Beclin1 is essential for the pancreas development.

Beclin1 (Becn1) is a multifunctional protein involved in autophagy regulation, membrane trafficking, and tumor suppression. In this study, we examined the roles of Becn1 in the pancreas development by generating mice with conditional deletion of Becn1 in the pancreas using pancreatic transcriptional factor 1a (Ptf1a)-Cre mice (Becn1f/f; Ptf1aCre/+). Surprisingly, loss of Becn1 in the pancreas resulted in severe pancreatic developmental defects, leading to insufficient exocrine and endocrine pancreatic function. Approximately half of Becn1f/f; Ptf1aCre/+ mice died immediately after birth. However, duodenum and neural tissue development were almost normal, indicating that pancreatic insufficiency was the cause of death. These findings demonstrated a novel role for Becn1 in pancreas morphogenesis, differentiation, and growth, and suggested that loss of this factor leaded to pancreatic agenesis at birth.

The potential mechanism underlying the hepatorenal toxicity induced by hymexazol in rats and the role of NF-κB signaling pathway.

Hymexazol (HML) is widely used in agriculture as a systemic fungicide and plant growth promoter. Humans are continuously exposed to HML via various routes. The liver and kidneys are essential organs for the detoxification, metabolism, and excretion of HML. However, data concerning the impact of HML on nontarget organisms are scarce. The present study aimed to determine the mechanism of dose-dependent hepatorenal toxicity of HML in rats. Twenty-one rats were divided into three equal groups that received the following treatments via oral intake daily for 14 days: group 1, normal saline; group 2, low dose of HML (1/80 LD50 ); group 3, high dose of HML (1/40 LD50 ). We weighed the rats at the beginning and the end of the experiment to record the weight gain in each group. The results showed that HML induced dose-dependent hepatorenal toxicity manifested by a significant increase in malondialdehyde levels, a decrease in total antioxidant capacity and reduced glutathione contents, and upregulation of the transcriptase levels of the nuclear factor kappa B (NF-κB), tumor necrosis factor alpha (TNF-α), and interleukin-1 beta (IL-1ß) genes. The HML-exposed groups displayed various histopathological changes in both organs, with significant elevation of all serum liver and kidney biomarkers. In conclusion, HML produced hepatorenal toxicity in rats through oxidative stress that mediates the NF-κB signaling pathway in response to pro-inflammatory cytokines such as TNF-α and IL-1ß. We advise limiting the use of HML in agricultural and veterinary practices and finding an alternative agent to avoid the human and animal health risks induced by HML exposure.

Chitosan coating silver nanoparticles as a promising feed additive in broilers chicken.

The present study aimed to evaluate the potential of chitosan coating silver nanoparticles to enhance the growth performance and immune status of broilers without inducing oxidative stress-related pathological lesions in any organs or leaving residues of silver in the edible parts. Five clusters of Cobb one-day-old chicks (n = 10/group in each replication) were given oral therapy, once a week for 36 days as follows: (1) distilled water, (2, 3) 0.5- and 5 ppm silver nanoparticles (AgNPs), respectively, (4, 5) 0.5- and 5 ppm chitosan/silver nanoconjugates (CS/Ag-NCs), respectively. The results demonstrated a marked elevation in the body weight gain with a decline in the food conversion ratio and marked improvement in feeding and drinking behavior of all nanoparticles treated groups, but higher in CS/Ag-NCs groups than AgNPs groups and control group. In contrast to the 0.5 ppm AgNPs receiving group, the group receiving 5 ppm AgNPs noticed remarkable histological changes in some organs, including the liver, kidneys, spleen, and heart. Moreover, the administration of CS/Ag-NCs at two dosage levels didn't influence any histological changes. The AgNPs groups' antibody titers against the ND and AI viruses were almost identical to those of the control group. Otherwise, CS/Ag-NCs groups recorded the highest antibody titers. Additionally, there was a significant increase in silver content in most edible organs of AgNPs groups at a dosage level of 5 ppm. Otherwise, the coating of AgNPs by CSNPs could decrease the aggregation of silver in the biological organs. Thus, we recommend utilizing 0.5 ppm CS/Ag-NCs in broiler farms to promote their growth performance and strengthen their immune defense.

Targeting chemoresistance in Xp11.2 translocation renal cell carcinoma using a novel polyamide-chlorambucil conjugate.

Renal cell carcinoma with Xp11.2 translocation involving the TFE3 gene (TFE3-RCC) is a recently identified subset of RCC with unique morphology and clinical presentation. The chimeric PRCC-TFE3 protein produced by Xp11.2 translocation has been shown to transcriptionally activate its downstream target genes that play important roles in carcinogenesis and tumor development of TFE3-RCC. However, the underlying molecular mechanisms remain poorly understood. Here we show that in TFE3-RCC cells, PRCC-TFE3 controls heme oxygenase 1 (HMOX1) expression to confer chemoresistance. Inhibition of HMOX1 sensitized the PRCC-TFE3 expressing cells to genotoxic reagents. We screened for a novel chlorambucil-polyamide conjugate (Chb) to target PRCC-TFE3-dependent transcription, and identified Chb16 as a PRCC-TFE3-dependent transcriptional inhibitor of HMOX1 expression. Treatment of the patient-derived cancer cells with Chb16 exhibited senescence and growth arrest, and increased sensitivity of the TFE3-RCC cells to the genotoxic reagent etoposide. Thus, our data showed that the TFE3-RCC cells acquired chemoresistance through HMOX1 expression and that inhibition of HMOX1 by Chb16 may be an effective therapeutic strategy for TFE3-RCC.

A Comprehensive Study on the Mechanistic Way of Hexaflumuron and Hymexazol Induced Neurobehavioral Toxicity in Rats.

Pesticides are widely used in agriculture to kill pests, but their action is non-selective and results in several hazardous effects on humans and animals. Pesticide toxicity has been demonstrated to alter a variety of neurological functions and predisposes to various neurodegenerative diseases. Although, there is no data available for hexaflumuron (HFM) and hymexazol (HML) neurotoxicity. Hence, the present study aims to investigate the possible mechanisms of HFM and HML neurotoxicity. 21 male Wistar rats were divided into three groups and daily received the treatment via oral gavage for 14 days as follows: group (1) normal saline, group (2) HFM (1/100LD50), and group (3) HML (1/100 LD50). Our results revealed that both HFM and HML produced a significant increase in MDA levels and a decrease in GSH and CAT activity in some brain areas. There were severe histopathological alterations mainly neuronal necrosis and gliosis in different examined areas. Upregulation of mRNA levels of JNK and Bax with downregulation of Bcl-2 was also recorded in both pesticides exposed groups. In all studied toxicological parameters, HML produced neurotoxicity more than HFM. HFM targets the cerebral cortex and striatum, while HML targets the cerebral cortex, striatum, hippocampus, and cerebellum. We can conclude that both HFM and HML provoke neurobehavioral toxicity through oxidative stress that impairs the mitochondrial function and activates the JNK-dependent apoptosis pathway.

Antidepressant and Cardioprotective Effects of Self-Nanoemulsifying Self-Nanosuspension Loaded with Hypericum perforatum on Post-Myocardial Infarction Depression in Rats.

Hypericum perforatum (HP) is characterized by potent medicinal activity. However, the poor water solubility of many HP constituents limits their therapeutic effectiveness. Self-nanoemulsifying self-nanosuspension loaded with HP (HP.SNESNS) was formulated to improve the bioefficacy of HP. It was prepared using 10% triacetin, 57% Tween 20, and 33% PEG 400 and then incorporated with HP extract (100 mg/mL). HP.SNESNS demonstrated a bimodal size distribution (258.65 ± 29.35 and 9.08 ± 0.01 nm) corresponding to nanosuspension and nanoemulsion, respectively, a zeta potential of -8.03 mV, and an enhanced dissolution profile. Compared to the unformulated HP (100 mg/kg), HP.SNESNS significantly improved cardiac functions by decreasing the serum myocardial enzymes, nitric oxide (NO), and tumor necrosis factor- α (TNF-α) as well as restoring the heart tissue's normal architecture. Furthermore, it ameliorates anxiety, depressive-like behavior, and cognitive dysfunction by decreasing brain TNF-α, elevating neurotransmitters (norepinephrine and serotonin), and brain-derived neurotrophic factor (BDNF). In addition, HP.SNESNS augmented the immunohistochemical expression of cortical and hippocampal glial fibrillary acidic protein (GFAP) levels while downregulating the cortical Bcl-2-associated X protein (Bax) expression levels. Surprisingly, these protective activities were comparable to the HP (300 mg/kg). In conclusion, HP.SNESNS (100 mg/kg) exerted antidepressant and cardioprotective activities in the post-MI depression rat model.

Origanum majorana essential oil improves the rat's sexual behavior and testicular oxidative damage induced by imidacloprid via modulating the steroidogenesis pathways.

The neonicotinoid insecticide imidacloprid has been linked to significant reproductive damage in mammals. Origanum majorana essential oil (OME) is a natural herbal product used in the management of many diseases due to its strong antioxidant effects. The oil was hydrodistilled from O. Majorana and analyzed using GC/MS then its possible protective mechanisms against IMI-induced reprotoxicity in male rats were investigated. 28-adult male Wistar rats were divided into 4 groups as follows: group (1) control group, group (2) OME, group (3) IMI, and group (4) IMI + OME. The treatments were applied daily via oral gavage for 60 days. Remarkable abnormalities in both territorial aggressive and sexual behaviors were observed in IMI-treated rats with a significant elevation of serum FSH and LH as well as altered testicular redox status. Along with inhibition of the testicular expression of StAR and aromatase genes and serum total testosterone in addition to abnormal sperm count, viability, motility, and morphology. Histopathological examination showed severe degeneration and necrosis in both germ cells and Leydig cells with atrophy in most of the seminiferous tubules. Co-administration of OME with IMI notably improved all the above-mentioned studied parameters, and restored rats' spermatogenesis, sexual behavior, and favorably modulates the levels of both testosterone and gonadotropic hormones via its potent antioxidant effect. These findings support the use of OME as a fertility enhancer and suggest that it could be used to manage pesticide-induced male infertility.

Neuropathological and Cognitive Effects Induced by CuO-NPs in Rats and Trials for Prevention Using Pomegranate Juice.

Copper oxide nanoparticles (CuO-NPs) are extensively utilized in several industries and in pharmaceutical production. This excess exposure elevates the concern about its expected poisonous impacts on humans and animals. Pomegranate juice (PJ) is a natural source of polyphenols and exhibits potent antioxidant activities. Our experiment intended to explore the neurobehavioral and toxicopathological impacts of CuO-NPs and to explain the mechanistic role of PJ to reduce their toxicity. Thirty Wistar albino rats received the subsequent materials through oral gavage, every day for 28d: (1) normal saline, (2) 3 mL/kg bwt PJ, (3) 6 mL/kg bwt PJ, (4) 300 mg/kg bwt CuO-NPs, (5) CuO-NPs + 3 mL/kg bwt PJ, (6) CuO-NPs + 6 mL/kg bwt PJ. Continuous exposure to CuO-NPs caused a significant elevation of MDA levels and reduction of total antioxidant capacity associated with remarkable pathological alterations in all brain regions including cerebrum, hippocampus and cerebellum. Progressive decline of memory along with cognitive and psychiatric disturbances were observed in rats exposed to CuO-NPs not in PJ co-treated rats. Continuous exposure to CuO-NPs caused over expression of the immunohistochemical markers of caspase-3, iNOS and GFAP altogether with DAN fragmentation and down-regulation of HO-1 and Nrf2 gene in the whole brain tissues. Conversely, rats co-treated with PJ showed dose dependent improvements in the entire toxicological, behavioral, and pathological parameters. We showed that PJ had the ability to reduce the oxidative stress damage via up-regulation of HO-1 and Nrf2 genes in the brain. So that PJ had the ability to protect the brain and DNA from further damage.

Cathepsin D in pancreatic acinar cells is implicated in cathepsin B and L degradation, but not in autophagic activity.

Cathepsin D (CD) is the major lysosomal aspartic protease and is widely distributed in the cells of various mammalian tissues. CD participates in various physiological events such as regulation of programmed cell death, activation of enzymatic precursors, and metabolic degradation of intracellular proteins through macroautophagy. To investigate the role of CD in pancreatic acinar cells, which constitute the exocrine pancreas, we generated and examined mice specifically deficient for CD in pancreatic acinar cells. CD deficient mice showed normal pancreatic development and autophagic activity, although LC3-II, which is a marker of the autophagosome, accumulates in both physiological and pancreatitis conditions. Moreover, CD deficiency leads to accumulation of matured cathepsin B (CB) and cathepsin L (CL) which are members of the cysteine protease family. We therefore conclude that CD in pancreatic acinar cells is implicated in CB and CL degradation but not in autophagic activity.

Potential Mechanisms of Imidacloprid-Induced Neurotoxicity in Adult Rats with Attempts on Protection Using Origanum majorana L. Oil/Extract: In Vivo and In Silico Studies.

Imidacloprid (IMI) insecticide is rapidly metabolized in mammals and contributes to neurotoxicity via the blocking of nicotinic acetylcholine receptors, as in insects. Origanum majorana retains its great antioxidant potential in both fresh and dry forms. No data is available on the neuroprotective effect of this plant in laboratory animals. In this context, aerial parts of O. majorana were used to prepare the essential oil (OMO) and methanol extract (OME). The potential neuroprotective impact of both OMO and OME against IMI-induced neurotoxicity in rats was explored. Forty-two rats were divided into 6 groups, with 7 rats in each one. Rats were daily administered the oral treatments: normal saline, OMO, OME, IMI, IMI + OMO, and IMI + OME. Our results revealed the identification of 55 components in O. majorana essential oil, most belonging to the oxygenated and hydrocarbon monoterpenoid group. Moreover, 37 constituents were identified in the methanol extract, mostly phenolics. The potent neurotoxic effect of IMI on rats was confirmed by neurobehavioral and neuropathological alterations and a reduction of both acetylcholine esterase (AchE) activity and dopamine (DA), serotonin (5HT), and γ-aminobutyric acid (GABA) levels in the brain. Exposure of rats to IMI elevates the malondialdehyde (MDA) levels and reduces the antioxidant capacity. IMI could upregulate the transcription levels of nuclear factor-κB (NF-κB), interleukin-1 ß (IL-1ß), and tumor necrosis factor (TNF-α) genes and express strong caspase-3 and inducible nitric oxide synthase (iNOS) immunostaining in most examined brain areas. On the other hand, rats coadministered OMO or OME with IMI showed a marked improvement in all of the studied toxicological parameters. In conclusion, cotreatment of O. majorana extracts with IMI can protect against IMI neurotoxicity via their potent antioxidant, anti-inflammatory, and anti-apoptotic effects. Thus, we recommend a daily intake of O. majorana to protect against insecticide's oxidative stress-mediated neuroinflammatory stress and apoptosis. The molecular docking study of linalool, rosmarinic acid, γ-terpene, and terpene-4-ol justify the observed normalization of the elevated iNOS and TNF-α levels induced after exposure to IMI.

Comparative assessment on the probable mechanisms underlying the hepatorenal toxicity of commercial imidacloprid and hexaflumuron formulations in rats.

Pesticides are viewed as a major wellspring of ecological contamination and causing serious risky consequences for people and animals. Imidacloprid (IM) and hexaflumuron (HFM) are extensively utilized insect poisons for crop assurance on the planet. A few investigations examined IM harmfulness in rodents, but its exact mechanism hasn't been mentioned previously as well as the toxicity of HFM doesn't elucidate yet. For this reason, the present study was designed to explore the mechanism of each IM and HFM-evoked rat liver and kidney toxicity and to understand its molecular mechanism. 21 male Wistar albino rats were divided into 3 groups, as follows: group (1), normal saline; group (2), IM; and group (3), HFM. Both insecticides were orally administered every day for 28 days at a dose equal to 1/10 LD50 from the active ingredient. After 28 days postdosing, rats were anesthetized to collect blood samples then euthanized to collect liver and kidney tissue specimens. The results showed marked changes in walking, body tension, alertness, and head movement with a significant reduction in rats' body weight in both IM and HFM receiving groups. Significant increases in MDA levels and decrease of GHS levels were recorded in liver and kidney homogenates of either IM or HFM groups. Liver and kidney tissues obtained from both pesticide receiving groups showed extensive histopathological alterations with a significant increase in the serum levels of ALT, AST, urea, and creatinine and a decrease in total proteins, albumin, and globulin levels. In addition, there was upregulation of the transcript levels of casp-3, JNK, and HO-1 genes with strong immunopositivity of casp-3, TNF-á½°, and NF-KB protein expressions in the liver and kidneys of rats receiving either IM or HFM compared with the control group. In all studied parameters, HFM caused hepatorenal toxicity more than those induced by IM. We can conclude that each IM and HFM provoked liver and kidneys damage through overproduction of ROS, activation of NF-KB signaling pathways and mitochondrial/JNK-dependent apoptosis pathway.

Cathepsin B and D deficiency in the mouse pancreas induces impaired autophagy and chronic pancreatitis.

The major lysosomal proteases, Cathepsin B (CTSB), Cathepsin D (CTSD) and Cathepsin L (CTSL), are implicated in autophagic activity. To investigate the role of each cathepsin in the exocrine pancreas, we generated mice in which the pancreas was specifically deficient in Ctsb, Ctsd and Ctsl. Each of these gene knockout (KO) and Ctsb;Ctsl and Ctsd;Ctsl double-knockout (DKO) mice were almost normal. However, we found cytoplasmic degeneration in the pancreatic acinar cells of Ctsb;Ctsd DKO mice, similar to autophagy related 5 (Atg5) KO mice. LC3 and p62 (autophagy markers) showed remarkable accumulation and the numbers of autophagosomes and autolysosomes were increased in the pancreatic acinar cells of Ctsb;Ctsd DKO mice. Moreover, these Ctsb;Ctsd DKO mice also developed chronic pancreatitis (CP). Thus, we conclude that both Ctsb and Ctsd deficiency caused impaired autophagy in the pancreatic acinar cells, and induced CP in mice.