Hesperidin attenuates radiation-induced ovarian failure in rats: Emphasis on TLR-4/NF-ĸB signaling pathway.

Young women suffering from premature ovarian failure after radiotherapy carry a huge burden in the field of cancer therapy including reproductive loss, emotional stress, and physical troubles that reduce their long-term quality of life. Hesperidin (HSP) exhibited antioxidant, anti-inflammatory, and anti-apoptotic properties. HSP enhanced in vitro follicular maturation and preserved in vivo ovarian stockpile. In this research, the role of HSP in radiation-induced POF in rats was investigated besides ascertaining its underlying mechanisms. Female Sprague-Dawley rats were arbitrarily allocated into four groups: control-group, ϒ-irradiated-group (3.2 Gy once on the 7th day), HSP-group (100 mg/kg, orally for 10 days), and HSP/ϒ-irradiated-group (ϒ-radiation was applied one hour after HSP). At the end of experiment, the whole ovaries were collected for histological and biochemical analyses. Administration of HSP preserved the ovarian histoarchitecture and follicular stock, retained ovarian weight, and conserved serum estradiol and AMH levels following radiation exposure. HSP ameliorated the ovarian oxidative damage mediated by radiation through augmenting the activities of glutathione peroxidase, glutathione reductase, and catalase antioxidant enzymes. HSP exhibited remarkable anti-inflammatory activity by downregulating the expression of ovarian TLR-4, NF-ĸB, and TNF-α. Moreover, HSP suppressed the apoptotic machinery triggered by radiation by reducing p53 and Bax while increasing Bcl-2 mRNA expressions alongside diminishing caspase-3 expression. Additionally, HSP regulated estrous cycle disorder of irradiated rats and improved their reproductive capacity reflected by enhancing pregnancy outcomes. Therefore, HSP represents an appealing candidate as an adjunct remedy for female cancer patients during radiotherapy protocols owing to its antioxidant, anti-inflammatory, anti-apoptotic, and hormone-regulatory effects.

Coenzyme Q10 ameliorates cyclophosphamide-induced chemobrain by repressing neuronal apoptosis and preserving hippocampal neurogenesis: Mechanistic roles of Wnt/ ß-catenin signaling pathway.

Deterioration in the neurocognitive function of cancer patients referred to as "Chemobrain" is a devastating obstacle associated with cyclophosphamide (CYP). CYP is an alkylating agent, clinically utilized as an efficient anticancer and immunosuppressant. Coenzyme Q10 (CoQ10) is a worthwhile micronutrient with diverse biological activities embracing antioxidant, anti-apoptotic, and neuroprotective effects. The current experiment was designed for investigating the neuroprotective capability of CoQ10 versus CYP-elicited chemobrain in rats besides elucidating the causal molecular mechanisms. Male Sprague Dawley rats received CoQ10 (10 mg/kg, orally, once daily, for 10 days) and/or a single dose of CYP (200 mg/kg i.p. on day 7). CoQ10 counteracted CYP-induced cognitive and motor dysfunction as demonstrated by the findings of neurobehavioral tests (passive avoidance, Y maze, locomotion, and rotarod tests). Histopathological analysis further affirmed the neuroprotective abilities of CoQ10. CoQ10 effectually diminished CYP-provoked oxidative injury by restoring the antioxidant activity of catalase (CAT) enzyme while reducing malondialdehyde (MDA) levels. Besides, CoQ10 efficiently repressed CYP-induced neuronal apoptosis by downregulating the expression of Bax and caspase-3 while upregulating the Bcl-2 expression. Moreover, CoQ10 hampered CYP-provoked upregulation in acetylcholinesterase (AChE) activity. Furthermore, CoQ10 considerably augmented hippocampal neurogenesis by elevating the expressions of brain-derived neurotrophic factor (BDNF) and Ki-67. These promising neuroprotective effects can be credited to upregulating Wnt/ß-catenin pathway as evidenced by the elevated expressions of Wnt-3a, ß-catenin, and Phoshpo-glycogen synthase kinase-3 ß (p-GSK-3ß). Collectively, these findings proved the neuroprotective capabilities of CoQ10 against CYP-induced chemobrain through combating oxidative injury, repressing intrinsic apoptosis, boosting neurogenesis, and eventually upregulating the Wnt/ß-catenin pathway.

Neuroprotective effects of saxagliptin against radiation-induced cognitive impairment: Insights on Akt/CREB/SIRT1/BDNF signaling pathway.

Radiation-induced cognitive impairment has recently fueled scientific interest with an increasing prevalence of cancer patients requiring whole brain irradiation (WBI) in their treatment algorithm. Saxagliptin (SAXA), a dipeptidyl peptidase-IV (DPP-IV) inhibitor, has exhibited competent neuroprotective effects against varied neurodegenerative disorders. Hence, this study aimed at examining the efficacy of SAXA in alleviating WBI-induced cognitive deficits. Male Sprague Dawley rats were distributed into control group, WBI group exposed to 20 Gy ϒ-radiation, SAXA group treated for three weeks with SAXA (10 mg/kg. orally, once daily), and WBI/SAXA group exposed to 20 Gy ϒ-radiation then treated with SAXA (10 mg/kg. orally, once daily). SAXA effectively reversed memory deterioration and motor dysfunction induced by 20 Gy WBI during behavioural tests and preserved normal histological architecture of the hippocampal tissues of irradiated rats. Mechanistically, SAXA inhibited WBI-induced hippocampal oxidative stress via decreasing lipid peroxidation while restoring catalase antioxidant activity. Moreover, SAXA abrogated radiation-induced hippocampal neuronal apoptosis through downregulating proapoptotic Bcl-2 Associated X-protein (Bax) and upregulating antiapoptotic B-cell lymphoma 2 (Bcl-2) expressions and eventually diminishing expression of cleaved caspase 3. Furthermore, SAXA boosted hippocampal neurogenesis by upregulating brain-derived neurotrophic factor (BDNF) expression. These valuable neuroprotective capabilities of SAXA were linked to activating protein kinase B (Akt), and cAMP-response element-binding protein (CREB) along with elevating the expression of sirtuin 1 (SIRT-1). SAXA successfully mitigated cognitive dysfunction triggered by WBI, attenuated oxidative injury, and neuronal apoptosis, and enhanced neurogenesis through switching on Akt/CREB/BDNF/SIRT-1 signaling axes. Such fruitful neurorestorative effects of SAXA provide an innovative therapeutic strategy for improving the cognitive capacity of cancer patients exposed to radiotherapy.

Effect of carvedilol on pharmacokinetics of sofosbuvir and its metabolite GS-331007: role of P-glycoprotein.

Sofosbuvir (SOF) is a P-glycoprotein (P-gp) substrate, and carvedilol (CAR) is an inhibitor of P-gp, suggesting that it may affect the oral pharmacokinetics and safety of SOF. The current study investigated the pharmacokinetic interaction of CAR with SOF and its metabolite, GS-331007, and the possible consequent toxicities in rats. To assess the pharmacokinetics of SOF and GS-331007, rats were divided into three groups; all received a single oral dose of SOF preceded with saline (SAL), verapamil (VER) as a standard P-gp inhibitor, or CAR, respectively. The serosal, plasma, and hepatic tissue contents of SOF and GS-331007 were assessed using LC-MS/MS. Renal and hepatic toxicities were assessed using biochemical and histopathological tests. Serosal and plasma concentrations of SOF and GS-331007 were increased in the presence of CAR, suggesting a significant inhibitory effect of CAR on intestinal P-gp. Simultaneously, the pharmacokinetic profile of SOF showed a significant increase in the Cmax, AUC(0-t), AUC (0-∞), t1/2, and a reduction in its apparent oral clearance. While the pharmacokinetic profile of GS-331007 was not significantly affected. However, this notable elevation in drug oral bioavailability was corroborated by a significant alteration in renal functions. Hence, further clinical investigations are recommended to ensure the safety and dosing of CAR/SOF combination.

Ondansetron attenuates cisplatin-induced behavioral and cognitive impairment through downregulation of NOD-like receptor inflammasome pathway.

Cisplatin is an effective and commonly used chemotherapeutic drug; however, its use is accompanied by several adverse effects, including chemobrain. Ondansetron is a 5-HT3 antagonist, commonly used in prophylactic against chemotherapy-induced nausea and vomiting. Moreover, it has been identified as a novel neuroprotective agent in different animal models. However, its protective role against chemotherapy-induced chemobrain has not been investigated. The current study was the first study that explored the potential neuroprotective effect of ondansetron against cisplatin-induced chemobrain in rats. Cisplatin (5 mg/Kg) was injected intraperitoneally, once weekly, for 4 weeks with the daily administration of ondansetron (0.5 and 1 mg/Kg). Compared to the cisplatin-treated group, ondansetron administration showed a significant decrease in the latency time and a significant increase in ambulation, rearing, and grooming frequency in the open field test (OFT). Moreover, a significant improvement in the latency time in the rotarod and passive avoidance tests, following ondansetron administration. In addition, ondansetron treatment increased the percentage of alternation in the Y-maze test. Also, ondansetron showed a remarkable enhancement in the biochemical parameters in the hippocampus. It increased the acetylcholine (Ach) level and decreased the level of the acetylcholine esterase enzyme (AchE). Ondansetron significantly decreased interleukin-1ß (Il-1ß), tumor necrosis factor-alpha (TNF-α), toll-like receptor-4 (TLR-4), NOD-like receptor-3 (NLRP3) inflammasome as well as caspase-1 and caspase-3 levels. Furthermore, ondansetron significantly decreased the levels of copper transporter-1(CTR1) expression in the hippocampus. Collectively, these findings suggest that ondansetron may exhibit a neuroprotective and therapeutic activity against cisplatin-induced chemobrain.

The role of mitochondrial/metabolic axis in development of tamoxifen resistance in breast cancer.

Only a few investigations, to our knowledge, have examined the bioenergetics of Tamoxifen (TMX) resistant individuals and reported altered mitochondrial activity and metabolic profile. The primary cause of TMX resistance is firmly suggested to be metabolic changes. Metabolic variations and hypoxia have also been linked in a bidirectional manner. Increased hypoxic levels correlate with early recurrence and proliferation and have a negative therapeutic impact on breast cancer (BC) patients. Hypoxia, carcinogenesis, and patient death are all correlated, resulting in more aggressive traits, a higher chance of metastasis, and TMX resistance. Consequently, we sought to investigate the possible role of the metabolic/hypoxial axis Long non-coding RNA (LncRNA) Taurine up-regulated 1 (TUG-1), Micro-RNA 186-5p (miR-186), Sirtuin-3 (SIRT3), Peroxisome Proliferator Activator Receptor alpha (PPAR-α), and Hypoxia-Inducible Factor-1 (HIF-1) in the development of TMX resistance in BC patients and to correlate this axis with tumor progression. Interestingly, this will be the first time to explore epigenetic regulation of this axis in BC.

Molecular mechanisms underlying cyclophosphamide-induced cognitive impairment and strategies for neuroprotection in preclinical models.

Cyclophosphamide has drastically enhanced the expectancy and quality of life of cancer patients. However, it is accompanied by diverse neurological complications which are considered a dose-limiting adverse effect. Neurotoxicity caused by cyclophosphamide can manifest in numerous manners including anxiety, depression, motor dysfunction and cognitive deficits. This review article offers an overview on cyclophosphamide-induced neurotoxicity, providing a unified point of view on the possible underlying molecular mechanisms including oxidative brain damage, neuroinflammation, apoptotic neuronal cell death as well as disruption of the balance of brain neurotransmitters and neurotrophic factors. Besides, this review sheds light on the promising protective agents that have been investigated using preclinical animal models as well as their biological targets and protection mechanisms. Despite promising results in experimental models, none of these agents has been studied in clinical trials. Thus, there is lack of evidence to advocate the use of any neuroprotective agent in the clinical setting. Furthermore, none of the protective agents has been evaluated for its effect on the anticancer activity of cyclophosphamide in tumor-bearing animals. Therefore, there is a great necessity for adequate well-designed clinical studies for evaluation of the therapeutic values of these candidates. Conclusively, this review summarizes the molecular mechanisms accounting for cyclophosphamide-induced neurotoxicity together with the potential protective strategies seeking for downgrading this neurological complication, thus enhancing the quality of life and well-being of cancer patients treated with cyclophosphamide.

Effect of renin angiotensin blockers on angiotensin converting enzyme 2 level in cardiovascular patients.

BACKGROUND: Renin-angiotensin-aldosterone system (RAAS) is hypothesized to be in the center of COVID pathophysiology as the angiotensin converting enzyme 2 (ACE2) represents the main entrance of the virus, thus there is a need to address the effect of chronic use of RAAS blockers, as in case of treatment of cardiovascular diseases, on the expression of ACE2. Accordingly, this study aimed to clarify the effect of ACE inhibitors (ACEIs) and angiotensin-receptor blockers (ARBs) on ACE2 and to assess the correlation between ACE2 and several anthropometric and clinic-pathological factors. METHODS: A total of 40 healthy controls and 60 Egyptian patients suffering from chronic cardiovascular diseases were enrolled in this study. Patients were divided into 40 patients treated with ACEIs and 20 patients treated with ARBs. Serum ACE2 levels were assessed by ELISA. RESULTS: Assessment of serum ACE2 level in different groups showed a significant difference between ACEIs and healthy groups and ACEIs and ARBs group, while there was no difference between ARBs and healthy. Multivariate analysis using ACE2 level as constant and age, female sex, ACEIs use and myocardial infarction (MI) showed that there was a significant effect of female sex and ACEIs use on ACE2 level with no effect of age, MI and diabetes. CONCLUSION: ACE2 levels varied between ACEIs and ARBs. It tends to be lower in ACEIs group and there is a strong positive association between ACE2 level and the female sex. This needs to be considered in Future studies to further understand the relationship between gender, sex hormones and ACE2 level. TRIAL REGISTRATION: Retrospectively registered ClinicalTrials.gov ID: NCT05418361 (June 2022).

Vildagliptin restores cognitive function and mitigates hippocampal neuronal apoptosis in cisplatin-induced chemo-brain: Imperative roles of AMPK/Akt/CREB/ BDNF signaling cascades.

Cisplatin (CP) is a broad-spectrum antineoplastic agent used to treat many human cancers. Nonetheless, most patients receiving CP suffer from cognitive deficits, a phenomenon termed "chemo-brain". Recently, vildagliptin (Vilda), a DPP-4 inhibitor, has demonstrated promising neuroprotective properties against various neurological diseases. Therefore, the present study aims to investigate the potential neuroprotective properties of Vilda against CP-induced neurotoxicity and elucidate the underlying molecular mechanisms. Chemo-brain was induced in Sprague-Dawley rats by i.p injection of CP at a dose of 5 mg/kg once weekly for four weeks. Vilda was administered daily at a dose (10 mg/kg; P.O) for four weeks. The results revealed that Vilda restored the cognitive function impaired by CP, as assessed by the Morris water maze, Y-maze, and passive avoidance tests. Moreover, Vilda alleviated the CP-induced neurodegeneration, as shown by toluidine blue staining, besides markedly reduced amyloid plaque deposition, as evidenced by Congo red staining. Notably, Vilda boosted cholinergic neurotransmission through the downregulation of the acetylcholinesterase enzyme. In addition, the neuroprotective mechanisms of Vilda include diminishing oxidative stress by reducing MDA levels while raising GSH levels and SOD activity, repressing neuronal apoptosis as shown by elevated Bcl-2 levels together with diminished Bax and caspase-3 expressions, inhibiting neuroinflammation as shown by decreased GFAP expression, and finally boosting hippocampal neurogenesis and survival by upregulating expressions of BDNF and PCNA. These effects were mainly mediated by activating AMPK/Akt/CREB signaling cascades. In summary, Vilda can be considered a promising candidate for guarding against CP-induced chemo-brain and neurodegeneration, thus improving the quality of life of cancer patients.

Effect of phylloquinone on indomethacin-induced gastric ulceration in rats: Role of SIRT-1.

Gastric ulcer is the most common gastrointestinal disorder affecting people globally. Although many drugs are available to treat ulcers, the mortality rate is relatively high, and drugs lack selectivity to treat ulcers without causing side effects. In this study, the potential therapeutic effects of phylloquinone were tested against indomethacin-induced gastric ulcer in rats by giving rats a single oral dose of indomethacin (48 mg/kg), followed by phylloquinone (10 mg/kg) orally, once daily for six consecutive days. Phylloquinone significantly attenuated indomethacin-induced oxidative and inflammatory responses through hindering the inflammatory cascade by decreasing the levels of TNF-α, NF-κB, INOS and COX-2 which counteracts indomethacin effects. Also, it increased NAD+ which enhanced SIRT-1 level. Furthermore, phylloquinone was effective in increasing mucus secretion, decreasing acid secretion, reversing histological effects caused by indomethacin and minimizing ulcer and lesion indices All these findings indicate that phylloquinone may be used in protection and treatment of indomethacin-induced gastric ulcer.

The Cannabinoid-2 receptor agonist, 1-phenylisatin, protects against cisplatin-induced nephrotoxicity in mice.

AIM: The present study investigated the potential protective effect of a selective Cannabinoid-2 (CB2) receptor agonist, 1-phenylisatin, in acute nephrotoxicity induced by cisplatin. MATERIALS AND METHODS: Animals were arranged into 5 groups. Group I; normal saline, group II; 1-phenylisatin for 7 days, group III: received a single injection of cisplatin (20 mg/kg, i.p.) on day 5, group IV: 1-phenylisatin for 7 days and cisplatin on day 5 and group V: AM630, CB2 antagonist, 15 min before 1-phenylisatin for 7 days and a single injection of cisplatin on day 5. Mice were sacrificed 72 h after cisplatin injection. Kidneys were isolated for histopathological and biochemical analyses. Nephrotoxicity parameters including serum creatinine and urea were assessed as well as histopathological examination was done. Also, Oxidative stress markers; MDA and GSH, inflammatory markers; TNF-α, NF-κB (p65), MCP-1, MIP-2, and ICAM-1, along with apoptotic markers, Bax, Bcl2, and caspase-3 were studied. Further, CB2 receptor expression was investigated. KEY FINDINGS: Cisplatin injection increased serum creatinine and urea levels, and increased lipid peroxidation, decreased glutathione level and increased the renal expression of pro-inflammatory markers, TNF-α, NF-κB, MCP-1, MIP-2, and ICAM-1, along with increased apoptotic markers and significantly reduced the expression of the anti-apoptotic Bcl2. Pretreatment with 1-phenylisatin significantly counteracted these effects. The CB2 receptor antagonist; AM630, increased the renal expression of caspase-3 and Bax whereas Bcl2 expression decreased. SIGNIFICANCE: 1-Phenylisatin protected against cisplatin-induced nephrotoxicity owing to its anti-apoptotic, anti-inflammatory, and antioxidant effects. These actions were mostly mediated through CB2 receptor.

Metabolic/hypoxial axis predicts tamoxifen resistance in breast cancer.

We sought in our cross-sectional study to investigate the role of metabolic/hypoxial axis in the development of tamoxifen (TMX) resistance in BC patients. Quantification of plasma LncRNA Taurine upregulated-1 (TUG-1), miRNA 186-5p (miR-186), serum Sirtuin-3 (SIRT3), Peroxisome Proliferator Activator Receptor alpha (PPAR-1 α) and Hypoxia Inducible Factor-1 (HIF-1α) was done in a cohort of patients divided into TMX-sensitive and TMX-resistant candidates. Multiple logistic regression and Receiver Operating Characteristic curve were developed for significant predictors. Plasma TUG-1 and miR-186 were significantly elevated in TMX resistant patients. Serum proteins SIRT3, PPAR-1 α and HIF-1α were deficient in TMX resistant patients compared to TMX sensitive patients, respectively. miR-186 was associated with respiratory symptoms, while, HIF-1α was associated with metastases in TMX resistant patients. Strong correlations were found between all parameters. A predictive model was constructed with TUG-1 and HIF-1α to estimate TMX resistance in BC patients with 88.3% sensitivity and 91.6% specificity. Hypoxia and metabolic dysregulations play important role in the development of TMX resistance in BC patients. Correlation between hypoxia, carcinogenesis and patient's mortality have led to more aggressive phenotypes, increased risk of metastasis and resistance to TMX.

Effects of aged garlic and ginkgo biloba extracts on the pharmacokinetics of sofosbuvir in rats.

Sofosbuvir is a direct acting antiviral (DAA) approved for the treatment of hepatitis C virus (HCV). Sofosbuvir is a substrate of P-glycoprotein (P-gp). For this reason, inhibitors, or inducers of intestinal P-gp may alter the plasma concentration of sofosbuvir and increase or decrease its efficacy causing a significant change in its pharmacokinetic parameters. The purpose of the study was to evaluate the pharmacokinetic interaction between either aged garlic or ginkgo biloba extracts with sofosbuvir through targeting P-gp as well as possible toxicities in rats. Rats were divided into four groups and treated for 14 days with saline, verapamil (15 mg/kg, PO), aged garlic extract (120 mg/kg, PO), or ginkgo biloba extract (25 mg/kg, PO) followed by a single oral dose of sofosbuvir (40 mg/kg). Validated LC-MS/MS was used to determine sofosbuvir and its metabolite GS-331007 in rat plasma. Aged garlic extract caused a significant decrease of sofosbuvir AUC(0-t) by 36%, while ginkgo biloba extract caused a significant increase of sofosbuvir AUC(0-t) by 11%. Ginkgo biloba extract exhibited a significant increase of the sofosbuvir t1/2 by 60%, while aged garlic extract significantly increased the clearance of sofosbuvir by 63%. The pharmacokinetic parameters of GS-331007 were not affected. The inhibitory action of ginkgo biloba on P-gp and the subsequent increase in the sofosbuvir plasma concentration did not show a significant risk of renal or hepatic toxicity. Conversely, although aged garlic extracts increased intestinal P-gp expression, they did not alter the Cmax and Tmax of sofosbuvir and did not induce significant hepatic or renal toxicities.

Vildagliptin alleviates liver fibrosis in NASH diabetic rats via modulation of insulin resistance, oxidative stress, and inflammatory cascades.

AIMS: This study investigates the therapeutic potential of Vilda in a NASH model with liver fibrosis and elucidates the underlying molecular mechanisms. MAIN METHODS: To induce NASH, male Sprague-Dawley rats were fed a high-fat diet for 24 weeks with a single dose of STZ (40 mg/kg, IP). Vilda was orally administered at two doses (10 and 20 mg/kg) for 20 weeks. KEY FINDINGS: The induction of NASH was validated by abnormalities in hepatotoxicity indices, lipid profile, oxidative stress markers, and pathologically by marked fat deposition in hepatic tissues together with severe inflammatory cell infiltration. Moreover, NASH-affected rats demonstrated reduced insulin sensitivity manifested as elevated fasting blood glucose levels and disrupted homeostasis model assessment for insulin resistance. Vilda, at both doses, effectively abrogated all these pathological features of NASH. Mechanistically, these hepatoprotective properties of Vilda can be attributed to its antioxidant effects, anti-inflammatory effects (by inhibiting the TNF-α, NF-κB, JNK, and JAK/STAT pathways), and insulin-sensitizing effect (by upregulating the IRS-1/PI3K/Akt pathway). Besides, Vilda successfully counteracted NASH-associated liver fibrosis by downregulating the TGF-ß1 pathway. SIGNIFICANCE: The hepatoprotective and antifibrotic effects of Vilda were mostly dose-dependent. Collectively, this study offered a promising therapeutic avenue for Vilda as a novel strategy for counteracting the pathological progression of NASH and associated liver fibrosis.

Effect of Atorvastatin on Single Oral Pharmacokinetics and Safety of Daclatasvir in Rats: Emphasis on P-glycoprotein and Cytochrome P450.

OBJECTIVE: This study aimed to investigate the effect of atorvastatin on daclatasvir oral pharmacokinetics and safety and assess the possible underlining mechanisms by targeting P-glycoprotein (P-gp) and cytochrome P450 (CYP3A4). METHODS: The transport of daclatasvir, as well as the standard rhodamine 123 by P-gp across the rat intestine, was studied in vitro using the non-everted sac method. To assess the pharmacokinetic profile of daclatasvir in vivo, rats were divided into three groups receiving either saline, standard P-gp inhibitor verapamil (25 mg/kg), or atorvastatin (10 mg/kg), 2 hrs prior to a single dose of daclatasvir (7 mg/kg). In addition, the markers of liver and kidney functions and muscle rhabdomyolysis were assessed. Further, histopathological examination of liver and kidney tissue and assessment of CYP3A4 level was done. RESULTS: The inhibitory effect of atorvastatin on Pgp activity and expression was manifested by increased serosal transport of the standard rhodamine 123, as well as daclatasvir. In vivo, Cmax (peak plasma concentration) and area under the curve (AUC (0-t)) of daclatasvir after atorvastatin treatment increased compared to the vehicle group but not in a significant manner. On the other hand, atorvastatin caused a significant increase in the clearance of daclatasvir. Concomitant administration of atorvastatin with daclatasvir significantly decreased CYP3A4 content compared to the control group. The combination also showed increased liver enzymes and some pathological alterations in the liver. CONCLUSION: Atorvastatin has a significant effect on P-gp mediated intestinal transport of daclatasvir; however, it did not affect the systemic bioavailability of a single oral dose of daclatasvir.

Thymoquinone attenuates isoproterenol-induced myocardial infarction by inhibiting cytochrome C and matrix metalloproteinase-9 expression.

Thymoquinone (TQ) is the main active constituent of Nigella sativa. The present study aimed to investigate the effect of TQ on apoptotic parameters and MMP-9 expression in isoproterenol (ISP)-induced myocardial infarction (MI). TQ was given once daily for 7 days at doses of 10 and 20 mg/kg orally with ISP (86 mg/kg; s.c.) administered on the sixth and seventh days. TQ pre-treatment protected against ISP-induced MI as approved by normalisation of electrocardiogram (ECG) and b (CK)-MB, minimal histopathological changes, and reduction of the infarction size. Effects of TQ could be supported by its antioxidant activity, evidenced by the increase of cardiac reduced glutathione and total serum antioxidant capacity, and the inhibition of ISO-induced lipid peroxidation. TQ anti-inflammatory activity was associated with reduced expression of NF-κB and TNF-α. TQ ameliorated cardiomyocytes, apoptotic pathways by inhibiting both the intrinsic pathway, via reducing cytoplasmic cytochrome C, and the extrinsic pathway, by inhibiting TNF-α and caspases, and the effect of TQ was dose-dependent. Moreover, TQ reduced the expression of metalloproteinase (MMP)-9, which is considered as a prognostic marker of ventricular remodelling, recommending that TQ can be used as a possible supplement to minimise post-MI changes. So, we conclude that TQ antiapoptotic activity and the inhibitory modulation of MMP-9 expression contribute to TQ protective effects in MI. To our knowledge, this is the first study reporting the effect of TQ on cytochrome c activity and MMP-9 expression in MI.

Pharmacology of Diosmin, a Citrus Flavone Glycoside: An Updated Review.

Flavonoids are phytochemicals that are well known for their beneficial pharmacological properties. Diosmin is a flavone glycoside derived from hesperidin, a flavanone abundantly found in citrus fruits. Daflon is an oral phlebotonic flavonoid combination containing diosmin and hesperidin (9:1) that is commonly used for the management of blood vessel disorders. After oral administration, diosmin is converted to diosmetin, which is subsequently absorbed and esterified into glucuronide conjugates that are excreted in the urine. Pharmacological effects of diosmin have been investigated in several in vitro and in vivo studies, and it was found to possess anti-inflammatory, antioxidant, antidiabetic, antihyperlipidemic, and antifibrotic effects in different disease models. Diosmin also demonstrated multiple desirable properties in several clinical studies. Moreover, toxicological studies showed that diosmin has a favorable safety profile. Accordingly, diosmin is a potential effective and safe treatment for many diseases. However, diosmin exhibits inhibitory effects on different metabolic enzymes. This encourages the investigation of its potential therapeutic effect and safety in different diseases in clinical trials, while taking potential interactions into consideration.

The diuretic amiloride attenuates doxorubicin-induced chemobrain in rats: Behavioral and mechanistic study.

Cognitive impairment or "chemobrain" is a troublesome adverse effect which had been increasingly reported by cancer patients after doxorubicin (DOX) chemotherapy. Notably, Hypertension, a very common comorbidity in cancer patients, could pose a greater risk for negative cognitive outcomes. Amiloride (AML) is an antihypertensive, potassium-sparing diuretic that has been proven to be neuroprotective in different experimental models; this can be attributed to its ability to inhibit different ion transporters such as Na+/H+ exchanger (NHE), which upon excessive activation can result in intracellular cationic overload, followed by oxidative damage and cellular death. Accordingly, this study was designed to investigate the potential neuroprotective effect of AML against DOX-induced chemobrain and to elucidate possible underlying mechanisms. Briefly, Histopathological examination and neurobehavioral testing (Morris water maze, Y maze and passive avoidance test) showed that AML co-treatment (10 mg/kg/day) markedly attenuated DOX (2 mg/kg/week)-induced neurodegeneration and memory impairment after 4 weeks of treatments. We found that DOX administration up-regulated NHE expression and increased lactic acid content in the hippocampus which were markedly opposed by AML. Moreover, AML mitigated DOX-induced neuroinflammation and decreased hippocampal tumor necrosis factor-α level, nuclear factor kappa-B, and cyclooxygenase-2 expression. Additionally, AML counteracted DOX-induced hippocampal oxidative stress as indicated by normalized malondialdehyde and glutathione levels. Furthermore, AML halted DOX-induced hippocampal apoptosis as evidenced by decreased caspase-3 activity and lower cytochrome c immunoexpression. Our results in addition to the previously reported antitumor effects of AML and its ability to mitigate cancer resistance to DOX therapy could point toward possible new repositioning scenarios of the diuretic AML especially regarding hypertensive cancer patients.

Fenofibrate ameliorates olanzapine's side effects without altering its central effect: emphasis on FGF-21-adiponectin axis.

The present work was designed to investigate whether fenofibrate could ameliorate olanzapine deleterious effect on insulin resistance via its effect on fibroblast growth factor-21 (FGF-21)-adiponectin axis without affecting olanzapine antipsychotic effect in postweaning socially isolated reared female rats. Treatment with olanzapine (6 mg/kg, intraperitoneally) or fenofibrate (100 mg/kg, orally) have been started 5 weeks after isolation, then behavioral tests, hippocampal content of neurotransmitters, and brain-derived neurotrophic factor (BDNF) were assessed. Moreover, insulin resistance, lipid profile, FGF-21, adiponectin, inflammatory, and oxidative stress markers of adipose tissue were assessed. Treatment of isolated-reared animals with olanzapine, or fenofibrate significantly ameliorated the behavioral and biochemical changes induced by postweaning social isolation. Co-treatment showed additive effects in improving hippocampal BDNF level. Besides, fenofibrate reduced the elevation in weight gain, adiposity index, insulin resistance, lipid profile, and FGF-21 level induced by olanzapine treatment. Also, fenofibrate increased adiponectin level which was reduced upon olanzapine treatment. Moreover, fenofibrate improved both adipose tissue oxidative stress and inflammatory markers elevation as a result of olanzapine treatment. Fenofibrate could ameliorate olanzapine-induced insulin resistance without affecting its central effect in isolated reared rats via its action on FGF-21-adiponectin axis.