study, and in vivo xenograft tumor detection. The probes are competitively replaceable by other HER1/HER2 inhibitors; thus, they are potentially useful in fluorometric high-throughput screening for drug discovery.

Metabolic benefits of inhibition of p38α in white adipose tissue in obesity.

p38 has long been known as a central mediator of protein kinase A (PKA) signaling in brown adipocytes, which positively regulate the transcription of uncoupling protein 1 (UCP-1). However, the physiological role of p38 in adipose tissues, especially the white adipose tissue (WAT), is largely unknown. Here, we show that mice lacking p38α in adipose tissues display a lean phenotype, improved metabolism, and resistance to diet-induced obesity. Surprisingly, ablation of p38α causes minimal effects on brown adipose tissue (BAT) in adult mice, as evident from undetectable changes in UCP-1 expression, mitochondrial function, body temperature (BT), and energy expenditure. In contrast, genetic ablation of p38α in adipose tissues not only markedly facilitates the browning in WAT upon cold stress but also prevents diet-induced obesity. Consistently, pharmaceutical inhibition of p38α remarkably enhances the browning of WAT and has metabolic benefits. Furthermore, our data suggest that p38α deficiency promotes white-to-beige adipocyte reprogramming in a cell-autonomous manner. Mechanistically, inhibition of p38α stimulates the UCP-1 transcription through PKA and its downstream cAMP-response element binding protein (CREB), which form a positive feedback loop that functions to reinforce the white-to-beige phenotypic switch during cold exposure. Together, our study reveals that inhibition of p38α is able to promote WAT browning and confer metabolic benefits. Our study also indicates that p38α in WAT represents an exciting pharmacological target to combat obesity and metabolic diseases.

Maize purple plant pigment protects against fluoride-induced oxidative damage of liver and kidney in rats.

Anthocyanins are polyphenols and well known for their biological antioxidative benefits. Maize purple plant pigment (MPPP) extracted and separated from maize purple plant is rich in anthocyanins. In the present study, MPPP was used to alleviate the adverse effects generated by fluoride on liver and kidney in rats. The results showed that the ultrastructure of the liver and kidney in fluoride treated rats displayed shrinkage of nuclear and cell volume, swollen mitochondria and endoplasmic reticulum and vacuols formation in the liver and kidney cells. MPPP significantly attenuated these fluoride-induced pathological changes. The MDA levels in serum and liver tissue of fluoride alone treated group were significantly higher than those of the control group (p < 0.05). The presence of 5 g/kg MPPP in the diet reduced the elevation of MDA levels in blood and liver, and increased the SOD and GSH-Px activities in kidney and GSH level in liver and kidney compared with the fluoride alone treated group (p < 0.05). In addition, MPPP alleviated the decrease of Bcl-2 protein expression and the increase of Bax protein expression induced by fluoride. This study demonstrated the protective role of MPPP against fluoride-induced oxidative stress in liver and kidney of rats.