Targeting the PI3K/pAKT/mTOR/NF-κB/FOXO3a signaling pathway for suppressing the development of hepatocellular carcinoma in rats: Role of the natural remedic Suaeda vermiculata forssk.

Liver malignancy is well recognized as a prominent health concern, with numerous treatment options available. Natural products are considered a renewable source, providing inspiring chemical moieties that could be used for cancer treatment. Suaeda vermiculata Forssk has traditionally been employed for management of hepatic conditions, including liver inflammation, and liver cirrhosis, as well as to improve general liver function. The findings of our earlier study demonstrated encouraging in vivo hepatoprotective benefits against liver injury generated by paracetamol and carbon tetrachloride. Additionally, Suaeda vermiculata Forssk exhibited cytotoxic activities in vitro against Hep-G2 cell lines and cell lines resistant to doxorubicin. The present investigation aimed to examine the potential in vivo hepatoprotective efficacy of Suaeda vermiculata Forssk extract (SVE) against hepatocellular carcinoma induced by diethylnitrosamine (DENA) in rats. The potential involvement of the PI3K/AKT/mTOR/NF-κB pathway was addressed. Sixty adult male albino rats were allocated into five groups randomly (n = 10). First group received a buffer, whereas second group received SVE only, third group received DENA only, and fourth and fifth groups received high and low doses of SVE, respectively, in the presence of DENA. Liver toxicity and tumor markers (HGFR, p-AKT, PI3K, mTOR, NF-κB, FOXO3a), apoptosis markers, and histopathological changes were analyzed. The current results demonstrated that SVE inhibited PI3K/AKT/mTOR/NF-κB pathway as well as increased expression of apoptotic parameters and FOXO3a levels, which were deteriorated by DENA treatment. Furthermore, SVE improved liver toxicity markers and histopathological changes induced by DENA administration. This study provided evidence for the conventional hepatoprotective properties attributed to SV and investigated the underlying mechanism by which its extract, SVE, could potentially serve as a novel option for hepatocellular carcinoma (HCC) treatment derived from a natural source.

Involvement of PI3K/HIF-1α/c-MYC/iNOS Pathway in the Anticancer Effect of Suaeda vermiculata in Rats.

Suaeda vermiculata Forssk. ex JF Gmel. (SV), a traditional known plant, has shown in vitro cytotoxic activity against HepG2 and HepG-2/ADR (doxorubicin-resistant cells) liver cell carcinoma cell lines, as well as hepatoprotection against paracetamol and carbon tetrachloride (CCl4)-induced liver injury. The current study evaluated the protective effect of SV, administered against N-diethylnitrosamine (NDEA)-induced HCC in rats. The possible modulatory effect of SV on the PI3K/HIF-1α/c-MYC/iNOS pathway was investigated. Sixty male adult albino rats (200 ± 10 g) were equally classified into five groups. Group I served as a control; Group 2 (SV control group) received SV (p.o., 200 mg/kg body weight); Group 3 (NDEA-administered rats) received freshly prepared NDEA solution (100 mg/L); and Groups 4 and 5 received simultaneously, for 16 weeks, NDEA + SV extract (100 and 200 mg/kg, orally). NDEA-treated rats displayed significant increases in serum levels of AFP, CEA, PI3K, malondialdehyde (MDA), epidermal growth factor receptor (EGFR), and vascular endothelial growth factor (VEGFR), with increased liver tissue protein expression of fibrinogen concomitant and significantly decreased concentrations of antioxidant parameters (catalase (CAT), superoxide dismutase (SOD), and reduced glutathione (GSH)) in comparison to normal rats. On the flip side, AFP, CEA, PI3K, MDA, EGFR, and VEGFR serum levels were significantly reduced in rats that received NDEA with SV, both at low (SV LD) and high (SV HD) doses, accompanied by significant improvements in antioxidant parameters compared to the NDEA-treated group. Conclusions: SV possesses a significant hepatoprotective effect against NDEA-induced HCC via inhibiting the PI3K/HIF-1α/c-MYC/iNOS pathway, suggesting that SV could be a promising hepatocellular carcinoma treatment.

Lipid nanoparticles technology in vaccines: Shaping the future of prophylactic medicine.

Throughout decades, the intrinsic power of the immune system to fight pathogens has inspired researchers to develop techniques that enable the prevention or treatment of infections via boosting the immune response against the target pathogens, which has led to the evolution of vaccines. The recruitment of Lipid nanoparticles (LNPs) as either vaccine delivery platforms or immunogenic modalities has witnessed a breakthrough recently, which has been crowned with the development of effective LNPs-based vaccines against COVID-19. In the current article, we discuss some principles of such a technology, with a special focus on the technical aspects from a translational perspective. Representative examples of LNPs-based vaccines against cancer, COVID-19, as well as other infectious diseases, autoimmune diseases, and allergies are highlighted, considering the challenges and promises. Lastly, the key features that can improve the clinical translation of this area of endeavor are inspired.

Upregulation of Nrf2 signaling and suppression of ferroptosis and NF-κB pathway by leonurine attenuate iron overload-induced hepatotoxicity.

Hepatotoxicity is a major health concern that associates the iron overload diseases including hemochromatosis, sickle cell anemia, and thalassemia. Induction of ferroptosis, oxidative stress, and inflammation substantially mediates the iron-evoked hepatotoxicity. The current work investigated the potential protective effect of the natural alkaloid leonurine against the iron-induced hepatotoxicity and elucidated the underlining molecular mechanisms. Male Wistar rats were treated with iron only (30 mg/kg every other day over a ten-day period via intraperitoneal injection) or with iron and leonurine (leonurine: 100 mg/kg/day per oral via gastric gavage for 10 days) to establish the iron-overload model. Liver and blood specimens were then collected and subjected to molecular, biochemical, and histopathological investigations. The results revealed the ability of leonurine to suppress the iron-induced ferroptosis as reflected by modulation of the ferroptotic biomarkers glutathione peroxidase 4, cyclooxygenase-2, liver iron content, lipid hydroperoxides, and the leakage of the liver intracellular enzymes. Leonurine alleviated the iron-induced oxidative damage and inflammatory response in the liver tissues as indicated by decreased levels of DNA oxidation, lipid peroxidation, and the pro-inflammatory cytokines. In the same context, it improved the antioxidant potential of the liver tissues and ameliorated the iorn-induced histopathological abnormalities. Mechanistically, leonurine enhanced nuclear translocation of the antioxidant transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) and increased protein levels of its downstream targets NAD(P)H-quinone oxidoreductase 1 and heme oxygenase-1. Additionally, it suppressed the nuclear translocation of the inflammatory transcription factor nuclear factor kappa B (NF-κB) and downregulated its downstream pro-inflammatory cytokines tumor necrosis factor-alpha and interleukin-1 beta. The study highlights the hepatoprotective activity of leonurine against the iron-evoked hepatotoxicity that is potentially mediated through modulation of Nrf2 and NF-κB signaling.

Arctigenin alleviates cadmium-induced nephrotoxicity: Targeting endoplasmic reticulum stress, Nrf2 signaling, and the associated inflammatory response.

AIM: Nephrotoxicity is a critical consequence of cadmium toxicity. Cadmium induces nephrotoxicity through disruption of cellular redox balance and induction of endoplasmic reticulum stress (ERS) and inflammatory responses. The present study investigated the renoprotective effects of the naturally occurring arctigenin against the cadmium-induced nephrotoxicity. MAIN METHODS: Male Wistar rats were randomized into normal control, arctigenin control, cadmium, and cadmium/arctigenin groups. Cadmium and arctigenin were administered daily over a seven-day period. On the eighth day, blood and kidney tissue specimens were collected and subjected to spectrophotometric, ELISA, and immunoblotting analysis. KEY FINDINGS: Arctigenin significantly improved renal functions and reduced renal tubular injury in the cadmium-intoxicated rats as reflected by increased GFR and reduced levels of serum creatinine, BUN, urinary albumin-to-creatinine ratio, and protein expression of KIM-1. Arctigenin alleviated the cadmium-induced oxidative DNA damage and lipid peroxidation while boosted reduced glutathione level and antioxidant enzymes activity. Mechanistically, arctigenin enhanced nuclear translocation of the antioxidant transcription factor Nrf2 and up-regulated its downstream redox-regulating enzymes HO-1 and NQO1. Importantly, arctigenin ameliorated the cadmium-evoked ERS as demonstrated by reduced protein expression of the key molecules Bip, PERK, IRE1α, CHOP, phspho-eIF2α, and caspase-12 and diminished activity of caspase-12. Additionally, arctigenin down-regulated the cadmium-induced NF-κB nuclear translocation and decreased its downstream pro-inflammatory cytokines TNF-α and IL-1ß. SIGNIFICANCE: The current work underlines the alleviating activity of arctigenin against cadmium-evoked nephrotoxicity potentially through mitigating ERS and targeting Nrf2 and NF-κB signaling. The current findings support possible therapeutic application of arctigenin in controlling cadmium-induced nephrotoxicity although clinical investigations are necessary.

Mental depression: Relation to different disease status, newer treatments and its association with COVID-19 pandemic (Review).

The present study aimed to review major depression, including its types, epidemiology, association with different diseases status and treatments, as well as its correlation with the current COVID-19 pandemic. Mental depression is a common disorder that affects most individuals at one time or another. During depression, there are changes in mood and behavior, accompanied by feelings of defeat, hopelessness, or even suicidal thoughts. Depression has a direct or indirect relation with a number of other diseases including Alzheimer's disease, stroke, epilepsy, diabetes, cardiovascular disease and cancer. In addition, antidepressant drugs have several side effects including sedation, increased weight, indigestion, sexual dysfunction, or a decrease in blood pressure. Stopping medication may cause a relapse of the symptoms of depression and pose a risk of attempted suicide. The pandemic of COVID-19 has affected the mental health of individuals, including patients, individuals contacting patients and medical staff with a number of mental disorders that may adversely affect the immune ability of their bodies. Some of the drugs currently included in the protocols for treating COVID-19 may negatively affect the mental health of patients. Evidence accumulated over the years indicates that serotonin (5HT) deficiencies and norepinephrine (NE) in the brain can lead to mental depression. Drugs that increase levels of NE and 5HT are commonly used in the treatment of depression. The common reason for mood disorders, including mania and bipolar disease are not clearly understood. It is assumed that hyperactivity in specific parts of the brain and excessive activity of neurotransmitters may be involved. Early diagnosis and developing new treatment strategies are essential for the prevention of the severe consequences of depression. In addition, extensive research should be directed towards the investigation of the mental health disturbances occurring during and/or after COVID-19 infection. This may lead to the incorporation of a suitable antidepressant into the current treatment protocols.

Design, Synthesis and Anticancer Profile of New 4-(1H-benzo[d]imidazol-1-yl)pyrimidin-2-amine-Linked Sulfonamide Derivatives with V600EBRAF Inhibitory Effect.

A new series of 4-(1H-benzo[d]imidazol-1-yl)pyrimidin-2-amine linked sulfonamide derivatives 12a-n was designed and synthesized according to the structure of well-established V600EBRAF inhibitors. The terminal sulfonamide moiety was linked to the pyrimidine ring via either ethylamine or propylamine bridge. The designed series was tested at fixed concentration (1 µM) against V600EBRAF, finding that 12e, 12i and 12l exhibited the strongest inhibitory activity among all target compounds and 12l had the lowest IC50 of 0.49 µM. They were further screened on NCI 60 cancer cell lines to reveal that 12e showed the most significant growth inhibition against multiple cancer cell lines. Therefore, cell cycle analysis of 12e was conducted to investigate the effect on cell cycle progression. Finally, virtual docking studies was performed to gain insights for the plausible binding modes of vemurafenib, 12i, 12e and 12l.

Resveratrol inhibits macrophage infiltration of pancreatic islets in streptozotocin-induced type 1 diabetic mice via attenuation of the CXCL16/NF-κΒ p65 signaling pathway.

AIM: Despite CXC chemokine ligand 16 (CXCL16) contributes to the pathogenesis of many inflammatory disorders, the mechanism by which CXCL16 is involved in T1DM remains unclear. In this study, we examined the role of the CXCL16/NF-κΒ p65 signaling pathway in the progression of this disease and the possible protective effect of resveratrol (RES) on streptozotocin (STZ)-induced T1DM. MAIN METHODS: Mice were classified into four groups of 10 animals each. The control group received citrate buffer. The RES group received 50 mg/kg i.p. RES for 12 days beginning on day 4 of citrate buffer. The STZ group received 55 mg/kg i.p. STZ once a day for 5 consecutive days. The fourth group injected with RES (50 mg/kg) for 12 days starting on day 4 of STZ injection. Biochemical, physical and oxidative stress parameters were measured in all groups. Moreover, expression of CXCL16 and CD45 was measured in pancreatic islets and spleen. Additionally, NF-κΒ p65 was investigated in isolated islets. KEY FINDINGS: Our results showed a significant elevation of CXCL16, NF-κΒ p65 and CD45 in islets of diabetic (DM) mice. Intriguingly, RES significantly restored distorted biochemical, physical and oxidative stress parameters after STZ treatment as well as inhibited the expression of CXCL16/NF-κΒ p65 in pancreatic islets. Moreover, RES normalized CXCL16 and CD45 expression in islets and spleen. SIGNIFICANCE: This study demonstrates first evidence that CXCL16/NF-κΒ p65 signaling pathway is associated with macrophage infiltration to pancreatic islet in T1DM and that RES successfully improved T1DM may be at least via inhibiting this pathway.

Introducing of potent cytotoxic novel 2-(aroylamino)cinnamamide derivatives against colon cancer mediated by dual apoptotic signal activation and oxidative stress.

Curcumin and trans-cinnamaldehyde are acrolein-based Michael acceptor compounds that are commonly found in domestic condiments, and known to cause cancer cell death via redox mechanisms. Based on the structural features of these compounds we designed and synthesized several 2-cinnamamido-N-substituted-cinnamamide (bis-cinnamamide) compounds. One of the derivatives, (Z)-2-[(E)-cinnamamido]-3-phenyl-N-propylacrylamide 8 showed a moderate antiproliferative potency (HCT-116 cell line inhibition of 32.0 µM), no inhibition of normal cell lines C-166, and proven cellular activities leading to apoptosis. SAR studies led to more than 10-fold increase in activity. Our most promising compound, [(Z)-3-(1H-indol-3-yl)-N-propyl-2-[(E)-3-(thien-2-yl)propenamido)propenamide] 45 killed colon cancer cells at IC50 = 0.89 µM (Caco-2), 2.85 µM (HCT-116) and 1.65 µM (HT-29), while exhibiting much weaker potency on C-166 and BHK normal cell lines (IC50 = 71 µM and 77.6 µM, respectively). Cellular studies towards identifying the compounds mechanism of cytotoxic activities revealed that apoptotic induction occurs in part as a result of oxidative stress. Importantly, the compounds showed inhibition of cancer stem cells that are critical for maintaining the potential for self-renewal and stemness. The results presented here show discovery of covalently acting Michael addition compounds that potently kill cancer cells by a defined mechanism, with prominent selectivity profile over non-cancerous cell lines.

Interruption of platelets and thrombin function as a new approach against liver fibrosis induced experimentally in rats.

AIM: Liver fibrosis is a serious health problem which is a critical cause of morbidity and mortality worldwide. It is the main complication of untreated chronic inflammatory liver diseases which can progress to liver cirrhosis, hepatocellular carcinoma, and finally death. Coagulation cascade plays a mechanistic role in the pathogenesis of different chronic inflammatory disease including atherosclerosis, stroke, and tissue fibrosis. The current study was designed to investigate the effect of inhibition of coagulation cascade on carbon tetrachloride (CCl4)-induced liver fibrosis in rats. MATERIAL AND METHODS: The study was conducted in rats. Rats were treated with CCl4 subcutaneously for 6 consecutive weeks to determine the onset of coagulation system activation in relation to development of fibrosis. To investigate the effects of coagulation system inhibition in CCl4-induced liver fibrosis, the anticoagulants drugs dabigatran and clopidogrel were administrated orally concurrently with CCl4 treatment. KEY FINDINGS: The results of our study revealed that during the first week, there were significant elevations of fibrin, tissue factor expressions, and prothrombin time (PT) coupled with neutropenia without significant changes in liver fibrosis markers such as TGF-ß, α-SMA and collagen deposition. Starting from the second week, tissue injury markers including the oxidative, inflammatory and fibrosis markers as well as histopathological changes became evident progressively. Intriguingly, dabigatran and clopidogrel significantly normalized the biochemical and pathological changes. SIGNIFICANCE: In conclusion, activation of coagulation cascade is a triggering stimulus in the initiation of CCl4-induced liver fibrosis and the anticoagulant drugs may exert promising anti-fibrotic effect.

Tempol, a superoxide dismutase mimetic agent, reduces cisplatin-induced nephrotoxicity in rats.

Cisplatin (CP) is one of the most potent anti-cancer drugs used against different types of cancer. Its use is limited due to its nephrotoxicity. This study is aimed to evaluate the role of a super oxide dismutase (SOD) mimetic agent, tempol, in protection against CP nephrotoxicity in rats. Animals were divided into four groups: Group-1: Normal control group, Group-2: CP group (single dose of CP 6 mg/kg, i.p.), Group-3 and Group-4: Tempol-treated groups (50 mg/kg p.o. and 100 mg/kg p.o. respectively) daily for a week before CP injection and continued for an additional four days after CP injection. Urine and blood samples were collected for the evaluation of kidney function including serum creatinine, BUN, cystatin-c, and creatinine clearance. In addition, western blotting was used to determine urine lipocalin-2 content. Furthermore, kidney tissue was collected for the determination of oxidative stress markers, caspase-3 expression, and histopathological examination. We noticed that both doses of tempol significantly improved kidney function, which was deteriorated by CP injection. Tempol significantly elevated kidney glutathione (GSH) content and SOD activity, and decreased kidney lipid peroxidation and NOx production. Tempol also significantly decreased kidney caspase-3 expression which was elevated by CP toxicity. Thus, we conclude that tempol can protect against CP nephrotoxicity. We noticed that both doses of tempol are effective in ameliorating CP-nephrotoxicity.

Interference With Coagulation Cascade as a Novel Approach to Counteract Cisplatin-Induced Acute Tubular Necrosis; an Experimental Study in Rats.

Coagulation system activation plays an important role in the pathophysiology of different diseases. In spite of massive research regarding cisplatin-induced nephrotoxicity, the role of coagulation cascade in such toxicity is still questionable. Here, we aim to investigate the role of activation of coagulation system in the initiation of cisplatin-induced acute renal tubular necrosis. Moreover, the role of the anticoagulant rivaroxaban against such toxicity was investigated. Briefly, animals were classified into seven groups, eight rats each. Group 1 served as normal control group, groups (2-7) received i.p. single doses of cisplatin (6 mg/kg b.w), groups (6-7) were treated with rivaroxaban (5 and 7 mg/kg b.w, p.o., respectively) 7 days before cisplatin injection and completed for 4 days. Animals in groups (2, 3, and 4) were sacrificed after 1, 2 and 3 days of cisplatin injection, respectively, while groups (1, 5, 6, and 7) were sacrificed after 4 days of cisplatin injection. Serum cystatin-c, urea, creatinine and γ-glutamyl transferase, urinary Lipocaline-2, and KIM-1 protein densities, as well as glomerular filtration rate (GFR) were assessed. Immunofluorescence examination of glomeruli fibrin and tissue factor (TF) was also performed coupled with a histopathological study. Cisplatin administration increased expression of fibrin and TF starting 24 h of cisplatin injection even before renal failure markers elevated. Leukocytosis, thrombocytopenia, and increased prothrombin time were also observed. Cisplatin also induced tubular damage evidenced by increased serum cystatin-c, urea, and creatinine with significant decrease in GFR and Gamma glutamyl transferase (GGT) activity. Rivaroxaban significantly decreased elevation of fibrin and TF with significant reduction in serum creatinine, BUN and cystatin-c levels. Rivaroxaban also significantly improved hematological markers and histological features as well. This study showed that activation of coagulation system plays an important role in the pathophysiology of cisplatin-induced acute renal tubular damage. Interference with coagulation cascade may be a promising nephroprotective strategy against chemical nephrotoxicity.

Design, Synthesis and Antiproliferative Activities of Oxidative Stress Inducers Based on 2-Styryl-3,5-dihydro-4H-imidazol-4-one Scaffold.

The 2-styryl-3,5-dihydro-4H-imidazol-4-one might be considered as a system with isosteric properties similar to trans-cinnamaldehyde (styrylaldehyde), a safe natural compound that exhibited interesting activities against various cancers. We synthesized a series of compounds that differ structurally in having different alkyl, aryl and heterocyclic substituents at the N3 position of the 2-styryl-4-imidaolone pharmacophore. The compounds were assayed for their cytotoxicity against both cancer and normal cell lines. In addition, their cellular mechanism of action as reactive oxygen species (ROS) inducers were investigated. Many of the synthesized compounds showed higher activities on colon, breast and hepatic cancer cell lines than the parent trans-cinnamaldehyde. Compounds 3a and 3e showed selective antiproliferative activity against cancer cell lines at low micromolar to sub-micromolar IC50 value. Compounds were extremely less toxic on normal cell lines baby hamster kidney fibroblasts (BHK) and human lung tissue fibroblast (WI-38). Similar to trans-cinnamaldehyde, the colon cancer cell cycle analysis indicated cell cycle changes consistent with increased oxidative stress leading to apoptosis. Compound 3e caused elevation of all cell oxidative indicators of ROS such as a decrease in reduced glutathione, increased malondialdehyde and suppression of catalase and superoxide dismutase activities. Dihydroethidium staining, nuclear fragmentation and increased caspase-3 further confirmed extensive apoptotic induction due to ROS accumulation upon treatment of human colon adenocarcinoma (HCT116) cells with compounds 3a and 3e. Changes in human breast adenocarcinoma (MCF7) cells were less revealing for ROS induction and increased oxidative stress. CONCLUSION: The compounds represent an example of efficient rescaffolding of a natural compound to a highly potent drug-like analogues.

Thymoquinone mitigate ischemia-reperfusion-induced liver injury in rats: a pivotal role of nitric oxide signaling pathway.

Oxidative and nitrosative stress-induced endothelial cell damage play an essential role in the pathogenesis of hepatic ischemia-reperfusion (IR) injury. IR is associated with reduced eNOS expression and exacerbated by superimposed stress. NOSTRIN induces intracellular endothelial nitric oxide synthase (eNOS) translocation and inducible nitric oxide synthase (iNOS) increases nitric oxide (NO) production. Our aim was to assess hepatic expression of iNOS, eNOS, and NOSTRIN in IR with or without N-acetylcysteine (NAC) or thymoquinone (TQ) pretreatment and to compare their hepatoprotective effects. Surgical induction of IR was performed by occlusion of hepatic pedicle for 30 min with mini-clamp and reperfused for 30 min. The effects of TQ (20 mg/kg/day) or NAC (300 mg/kg/day) administered orally for 10 days were evaluated by serum ALT and AST, oxidative stress parameters, NO production, and histopathological analysis. Also, localization and expression of iNOS, eNOS, and NOSTRIN were assessed by immunofluorescence. TQ or NAC pretreatment significantly decreased elevated serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and myeloperoxidase (MPO) activities, malondialdehyde (MDA) level, and NO production. In addition, they restored the depleted GSH content and alleviated histopathological changes. Furthermore, they up-regulated eNOS and down-regulated iNOS and NOSTRIN expressions. TQ exerts its hepatoprotective effect, at least in part, by nitric oxide signaling pathway through modulation of iNOS, eNOS, and NOSTRIN expressions as well as suppression of oxidative stress.

All-trans retinoic acid potentiates cisplatin-induced kidney injury in rats: impact of retinoic acid signaling pathway.

Cisplatin (cis-diammine dichloroplatinum (II), CDDP) is a widely used drug for treatment of various types of cancers. However, CDDP-induced nephrotoxicity remains the main dose-limiting side effect. Retinoids are a group of vitamin A-related compounds that exert their effects through retinoid receptors activation. In this study, we investigated the effect of CDDP treatment on retinoic acid receptor-α (RAR-α) and retinoid X receptor-α (RXR-α) expression. In addition, we investigated the possible modulatory effects of RAR agonist, all-trans retinoic acid (ATRA), on CDDP-induced nephrotoxicity. Rats were treated with saline, DMSO, CDDP, ATRA, or CDDP/ATRA. Twenty-four hours after the last ATRA injection, rats were killed; blood samples were collected; kidneys were dissected; and biochemical, immunohistochemical, and histological examinations were performed. Our results revealed that CDDP treatment significantly increased serum levels of creatinine and urea, with concomitant decrease in serum albumin. Moreover, reduced glutathione (GSH) content as well as superoxide dismutase (SOD) and catalase (CAT) activities were significantly reduced with concurrent increase in kidney malondialdehyde (MDA) content following CDDP treatment. Furthermore, CDDP markedly upregulated tubular RAR-α, RXR-α, fibrin, and inducible nitric oxide synthase (iNOS) protein expression. Although administration of ATRA to control rats did not produce marked alterations in kidney function parameters, administration of ATRA to CDDP-treated rats significantly exacerbated CDDP-induced nephrotoxicity. In addition, CDDP/ATRA co-treatment significantly increased RAR-α, RXR-α, fibrin, and iNOS protein expression compared to CDDP alone. In conclusion, we report, for the first time, the crucial role of retinoid receptors in CDDP-induced nephrotoxicity. Moreover, our findings indicate that co-administration of ATRA with CDDP, although beneficial on the therapeutic effects, their deleterious effects on the kidney may limit their clinical use.

Glutamyl cysteine dipeptide suppresses ferritin expression and alleviates liver injury in iron-overload rat model.

Despite its biological importance, iron is a pro-oxidant element and its accumulation results in tissue injury. Iron overload diseases such as thalassemia and hereditary hemochromatosis are commonly associated with liver tissue injury. Glutamyl cysteine (GC) is a dipeptide with antioxidant properties owing to its cysteine residue. The aim of the current work was to investigate the hepatoprotective effect of GC against iron overload-induced liver injury. Rats were distributed into five groups; normal control, GC control, iron-treated (150 mg/kg ip injection) and both iron and GC-treated (total iron: 150 mg/kg ip and GC: 50 mg or 100 mg/kg/day ip for 30 days). Our results showed that treatment with GC at the two-dose levels attenuated iron-induced liver tissue injury as evidenced by significant reduction in serum activity of liver enzymes ALT and AST, amelioration of iron-induced histopathological alteration, suppression of iron-induced oxidative stress as demonstrated by significant reduction of malondialdehyde and protein carbonyl content beside elevation of total antioxidant capacity, reduced glutathione and the antioxidant enzymes GPx and SOD in liver tissue. In addition, GC significantly reduced levels of the proinflammatory cytokines TNF-α, IL-6 and IL-1ß and activity of the apoptotic marker caspase-3 in liver tissues. To our surprise, GC reduced liver iron content and ferritin expression, denoting the possible iron chelation competency. Collectively our results highlight evidence for the hepatoprotective effect of GC against iron overload-induced liver injury that is potentially mediated through suppression of oxidative tissue injury, attenuation of inflammatory response, amelioration of hepatocellular apoptosis and possibly through iron chelation.

All-trans retinoic acid mitigates methotrexate-induced liver injury in rats; relevance of retinoic acid signaling pathway.

Methotrexate (MTX) is a widely used drug for treatment of rheumatic and autoimmune diseases as well as different types of cancer. One of the major side effects of MTX is hepatotoxicity. Retinoid receptors, including retinoid X receptor (RXR), and retinoic acid receptor (RAR) are vitamin A receptors that are highly expressed in the liver and regulate important physiological processes through regulation of different genes. In this study, we investigated the effect of MTX on RXR-α and RAR-α expression in the liver and the potential protective effects of all-trans retinoic acid (ATRA) in MTX-induced hepatotoxicity. Rats were randomly divided into five groups: The rates were treated with saline, DMSO, MTX (20 mg/kg/IP; single dose), ATRA (7.5 mg/kg/day, I.P), or MTX and ATRA. Rats were killed 24 h after the last ATRA injection. The liver tissues were dissected out, weighed, and subjected to histological, immunohistochemical, and biochemical examinations. Our results demonstrated that treatment with MTX resulted in significant decrease in reduced glutathione (GSH) content and superoxide dismutase (SOD) activity, with concomitant increase in ALT, AST, and MDA levels. In addition, MTX markedly downregulated the expression of both RXR-α and RAR-α, and changed the appearance of RXR-α to be very small speckled droplets. Treatment with ATRA significantly ameliorated MTX-induced effects on GSH, ALT, and MDA. Moreover, ATRA administration increased the expression and nuclear translocation of RXR-α in rat hepatocytes. In conclusion, our study revealed, for the first time, that retinoid receptors may play an important role in the MTX-induced hepatotoxicity.

ADAM10 is upregulated in melanoma metastasis compared with primary melanoma.

ADAM10 (a disintegrin and metalloproteinase 10) is involved in the ectodomain shedding of various substrates, including adhesion molecules such as L1 cell adhesion molecule (L1-CAM) and CD44, which are known to have important roles in the development of malignant melanoma. In our study, we characterized the expression of ADAM10 in melanoma cells in vitro and in vivo. Immunohistochemical analysis on tissue microarrays indicated that ADAM10 expression was significantly elevated in melanoma metastasis compared with primary melanomas. In vitro downregulation of ADAM10 with specific small interfering RNA (siRNA) resulted in a suppression of the anchorage-independent cell growth and reduced the migration of melanoma cells. In addition, overexpression of ADAM10 induced the migration of melanoma cells. In cell lines from melanoma patients with metastasis, ADAM10 was significantly overexpressed, and ADAM10 expression correlated with increased cell proliferation. Furthermore, we present evidence that ADAM10 is involved in the release of L1-CAM from melanoma cells. It is important that knockdown of cellular L1-CAM reduced the migration of melanoma cells and abrogated the chemoresistance against cisplatin. In contrast, soluble L1-CAM had no effect on melanoma cell migration or cell survival. Taken together, our data demonstrate that ADAM10 and L1-CAM have important roles during melanoma progression and both molecules represent attractive targets for therapeutical intervention of melanomas.