Metformin ameliorates cardiopulmonary toxicity induced by chlorpyrifos.

Chlorpyrifos (CPF) is a widely used pesticide that can impair body organs. Nonetheless, metformin is known for its protective role against dysfunction at cellular and molecular levels led by inflammatory and oxidative stress. This study aimed to investigate the modulatory impacts of metformin on CPF-induced heart and lung damage. Following the treatment of Wistar rats with different combinations of metformin and CPF, plasma, as well as heart and lung tissues, were isolated to examine the level of oxidative stress biomarkers like reactive oxygen species (ROS) and malondialdehyde (MDA), inflammatory cytokines such as tumor necrosis alpha (TNF-α), high mobility group box 1 (HMGB1) gene, deoxyribonucleic acid (DNA) damage, lactate, ADP/ATP ratio, expression of relevant genes (TRADD, TERT, KL), and along with histological analysis. Based on the findings, metformin significantly modulates the impairments in heart and lung tissues induced by CPF.

Trimetazidine Preconditioning Potentiates the Effect of Mesenchymal Stem Cells Secretome on the Preservation of Rat Pancreatic Islet Survival and Function In Vitro.

Islet transplantation offers improved glycemic control in individuals with type 1 diabetes mellitus. However, in vitro islet culture is associated with islet apoptosis and eventually will lose their functionality prior to transplantation. In this study, we examined the effects of mesenchymal stem cells (MSCs) secretome preconditioned with diazoxide (DZ) and trimetazidine (TMZ) on rat islet cells during pre-transplant culture. With and without preconditioned hAD-MSCs' concentrated conditioned media (CCM) were added to the culture medium containing rat islets every 12 h for 24 and 48 h, after testing for selected cytokine concentrations (interleukin (IL)-4, IL-6, IL-13). Insulin content, glucose-stimulated insulin secretion, islet cell apoptosis, and mRNA expression of pro-apoptotic (BAX, BAK-1, and PUMA) and anti-apoptotic factors (BCL-2, BCL-xL, and XIAP) in rat islets were assessed after 24 and 48 h of culture. The protein level of IL-6 and IL-4 was significantly higher in TMZ-MSC-CM compared to MSC-non-CM. In rat isolated islets, normalized secreted insulin in the presence of 16.7 mM glucose was significantly higher in treated islet groups compared to control islets at both 24 and 48 h cultivation. Also, the percentage of apoptotic islet cells TMZ-MSC-CCM-treated islets was significantly lower compared to MSC-CM and MSC-CCM-treated islets in both 24 and 48 h cultivation. Consistent with the number of apoptotic cells, after 24 h culture, the expression of BCL-2 and BCL-xL genes in the control islets was lower than all treatment islet groups and in 48 h was lower than only TMZ-MSC-CM-treated islets. Also, the expression of the XIAP gene in control islets was significantly lower compared to the TMZ-MSC-CCM-treated islets at both at 24 and 48 h. In addition, mRNA level of the BAX gene in TMZ-MSC-CCM-treated islets was significantly lower compared to other groups at 48 h. Our findings revealed that TMZ proved to be more effective than DZ and could enhance the potential of hAD-MSCs-CM to improve the function and viability of islets prior to transplantation.

Assessment of synthesized chitosan/halloysite nanocarrier modified by carbon nanotube for pH-sensitive delivery of curcumin to cancerous media.

Constructing a system to carry medicine for more effective remedy of cancer has been a leading challenge, as the number of cancer cases continues to increase. In this present research, a curcumin-loaded chitosan/halloysite/carbon nanotube nanomixture was fabricated by means of water/oil/water emulsification method. The drug loading efficiency (DL) and entrapment efficiency (EE), as a result, reached 42 % and 88 %, respectively and FTIR and XRD analysis confirmed the bonding between the drug and nanocarrier. Morphological observation through FE-SEM and characterization through DLS analysis demonstrated that the average size of nanoparticles is 267.37 nm. Assessment of release within 96 h in pH 7.4 and 5.4 showed sustained release. For more investigation, release data was analyzed by diverse kinetic models to understand the mechanism in the release procedure. An MTT assay was also carried out, and the results illustrated apoptosis induction on MCF-7 cells and exhibited ameliorated cytotoxicity of the drug-loaded nanocomposite compared to the free curcumin. These findings suggest that the unique pH-responsive chitosan/halloysite/carbon nanotube nanocomposite might make a good option for drug delivery systems, particularly for the cancer treatment.

Nanoemulsion carriers of porous γ-alumina modified by polyvinylpyrrolidone and carboxymethyl cellulose for pH-sensitive delivery of 5-fluorouracil.

5-Fluorouracil (5-FU) is a cytotoxic drug with a low half-life. These features can cause some problems such as burst drug release and numerous side effects. In the present study, a pH-sensitive nanocomposite of polyvinylpyrrolidone (PVP)/carboxymethyl cellulose (CMC)/γ-alumina developed by using water in oil in water (W/O/W) double emulsion method. The fabricated emulsion has been employed as the 5-FU carrier to investigate its effects on drug half-life, side effects, drug loading efficiency (DLE), and drug entrapment efficiency (DEE). Analyzing the FTIR and XRD indicated the successful loading of 5-FU into the nanocarrier and affirmed the synthesized nanocomposite's chemical bonding and crystalline features. Furthermore, by using DLS and Zeta potential assessment, size and undersize distribution, as well as the stability of the drug-loaded nanocomposite were determined, which demonstrated the monodisperse and stable nanoparticles. Moreover, the nanocomposites with spherical shapes and homogeneous surfaces were shown in FE-SEM, which indicated good compatibility for the constituents of the nanocomposites. Moreover, by employing BET analysis the porosity has been investigated. Drug release pattern was studied, which indicated a controlled drug release behavior with above 96 h drug retention. Besides, the loading and entrapment efficiencies were obtained 44 % and 86 %, respectively. Furthermore, the curve fitting technique has been employed and the predominant release mechanism has been determined to evaluate the best-fitted kinetic models. MTT assay and flow cytometry assessment has been carried out to investigate the cytotoxic effects of the fabricated drug-loaded nanocomposite on MCF-7 and normal cells. The results showed enhanced cytotoxicity and late apoptosis for the PVP/CMC/γ-alumina/5-FU. Based on the MTT assay outcomes on normal cell lines (L929), which indicated above 90 % cell viability, the biocompatibility and biosafety of the synthesized nanocarrier have been confirmed. Moreover, due to the porosity of the PVP/CMC/γ-alumina, this nanocarrier can exploit from high specific surface area and be more sensitive to environmental conditions such as pH. These outcomes propose that the novel pH-sensitive PVP/CMC/γ-alumina nanocomposite can be a potential candidate for drug delivery applications, especially for cancer therapy.

Wound dressing based on PVA nanofiber containing silk fibroin modified with GO/ZnO nanoparticles for superficial wound healing: In vitro and in vivo evaluations.

Silk fibroin (SF), extracted from Bombyx mori, has unique physicochemical properties to achieve an efficient wound dressing. In this study, reduced graphene oxide (RGO)/ZnO NPs/silk fibroin nanocomposite was made, and an innovative nanofiber of SF/polyvinyl alcohol (PVA)/RGO/ZnO NPs was ready with the electrospinning technique and successfully characterized. The results of MIC and OD analyses were used to investigate the synthesized materials' antibacterial effects and displayed that the synthesized materials could inhibit growth against Staphylococcus aureus and Escherichia coli bacteria. However, both in vitro cytotoxicity (MTT) and scratch wound studies have shown that RGO/ZnO NPs and SF/PVA/RGO/ZnO NPs are not only non-toxic to NIH 3T3 fibroblasts, but also can cause cell viability, cell proliferation, and cell migration. Furthermore, improving the synthesized nanofiber's structural properties in the presence of RGO and ZnO NPs has been confirmed by performing tensile strength, contact angle, and biodegradation analyses. Also, in a cell attachment analysis, fibroblast cells had migrated and expanded well in the nanofibrous structures. Moreover, in vivo assay, SF/PVA/RGO/ZnO NPs nanofiber treated rats and has been shown significant healing activity and tissue regeneration compared with other treated groups. Therefore, this study suggests that SF/PVA/RGO/ZnO NPs nanofiber is a hopeful wound dressing for preventing bacteria growth and improving superficial wound repair.

Novel carboxymethyl cellulose-halloysite-polyethylene glycol nanocomposite for improved 5-FU delivery.

Drug nano-carriers are crucial for achieving targeted treatment against cancer disorders with minimal side effects. In this study, a pH-responsive nanocomposite based on halloysite nanotube (HNT) coated with carboxymethyl cellulose (CMC)/polyethylene glycol (PEG) hydrogel for controlled delivery of 5-Fluorouracil (5-FU), a hydrophobic chemotherapy drug prescribed for different types of cancers was synthesized for the first time using the water-in-oil-in-water (W/O/W) technique. The developed CMC/PEG/HNT/5-FU nanocomposite was characterized by dynamic light scattering (DLS), zeta potential, Fourier-transform infrared spectroscopy (FTIR), X-ray diffraction (XRD) and Field emission scanning electron microscope (FE-SEM) to get information about the particle size, surface charge, interactions between functional groups, crystalline structure and morphology, respectively. High efficiencies in terms of drug entrapment and loading (46 % and 87 %, respectively) were attained. In-vitro drug release results revealed an improved and sustained 5-FU delivery in an acid environment compared to the physiological medium, corroborating the pH-sensitivity of the developed nano-carrier. Flow cytometry and MTT assays demonstrated that the 5-FU loaded nanocomposite had considerable cytotoxicity on MCF-7 breast cancer cells while it is not toxic against L929 fibroblast cells. The nanocomposite synthesized herein could serve as a platform for the pH-sensitive release of anti-cancer drugs.

Microfluidically fabricated fibers containing pancreatic islets and mesenchymal stromal cells improve longevity and sustained normoglycemia in diabetic rats.

Type 1 diabetes mellitus is an autoimmune disease characterized by the loss of pancreatic isletßcells. Insulin injections and pancreas transplants are currently available therapies. The former requires daily insulin injections, while the latter is constrained by donor organ availability. Islet transplantation is a promising alternative treatment for type 1 diabetes mellitus that may overcome the limitations of previous techniques. Two challenges, however, must be addressed: limited cell retention as a result of the immune response and limited function of the transplanted cells that survive. To address these problems, we developed a microfluidic technology for a one-step generation of islet-laden fibers to protect them from the immune response. This approach enables continuous generation of microfibers with a diameter suitable for islet encapsulation (275µm). We, then, transplanted islet-laden fibers into diabetic Wistar rats. While islet-laden fibers alone were unable to restore normoglycemia in diabetic rats, adding mesenchymal stromal cells (MSCs) restored normoglycemia for an extended time. It increased the animals' lifespan by up to 75 d. Additionally, it improved the glucose-stimulated response of islets to the point where there was no significant difference between the treatment group and the healthy animals. Additionally, the presence of MSCs suppressed the immune response, as seen by decreased levels of pro-inflammatory cytokines such as tumor necrosis factor-α. Taken together, these fibers including islet and MSCs provide a versatile platform for concurrently improving cell preservation and functioning followingin vivotransplantation.

Chitosan/Gamma-Alumina/Fe3O4@5-FU Nanostructures as Promising Nanocarriers: Physiochemical Characterization and Toxicity Activity.

Today, cancer treatment is an important issue in the medical world due to the challenges and side effects of ongoing treatment procedures. Current methods can be replaced with targeted nano-drug delivery systems to overcome such side effects. In the present work, an intelligent nano-system consisting of Chitosan (Ch)/Gamma alumina (γAl)/Fe3O4 and 5-Fluorouracil (5-FU) was synthesized and designed for the first time in order to influence the Michigan Cancer Foundation-7 (MCF-7) cell line in the treatment of breast cancer. Physico-chemical characterization of the nanocarriers was carried out using X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FTIR), vibrating sample magnetometry (VSM), dynamic light scattering (DLS), and scanning electron microscopy (SEM). SEM analysis revealed smooth and homogeneous spherical nanoparticles. The high stability of the nanoparticles and their narrow size distribution was confirmed by DLS. The results of the loading study demonstrated that these nano-systems cause controlled, stable, and pH-sensitive release in cancerous environments with an inactive targeting mechanism. Finally, the results of MTT and flow cytometry tests indicated that this nano-system increased the rate of apoptosis induction on cancerous masses and could be an effective alternative to current treatments.

Epigenetic effects of graphene oxide and its derivatives: A mini-review.

Graphene oxide (GO), an engineered nanomaterial, has a two-dimensional structure with carbon atoms arranged in a hexagonal array. While it has been widely used in many industries, such as biomedicine, electronics, and biosensors, there are still concerns over its safety. Recently, many studies have focused on the potential toxicity of GO. Epigenetic toxicity is an important aspect of a material's toxicological profile, since changes in gene expression have been associated with carcinogenicity and disease progression. In this review, we focus on the epigenetic alterations caused by GO, including DNA methylation, histone modification, and altered expression of non-coding RNAs. GO can affect DNA methyltransferase activity and disrupt the methylation of cytosine bases in DNA strands, leading to alteration of genome expression. Modulation of histones by GO, targeting histone deacetylase and demethylase, as well as dysregulation of miRNA and lncRNA expression have been reported. Further studies are required to determine the mechanisms of GO-induced epigenetic alterations.

A novel pH-responsive nanoniosomal emulsion for sustained release of curcumin from a chitosan-based nanocarrier: Emphasis on the concurrent improvement of loading, sustained release, and apoptosis induction.

Curcumin application as an anti-cancer drug is faced with several impediments. This study has developed a platform that facilitates the sustained release of curcumin, improves loading efficiency, and anti-cancer activity. Montmorillonite (MMT) nanoparticles were added to chitosan (CS)-agarose (Aga) hydrogel and then loaded with curcumin (Cur) to prepare a curcumin-loaded nanocomposite hydrogel. The loading capacity increased from 63% to 76% by adding MMT nanoparticles to a chitosan-agarose hydrogel. Loading the fabricated nanocomposite in the nanoniosomal emulsion resulted in sustained release of curcumin under acidic conditions. Release kinetics analysis showed diffusion and erosion are the dominant release mechanisms, indicating non-fickian (or anomalous) transport based on the Korsmeyer-Peppas model. FTIR spectra confirmed that all nanocomposite components were present in the fabricated nanocomposite. Besides, XRD results corroborated the amorphous structure of the prepared nanocomposite. Zeta potential results corroborated the stability of the fabricated nanocarrier. Cytotoxicity of the prepared CS-Aga-MMT-Cur on MCF-7 cells was comparable with that of curcumin-treated cells (p < 0.001). Moreover, the percentage of apoptotic cells increased due to the enhanced release profile resulting from the addition of MMT to the hydrogel and the incorporation of the fabricated nanocomposite into the nanoniosomal emulsion. To recapitulate, the current delivery platform improved loading, sustained release, and curcumin anti-cancer effect. Hence, this platform could be a potential candidate to mitigate cancer therapy restrictions with curcumin.

Molecular Evidence on the Inhibitory Potential of Metformin against Chlorpyrifos-Induced Neurotoxicity.

Chlorpyrifos (CPF) is an organophosphorus (OP) pesticide, resulting in various health complications as the result of ingestion, inhalation, or skin absorption, and leads to DNA damage and increased oxidative stress. Metformin, derived from Galega officinalis, is reported to have anti-inflammatory and anti-apoptotic properties; thus, this study aimed to investigate the beneficial role of metformin in neurotoxicity induced by sub-acute exposure to CPF in Wistar rats. In this study, animals were divided into nine groups and were treated with different combinations of metformin and CPF. Following the 28 days of CPF and metformin administration, brain tissues were separated. The levels of inflammatory biomarkers such as tumor necrosis factor alpha (TNFα) and interleukin 1ß (IL-1ß), as well as the expression of 5HT1 and 5HT2 genes, were analyzed. Moreover, the levels of malondialdehyde (MDA), reactive oxygen species (ROS), and the ADP/ATP ratio, in addition to the activity of acetylcholinesterase (AChE) and superoxide dismutase (SOD), were tested through in vitro experiments. This study demonstrated the potential role of metformin in alleviating the mentioned biomarkers, which can be altered negatively as a result of CPF toxicity. Moreover, metformin showed protective potential in modulating inflammation, as well as oxidative stress, the expression of genes, and histological analysis, in a concentration-dependent manner.

PVA based nanofiber containing cellulose modified with graphitic carbon nitride/nettles/trachyspermum accelerates wound healing.

Today, bacterial cellulose has received a great deal of attention for its medical applications due to its unique structural properties such as high porosity, good fluid uptake, good strength, and biocompatibility. This study aimed to fabricate and study bacterial cellulose/graphitic carbon nitride/nettles/trachyspermum nanocomposite by immersion and PVA/BC/g-C3 N4 /nettles/trachyspermum nanofiber by electrospinning method as a wound dressing. The g-C3 N4 and g-C3 N4 solution were synthesized and then were characterized using Fourier transform infrared, X-ray diffraction, Zeta Potential, and scanning electronic microscope analyzes. Also, the antibacterial properties of the synthesized materials were proved by gram-positive and gram-negative bacteria using the minimum inhibitory concentration method. Besides, the toxicity, migration, and cell proliferation results of the synthesized materials on NIH 3T3 fibroblasts were evaluated using MTT and scratch assays and showed that the BC/PVA/g-C3 N4 /nettles/trachyspermum composite not only had no toxic effect on cells but also contributed to cell survival, cell migration, and proliferation has done. To evaluate the mechanical properties, a tensile strength test was performed on PVA/BC/g-C3 N4 /nettles/trachyspermum nanofibers, and the results showed good strength of the nanocomposite. In addition, in vivo assay, the produced nanofibers were used to evaluate wound healing, and the results showed that these nanofibers were able to accelerate the wound healing process so that after 14 days, the wound healing percentage showed 95%. Therefore, this study shows that PVA/BC/g-C3 N4 /nettles/trachyspermum nanofibers effectively inhibit bacterial growth and accelerate wound healing.

Ameliorating quercetin constraints in cancer therapy with pH-responsive agarose-polyvinylpyrrolidone -hydroxyapatite nanocomposite encapsulated in double nanoemulsion.

Despite quercetin (QC) promising features for cancer therapy, low solubility, poor permeability, and short biological half-life time significantly confine its application in cancer therapy. In this study, a novel approach is developed to improve loading efficiency and attain quercetin sustained-release concurrently. In this direction, hydrogel nanocomposite of agarose (AG)-polyvinylpyrrolidone (PVP)-hydroxyapatite (HAp) was loaded with QC. Incorporating HAp nanoparticles in the AG-PVP hydrogel improved the loading efficiency up to 61%. Also, the interactions between nanoparticle, drug, and hydrogel polymers rendered the nanocomposite pH-responsive at acidic conditions and controlled the burst release at neutral conditions. Then, QC-loaded hydrogel was encapsulated into the water in oil in water nanoemulsions to further sustain the drug release. As a result, the pH-responsive release of QC with prolonged-release over 96 h was observed. In more detail, according to the Korsmeyer-Peppas mathematical model, the mechanism of release was anomalous (diffusion-controlled) at pH 7.4 and anomalous transport (dissolution-controlled) at pH 5.4. The presence of all nanocomposite components was confirmed with FTIR analysis, and XRD results approved the incorporation of QC in the fabricated nanocomposite. The homogeneous surface of the nanocomposite in FESEM images showed good compatibility between components. The zeta potential analysis confirmed the good stability of the nanocarriers. Besides, the fabricated AG-PVP-HAp-QC platform showed significant cytotoxicity on MCF-7 cells compared to QC as a free drug (p < 0.001) and to quercetin-loaded AG-PVP (AG-PVP-QC) (p < 0.001) with enhanced apoptosis induction after the addition of HAp. Accordingly, this delivery platform ameliorated loading and sustained-release of QC, as well as its anticancer activity by releasing the drug at an effective therapeutic level over a long period to induce apoptosis. Thus, turning this drug delivery system into a potential candidate for further biomedical applications.

Impact of Acrylamide on Cellular Senescence Response and Cell Cycle Distribution via an In-vitro Study.

Exposure to certain environmental toxins has been shown to be associated with cellular senescence mainly through induction of oxidative stress and impact on cellular systems. Acrylamide (ACR) has raised worldwide concerns regarding the high risk of human dietary exposure to its hazardous effect. Although there is ample evidence about the carcinogenicity of ACR, limited studies have focused on its impact on cellular aging. The levels of ß-galactosidase (SA-ß-gal) activity, cell cycle distribution, and the expression of the senescence-associated gene and inflammatory markers were evaluated following exposure of embryonic fibroblast cells to ACR. A significant elevation in SA-ß-gal activity after exposure to different concentrations of ACR was accompanied by a considerably increased level of reactive oxygen species and lipid peroxidation. ACR-treated cells showed a noticeable decline in the total antioxidant capacity and thiol molecules. Moreover, the expression of cellular senescence-related genes including p38, p53, and p21 significantly upregulated at the high concentration of 5 mM ACR. ACR also induced G0/G1 phase arrest in embryonic fibroblast cells. The current study results revealed that exposure to ACR could enhance senescence response, contributing to increased oxidative stress and cellular damage.

Short-term Effects of Metformin on Cardiac and Peripheral Blood Cells Following Cecal Ligation and Puncture-induced Sepsis.

AIM OF THE STUDY: Sepsis has well-documented inflammatory effects on cardiovascular and blood cells. This study is designed to investigate potential anti-inflammatory effects of metformin on cardiac and blood cells 12 and 24 h following cecal ligation and puncture (CLP)-induced sepsis. METHODS: For the purpose of this study, 36 male Wistar rats were divided into six groups: two groups underwent CLP, two groups underwent CLP and received metformin, and two groups only received sham operations. 12 h later, 18 rats (half of rats in each of the three aforementioned groups) were sacrificed and cardiac and blood cells were harvested. Subsequently, 12 h later, the rest of the rats were euthanatized. In all harvested blood and cardiac cells, oxidative stress indicators, antioxidant properties, count of blood cells, neutrophil infiltration, percentage of weight loss and pathological assessment were conducted. RESULTS: In our experiment, metformin elevated antioxidant levels, improved function of blood cells and percentage of weight loss. Moreover, in the groups which received metformin, oxidative stress and neutrophil infiltration markers were decreased significantly. Moreover, pathological investigations of cardiac cell injury were reduced in the metformin group. CONCLUSIONS: Our findings suggest that in CLP induced sepsis model, metformin can improve the function of blood and cardiac cells through alleviating inflammation, improvement of anti-inflammation properties, and enhancement of blood profile, and all these effects are more pronounced after 24 h in comparison with 12 h after induction of sepsis.

PVA based nanofiber containing CQDs modified with silica NPs and silk fibroin accelerates wound healing in a rat model.

In recent years, applying various wound dressings with antibacterial activities to expedite tissue repair stages has gained remarkable attention. The intertwined three-dimensional structure of nanofibers provides unique spaces for carrying drugs and repair agents during the wound healing process. In this research, a carbon quantum dot (CQD)/silica nanoparticle (Si NP)/silk fibroin (SF) nanocomposite was synthesized, and two novel wound dressings, a BC-CQD/Si NP/SF nanocomposite and a PVA-CQD/Si NP/SF nanofiber, were prepared by Spray Printing and Electrospinning methods and successfully characterized. The water-uptake capacity of the BC-CQD/Si NP/SF nanocomposite has been optimized to evaluate its swelling behavior. To determine the antibacterial effects of the synthesized materials both MIC and Optical Density (OD) methods were performed, and the results imply that materials have high antibacterial activity and could successfully inhibit the growth of both S. aureus and E. coli bacteria. Cell toxicity, viability, and proliferation on NIH 3T3 fibroblast cells with the MTT assay have proved that the CQD/Si NP/SF nanocomposite not only has no toxicity but also can accelerate cell viability and proliferation. To assess the effect of the CQD/Si NP/SF nanocomposite on cell migration and in vitro wound healing scratch, a wound assay was performed, and the nanocomposite exhibits the ability to promote wound healing. The PVA-CQD/Si NP/SF nanofiber was used to investigate wound healing in an animal model. The results show that the PVA-CQD/Si NP/SF nanofiber effectively accelerates the skin and hair follicle regeneration. Therefore, the PVA-CQD/Si NP/SF nanofiber is a promising wound dressing for inhibiting bacterial growth and promoting skin wound repair and hair regeneration.

Metformin Attenuates Brain Injury by Inhibiting Inflammation and Regulating Tight Junction Proteins in Septic Rats.

OBJECTIVE: Metformin has a potent inhibitory activity against inflammation and oxidative stress, which inevitably occur in sepsis-associated encephalopathy (SAE). The precise mechanisms underlying neuroprotective effects of metformin in SAE, are still unclear. In the present work, the protective effect of metformin on SAE using cecal ligation and puncture (CLP) model of sepsis, was assessed. MATERIALS AND METHODS: In this experimental study, CLP procedure was performed in Wistar rats and 50 mg/kg metformin was administered immediately. Specific markers of sepsis severity, inflammation, blood brain barrier (BBB) dysfunction, and brain injury, were investigated. Specific assay kits and real-time polymerase chain reaction (RT-PCR) were used. Histopathological assessment was also carried out. RESULTS: Treatment with metformin decreased murine sepsis score (MSS), lactate, platelet lymphocyte ratio (PLR), and high mobility group box (HMGB1) levels. The expression levels of claudin 3 (Cldn3) and claudin 5 (Cldn5) were increased following treatment with metformin. Metformin decreased the expression of S100b, neuron specific enolase (Nse), and glial fibrillary acidic protein (Gfap). CONCLUSION: Our study suggests that metformin may inhibit inflammation and increase tight junction protein expressions which may improve BBB function and attenuate CLP-induced brain injury. Hence, the potential beneficial effects of metformin in sepsis, should be considered in future.

Multi-organ Toxicity Attenuation by Cerium Oxide and Yttrium Oxide Nanoparticles: Comparing the Beneficial Effects on Tissues Oxidative Damage Induced by Sub-acute Exposure to Diazinon.

BACKGROUND: Excessive use of diazinon, as an organophosphate pesticide (OP), contributes to cytotoxic and pathologic cellular damage and, in particular, oxidative stress. However, metal-oxide nanoparticles (NPs), such as cerium oxide (CeO2) and yttrium oxide (Y2O3), with the property of free radical scavenging demonstrated beneficial effects in the alleviation of oxidative stress biomarkers. OBJECTIVE: The aims of this study include evaluating beneficial effects of CeO2 NPs, Y2O3 NPs, and their combination against diazinon-induced oxidative stress in different tissues of brain, heart, lung, kidney, liver, and spleen. METHODS: Eight randomized groups of 6 adult male Wistar rats were formed. Each group of rats administered a different combination of diazinon, CeO2 and Y2O3 NPs daily and levels of oxidative stress markers, such as reactive oxygen species (ROS), lipid peroxidation (LPO), total thiol molecules (TTM) and total anti-oxidant power (TAP) and catalase enzyme, were measured after 2 weeks of the treatment. RESULTS: Measurements of the mentioned markers in the brain, heart, lung, kidney, liver, and spleen showed that the administration of NPs could significantly alleviate the oxidative stress induced by diazinon. However, the findings of this study illustrated that the combination of both CeO2 and Y2O3 NPs led to a better reduction in oxidative stress markers. CONCLUSION: Sub-acute exposure of diazinon in rats led to increased levels of oxidative stress markers in pivotal tissues such as the brain, heart, lung, kidney, liver, and spleen. CeO2 and Y2O3 NPs neutralize the oxidative stress to compensate diazinon-induced tissue damages. Lay Summary: Organophosphate pesticides (OPs), which are mainly used for pest control, are responsible for the entry of pesticides into the human food cycle. Organophosphate such as diazinon increases the molecular biomarkers of oxidative stress inside the cells of vital tissues such as the heart, liver, lungs, etc. Metal oxide nanoparticles (NPs) such as cerium oxide (CeO2) and yitrium oxide (Y2O3) can have free radical scavenging potential under oxidative stress and through various mechanisms. Although these nanoparticles reduce oxidative stress, it should be borne in the design of the study that additional doses of these substances reverse the beneficial effects.

Estrogens counteract tributyltin-induced toxicity in the rat islets of Langerhans.

BACKGROUND: Tributyltin (TBT) is known as an endocrine disruptor able to interfere with estrogen receptors (ERs) leading to toxic effects on the related endocrine pathways. TBT is an obesogen, reported to disrupt glucose homeostasis leading to diabetes. The aim of this study was to assess the influence of TBT and ß-estradiol on the pancreatic islets of Langerhans in simultaneous exposures. EXPERIMENTAL: Pancreatic islets of 15 male rat were isolated and exposed to TBT (10 µM), ß-estradiol, and TBT plus ß-estradiol for 24 h. Therewith, cellular viability, oxidative stress, apoptosis, and insulin secretion markers were investigated. RESULTS: TBT decreased the viability and increased the apoptosis, reactive oxygen species, and insulin secretion TBT led to increased amounts of apaptosis, reactive oxygen species (ROS), and insulin secretion in pancreatic islets; however, cellular viability was reduced. Co-exposure with ß-estradiol ameliorated the entire mentioned variables near to the control level. CONCLUSION: These results showed that ß-estradiol protect pancreatic islets of Langerhans against TBT-induced toxicity by counteracting oxidative stress and apoptosis as well as insulin secretion. In this way, it is postulated that pancreatic ER pathways particularly in ß-cells might be the determinant target of toxic effects of xenoestrogens like TBT. Hence, evaluation of xenoestrogens-induced ER dysfunction in the endocrine pancreas can be helpful in diabetic risk assessment of these contaminants. Pharmacological modifications of ER pathway in the ß-cells seems promising for better management of diabetes.

Cerium and Yttrium Oxide Nanoparticles and Nano-selenium Produce Protective Effects Against H2O2-induced Oxidative Stress in Pancreatic Beta Cells by Modulating Mitochondrial Dysfunction.

BACKGROUND: Type 1 diabetes mellitus is characterized by the destruction of insulin- producing Beta cells in the pancreas. Researchers hope that islet transplantation will help to patients with insulin-dependent diabetes mellitus (IDDM). Oxidative stress is the most important challenge that beta cells face to it after isolation, and mitochondrial dysfunction is a crucial mediator in beta cells death. Hence, therapeutic approaches can shift to antioxidants through the application of nanoparticles such as cerium and yttrium oxide nanoparticles (Cer and Ytt Ox NPs) and nano-selenium (Nan Se). OBJECTIVE: This study evaluates the effects of Cer and Ytt Ox NPs and Nan Se on H2O2- induced oxidative stress in pancreatic beta cells with focus on mitochondrial dysfunction pathway. METHODS: CRI-D2 beta-cell line were pretreated with Cer Ox NPs (200 µM) + Ytt Ox NPs (0.5 µg/mL) for 3 days and/or Nan Se (0.01 µM) for 1 day. Then markers of oxidative stress, mitochondrial dysfunction, insulin and glucagon secretion were measured. RESULTS: We reported a decrease in H2O2-induced reactive oxygen species (ROS) level and glucagon secretion, and an increase in H2O2-reduced ATP/ADP ratio, MMP, as well as UCP2 protein expression, and insulin secretion by pretreatment of CRI-D2 cells with Cer and Ytt Ox NPs and/or Nan Se. CONCLUSION: We found maximum protective effect with Cer and Ytt Ox NPs on CRI-D2 beta-cell line exposed by H2O2 for keeping beta cells alive until transplant whereas combination of Cer and Ytt Ox NPs and Nan Se had very little protective effect in this condition.