Effect of activation of liver X receptor alpha on cardiac & hepatic ABCC10 and SLC17A5 drug transporters in hypercholesterolemic rat model.

BACKGROUND: Liver x receptor α (LXRα) is a ligand-activated transcription factor belonging to the nuclear receptor superfamily. Oxysterols (endogenous oxidized cholesterol derivatives) are the most potent endogenous LXRα-agonist. LXRα has a direct impact on several members of drug transporter superfamilies; ATP-binding cassette (ABC) and solute linked carrier (SLC). OBJECTIVE: The current study aimed to investigate the effect of LXRα-activation by either endogenous oxysterols or a synthetic LXRα-agonist (LXRa) such as TO901317 on hepatic and cardiac gene expression of ABCC10 and SLC17A5 drug transporters in an experimentally hypercholesterolemic rat model. METHODS: 48 male rats were divided randomly into four groups (n = 12); control group rats received vehicle; hypercholesterolemic group (HCH group) rats received diet contain 2.5% cholesterol &deoxycholic acid for 8 weeks; (LXRa group) rats were fed standard pellet chow for 8 weeks, then a single dose of LXRa was administered (IP) at a dose of 10 mg/kg; (HCH + LXRa group) rats received diet contain 2.5% cholesterol &deoxycholic acid for 8 weeks, then a single dose of LXRa was administered (IP) at a dose of 10 mg/kg. RESULTS: Our findings revealed that hypercholesterolemia and LXRa significantly activated LXRα to varying degrees in both hepatic and cardiac tissues with subsequent alteration of LXRα and ABCC10 gene expression. Whereas, SLC17A5 gene expression was primarily affected by elevated serum cholesterol level and unmediated via LXRα-activation. CONCLUSIONS: Accordingly, it was concluded that ABCC10 is a specific LXRα-target gene and that LXRα autoregulates its own expression in rats.

Long non-coding RNA FAM83H-AS1 as an emerging marker for diagnosis, prognosis and therapeutic targeting of cancer.

Incidence and mortality rates of cancer continue to increase greatly despite the improved diagnostic and therapeutic methods. Based on GLOBOCAN estimates, the numbers of new cancer cases reported in 2018 were ~18.1 million, while the numbers of cancer mortalities were ~9.6 million. It remains difficult to diagnose most cancer patients at early stages. Although cancer therapy market is rapidly evolving, the effectiveness of therapy is still inadequate. Therefore, exploring new biomarkers for diagnosis, prognosis and treatment is essential for cancer management. Long non-coding RNAs (lncRNAs) are unique regulatory molecules that control several cellular processes and are implicated in diverse human diseases including cancer. LncRNAs could serve as potential biomarkers for cancer patients to aid diagnosis and determine prognosis. In addition, numerous lncRNAs have proved their ability to predict response to cancer treatment. FAM83H antisense RNA 1 (FAM83H-AS1) is among those highly dysregulated lncRNAs in cancer. FAM83H-AS1 was demonstrated to participate in the progression of different malignancies and also shown to play a vital role in diagnosis, prognosis and treatment. Here, we analyse recent studies concerning the oncogenic role and molecular mechanisms of lncRNA FAM83H-AS1 in the following cancer types: bladder, breast, lung, hepatocellular, colorectal, gastric, pancreatic, ovarian, cervical cancer as well as glioma.

The role of WNT/ß-catenin signaling pathway and glutamine metabolism in the pathogenesis of CCl4-induced liver fibrosis: Repositioning of niclosamide and concerns about lithium.

BACKGROUND: Liver fibrosis is a serious health problem which may lead to advanced liver cirrhosis and hepatocellular carcinoma. OBJECTIVE: The present study aimed to investigate the role of Wnt/ß-catenin signaling pathway and glutamine aminohydrolase enzyme (l-glutaminase) in the pathogenesis of liver fibrosis and the potential benefits of niclosamide in treating liver fibrosis. METHODS: Ninety male Albino rats were divided into 6 equal groups (n = 15) as follows: a normal control group (NC), CCl4-only treated group (Fib.) which received 1 mg/kg CCl4 two times weekly, niclosamide-treated group (Niclo.) which received 5 mg/kg of niclosamide one time daily, lithium chloride-treated group (LiCl) which received 100 mg/kg of LiCl one time daily, niclosamide-and-CCl4-treated group (Niclo. + Fib.) which received same doses of niclosamide and CCl4 given to other groups, and finally lithium chloride-and-CCl4-treated rat group (LiCl + Fib.) which received same doses of LiCl and CCl4 given to other groups. All treatments were administered orally for 8 weeks. Liver tissue was assessed for l-hydroxyproline, beta-catenin (ß-catenin), l-glutaminase activity, as well as the gene expression of transforming growth factor beta-1 (TGF-ß1) and Dishevelled-2 (Dvl2). Histopathological and immunohistochemical analyses of alpha smooth muscle actin α-SMA were performed. Serum alanine transaminase (ALT), aspartate transaminase (AST), and total bilirubin were measured. RESULTS: The group of niclosamide-and-CCl4-treated rats showed a significant decrease in total bilirubin, ALT and AST, ß-catenin, l-hydroxyproline, l-glutaminase activity, and gene expression of TGF-ß1 and Dvl2. Moreover, the liver tissue in this group of rats showed mild α-SMA reactivity compared with the rats treated with CCl4 only (fibrosis group). On the other hand, lithium chloride-and-CCl4-treated rats showed a significant increase in liver indices, TGF-ß1 expression, ß-catenin, l-hydroxyproline, and l-glutaminase activity with severe α-SMA reactivity and apoptosis in the liver tissue. CONCLUSIONS: Niclosamide protected rats against liver fibrosis by inhibiting the Wnt/ß-catenin pathway and glutaminolysis.

Activation of EMT in colorectal cancer by MTDH/NF-κB p65 pathway.

Epithelial-mesenchymal transition (EMT) leads to tumor dissemination and metastasis. Metadherin (MTDH) is an oncogene that plays an important role in metastasis regulation. This study tries to investigate the effect of MTDH gene up-regulation on the activation of EMT in colorectal cancer (CRC) cells and identify the role of NF-κB p65. The CaCO2 cells were divided into three groups: one control group of cultured CaCO2 cells (C1), and two groups of CaCO2 cells co-transfected using human MTDH expression plasmid with either siRNA targeting human NF-κB p65 or its negative control (C2 and C3 respectively). The gene modification was confirmed by qPCR and the effect of gene modification on CRC aggravation was studied. MTDH up-regulation significantly promoted CRC cell proliferation, activated anaerobic respiration (glucose consumption and lactate production), and increased gene expression of multidrug resistance gene (MDR1), Snail transcription factor and NF-κB p65, but decreased the gene expression of E-cadherin. Moreover, MTDH up-regulation led to a significant increase in the acquisition of surface markers of CRC stem cells. Interference with NF-κB p65 gene expression reversed the action of MTDH gene up-regulation on MDR1 and E-cadherin gene expression and anaerobic respiration. Moreover, NF-κB p65 interference significantly decreased MTDH-induced cell proliferation and acquisition of surface markers of CRC stem cells but didn't affect the Snail transcription factor. MTDH-dependent EMT in CRC is activated via NF-κB p65 and is mediated by up-regulation of Snail. These results identify a pathway by which MTDH regulates NF-κB p65 induced EMT during CRC cell metastasis.

Ginger extract adjuvant to doxorubicin in mammary carcinoma: study of some molecular mechanisms.

PURPOSE: The present study aimed to investigate the molecular mechanisms underlying the anticancer properties of ginger extract (GE) in mice bearing solid Ehrlich carcinoma (SEC) and to evaluate the use of GE in combination with doxorubicin (DOX) as a complementary therapy against SEC. METHODS: SEC was induced in 60 female mice. Mice were divided into four equal groups: SEC, GE, DOX and GE + DOX. GE (100 mg/kg orally day after day) and DOX (4 mg/kg i.p. for 4 cycles every 5 days) were given to mice starting on day 12 of inoculation. On the 28th day, blood samples were collected, mice were scarified, tumor volume was measured, and tumor tissues were excised. RESULTS: The anti-cancer effect of GE was mediated by activation of adenosine monophosphate protein kinase (AMPK) and down-regulation of cyclin D1 gene expression. GE also showed pro-apoptotic properties as evidenced by elevation of the P53 and suppression of nuclear factor-kappa B (NF-κB) content in tumor tissue. Co-administration of GE alongside DOX markedly increased survival rate, decreased tumor volume, and increased the level of phosphorylated AMPK (PAMPK) and improved related pathways compared to DOX group. In addition, the histopathological results demonstrated enhanced apoptosis and absence of multinucleated cells in tumor tissue of GE + DOX group. CONCLUSION: AMPK pathway and cyclin D1 gene expression could be a molecular therapeutic target for the anticancer effect of GE in mice bearing SEC. Combining GE and DOX revealed a greater efficacy as anticancer therapeutic regimen.

Anti-inflammatory and Antioxidant Effects of Captopril Compared to Methylprednisolone in L-Arginine-Induced Acute Pancreatitis.

BACKGROUND: Acute pancreatitis (AP) is an inflammatory disease mediated by damage in acinar cells and pancreatic inflammation with infiltration of leukocytes. The pancreatic renin-angiotensin system may play an important role in the pathogenesis of AP. AIM: The present study aimed to investigate the possible protective role of captopril (CAP), an angiotensin-converting enzyme inhibitor, in attenuating L-arginine-induced AP rat model and to elucidate the underlying molecular mechanisms. METHODS: Forty-eight adult male Wister rats were divided into four equal groups: control group (vehicle, orally for 10 days), AP group (3 g/kg L-arginine, single i.p.) on 10th day of the experiment, CAP group (50 mg/kg captopril, orally, once daily), and MP group (30 mg/kg methylprednisolone, orally, once daily). CAP and MP were administered for 10 days prior to L-arginine injection. Rats were sacrificed 24 h after arginine injection. Inflammatory biomarkers; tumor necrosis factor alpha (TNF-α) concentration, myeloperoxidase (MPO) activity, and inducible nitric oxide synthase (iNOS) gene expression were determined in pancreas. Oxidative stress biomarkers; pancreatic nitric oxide (NO) and reduced glutathione (GSH) concentrations were measured. Moreover, serum α-amylase and lipase activities were measured and histopathological studies of the pancreas were done. RESULTS: CAP group showed a significant reduction in pancreatic TNF-α concentration, MPO activity, NO concentration, and downregulation of iNOS gene expression compared to AP group. CAP group also showed a significant increase in GSH concentration with amelioration of histological changes of AP as well as MP group. CONCLUSION: Captopril treatment showed a protective and comparable effect with MP treatment in AP rat model.

Downregulation of iNOS and elevation of cAMP mediate the anti-inflammatory effect of glabridin in rats with ulcerative colitis.

BACKGROUND: Alternative medicine is widely accepted by public and becoming an attractive approach for treatment of various diseases. Glabridin (Gla), a major flavonoid present in licorice root, was reported to have antioxidant and anti-inflammatory properties. OBJECTIVE: The study aimed to investigate the possible protective role of Gla against dextran sulphate sodium (DSS)-induced ulcerative colitis (UC) in rats and to clarify the molecular mechanisms underlying Gla function. METHODS: Forty male Wistar rats were divided into control, colitis group (rats received 5% DSS in drinking water for 7 days), Gla group (50 mg/kg, orally, once daily), and sulfasalazine (SLZ) group (500 mg/kg, orally, once daily). Each of Gla and SLZ was administered 1 week ahead of DSS and parallel with its administration. RESULTS: Gla ameliorated the inflammatory alterations induced by DSS. Gla group showed a reduction in colon concentration of tumor necrosis factor-alpha (TNF-α) and a decreased colon myeloperoxidase activity (MPO). Gla treatment downregulated inducible nitric oxide synthase (iNOS) gene expression in rat colon with a decreased content of nitric oxide (NO). Gla also increased cyclic AMP (cAMP) concentration in rat colon compared to colitis group. Such findings were comparable to or even better than those obtained by SLZ treatment. The histological features of UC such as ulceration and inflammatory cell infiltrations were improved in rat group treated by Gla. CONCLUSION: Gla proved a potent anti-inflammatory role in UC through different mechanisms and, being a natural product, it could be safely used as a protective measure in inflammatory bowel diseases.

Chemopreventive effect of omega-3 polyunsaturated fatty acids and atorvastatin in rats with bladder cancer.

Bladder cancer remains a huge concern for the medical community because of its incidence and prevalence rates, as well as high percentage of recurrence and progression. Omega-3 polyunsaturated fatty acids and atorvastatin proved anti-inflammatory effects through peroxisome proliferator-activated receptor gamma mechanism. However, their chemopreventive effect still remained to be examined and clarified. In this study, bladder cancer was induced in rats by the chemical carcinogen N-butyl-N-(4-hydroxybutyl)nitrosamine. Omega-3 polyunsaturated fatty acids (docosahexaenoic acid and eicosapentaenoic acid: 2:3 w/w; 1200 mg/kg) and/or atorvastatin (6 mg/kg) were given orally daily to rats for eight consecutive weeks concomitantly with N-butyl-N-(4-hydroxybutyl)nitrosamine and continued for further 4 weeks after cessation of N-butyl-N-(4-hydroxybutyl)nitrosamine administration. The histopathological examination of rat bladder revealed the presence of tumors and the absence of apoptotic bodies in sections from N-butyl-N-(4-hydroxybutyl)nitrosamine group, while tumors were absent and apoptotic bodies were clearly observed in sections from rat groups treated with omega-3 polyunsaturated fatty acids, atorvastatin, or both drugs. The study of the molecular mechanisms illustrated downregulation of COX-2 and P53 (mutant) genes and suppression of transforming growth factor beta-1 and the lipid peroxidation product malondialdehyde in serum of rats of the three treated groups. This chemopreventive effect was confirmed by and associated with lower level of bladder tumor antigen in urine. However, the combined treatment with both drugs exhibited the major protective effect and nearly corrected the dyslipidemia that has been induced by N-butyl-N-(4-hydroxybutyl)nitrosamine. Collectively, omega-3 polyunsaturated fatty acids and atorvastatin, besides having anti-inflammatory properties, proved a chemopreventive effect against bladder cancer, which nominates them to be used as adjuvant therapy with other chemotherapeutics.

Metformin augments doxorubicin cytotoxicity in mammary carcinoma through activation of adenosine monophosphate protein kinase pathway.

Since the incidence of breast cancer increases dramatically all over the world, the search for effective treatment is an urgent need. Metformin has demonstrated anti-tumorigenic effect both in vivo and in vitro in different cancer types. This work was designed to examine on molecular level the mode of action of metformin in mice bearing solid Ehrlich carcinoma and to evaluate the use of metformin in conjunction with doxorubicin as a combined therapy against solid Ehrlich carcinoma. Ehrlich ascites carcinoma cells were inoculated in 60 female mice as a model of breast cancer. The mice were divided into four equal groups: Control tumor, metformin, doxorubicin, and co-treatment. Metformin (15 mg/kg) and doxorubicin (4 mg/kg) were given intraperitoneally (i.p.) for four cycles every 5 days starting on day 12 of inoculation. The anti-tumorigenic effect of metformin was mediated by enhancement of adenosine monophosphate protein kinase activity and elevation of P53 protein as well as the suppression of nuclear factor-kappa B, DNA contents, and cyclin D1 gene expression. Metformin and doxorubicin mono-treatments exhibited opposing action regarding cyclin D1 gene expression, phosphorylated adenosine monophosphate protein kinase, and nuclear factor-kappa B levels. Co-treatment markedly decreased tumor volume, increased survival rate, and improved other parameters compared to doxorubicin group. In parallel, the histopathological findings demonstrated enhanced apoptosis and absence of necrosis in tumor tissue of co-treatment group. Metformin proved chemotherapeutic effect which could be mediated by the activation of adenosine monophosphate protein kinase and related pathways. Combining metformin and doxorubicin, which exhibited different mechanisms of action, produced greater efficacy as anticancer therapeutic regimen.

Effect of Pomegranate Hull Extract on Liver Neoplastic Changes in Rats: More than an Antioxidant.

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer-related mortality worldwide. The current work was designed to elucidate the molecular mechanisms underlying the antitumorigenic effect of pomegranate hull extract (PHE) in livers of rats exposed to the hepatocarcinogen diethyl nitrosamine (DENA) with emphasis on oxidative stress, proliferation, and apoptosis. Male albino rats were divided into three groups: normal control, DENA group, and PHE group. PHE was given to rats orally 3 times weekly for 10 wk, 4 wk before and 6 wk after DENA (200 mg/kg, single i.p. dose). The results indicated a prophylactic effect of PHE against neoplastic changes in the liver, which was evidenced by the decrease of tumor size, liver index, and the anti-apoptotic protein Bcl-2; and the increase of glutathione. PHE group also showed decreased expression of liver cyclin D1 and ß-catenin genes compared with DENA group. It is proved that PHE has antitumorigenic effect and could be a candidate for anticancer drugs.

Antifibrotic effect of AT-1 blocker and statin in rats with hepatic fibrosis.

Hepatic fibrosis is an outcome of chronic liver injury. Angiotensin II (ANG II) may play a role in the pathogenesis of hepatic fibrosis. Certain drugs such as ACE inhibitors, ANG II antagonists, and even statins could interfere with the renin angiotensin system and modulate its deleterious effects. This study was carried out to investigate the possible role of losartan and atorvastatin in liver fibrosis. Liver fibrosis was induced in rats by i.p. injection of 50% CCl4 twice per week for 8 weeks. The rats intoxicated with CCl4 were divided into four groups: fibrosis control; losartan group; atorvastatin group; and co-treated group. A fifth group of normal healthy rats served as a control group. The results showed that losartan and atorvastatin, either alone or in combination, significantly decreased ALT, AST, hyaluronic acid and hydroxyproline levels in their groups compared to those of the fibrosis control group. A significant decrease in TGF-ß was found in the losartan and co-treated groups but not in the atorvastatin group. These biochemical data were supported by liver histopathology and α-SMA. The results indicate that the combined treatment with both losartan and atorvastatin produced a greater effect than either drug alone and proved a beneficial role in inhibiting or reversing liver fibrosis.

A review on the role of L-carnitine in the management of tamoxifen side effects in treated women with breast cancer.

L-carnitine is an antioxidant and is found to be a protective agent against many diseases including cancer. This review illustrates the possible role of L-carnitine as an add-on therapy to breast cancer patients maintained on tamoxifen. The objectives of carnitine treatment are diverse: improving tamoxifen-related side effects, offering better cancer prognosis by reducing the risk of developing cancer recurrence or metastasis, and modulating the growth factors which may be, in part, a prospective illustration to overcome tamoxifen resistance. So, it could be recommended to supplement L-carnitine to breast cancer patients starting tamoxifen treatment.

Biochemical/metabolic changes associated with hepatocellular carcinoma development in mice.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality after lung and stomach cancers. This work was undertaken to investigate some of the biochemical mediators/pathways associated with or implicated in the pathogenesis of HCC. Male albino mice were classified into two groups: normal control group and HCC group. Early stage HCC was induced by injection of diethylnitrosamine (DEN) i.p. 200 mg/kg as a single dose, and after 2 weeks, the mice were given i.p. injection of thioacetamide (TAA) 100 mg/kg twice per week for 4 weeks. Mice were left for further 2 weeks without any treatment, after which, mice were sacrificed; blood and liver samples were collected. Serum was used for determination of activities of glucose-6-phosphate dehydrogenase (G6PDH) and aldolase as well as levels of insulin-like growth factor-1 (IGF-1) and epithelial cadherin (E-cadherin). One portion of the liver was used for histopathological examination and immunohistochemical staining of the tumor suppressor p53 protein. Another portion of the liver was used for determination of citrate synthase activity. Induction of HCC in mice resulted in significant increase in G6PDH and aldolase activities, and E-cadherin level, but significant decrease in IGF-1. HCC mice group showed moderate expression of p53 protein. These results suggest that the molecular pathogenesis of HCC in mice involves reduction of serum level of IGF-1 and increased serum level of E-cadherin accompanied by dysregulation of p53 protein expression. HCC was also associated with reprogrammed metabolic profile shifted toward increased glycolysis and lipogenesis.

Prostate cancer and the cell cycle: Focusing on the role of microRNAs.

Prostate cancer is the most frequent solid tumor in terms of incidence and ranks second only to lung cancer in terms of cancer mortality among men. It has a considerably high mortality rate; around 375,000 deaths occurred worldwide in 2020. In 2024, the American Cancer Society estimated that the number of new prostate cancer cases will be around 299,010 cases, and the estimated deaths will be around 32,250 deaths only in the USA. Cell cycle dysregulation is inevitable in cancer etiology and is targeted by various therapies in cancer treatment. MicroRNAs (miRNAs) are small, endogenous, non-coding regulatory molecules involved in both normal and abnormal cellular events. One of the cellular processes regulated by miRNAs is the cell cycle. Although there are some exceptions, tumor suppressor miRNAs could potentially arrest the cell cycle by downregulating several molecular machineries involved in catalyzing the cell cycle progression. In contrast, oncogenic miRNAs (oncomirs) help the cell cycle to progress by targeting various regulatory proteins such as retinoblastoma (Rb) or cell cycle inhibitors such as p21 or p27, and hence may contribute to prostate cancer progression; however, this is not always the case. In this review, we emphasize how a dysregulated miRNA expression profile is linked to an abnormal cell cycle progression in prostate cancer, which subsequently paves the way to a new therapeutic option for prostate cancer.

Suppression of inflammation in ulcerative colitis rats by avocado and pomegranate.

BACKGROUND: Pomegranate seed oil (PSO) and avocado seed oil (ASO) are natural polyphenols with established anti-inflammatory activity. PURPOSE: This study aimed to investigate the molecular mechanisms underlying the therapeutic efficacy of PSO and ASO in experimental ulcerative colitis (UC) with reference to sulfasalazine (SLZ). METHODS: Eighty male albino rats were divided equally into 8 groups; Normal, PSO, ASO, SLZ, UC-control, (UC + PSO), (UC + ASO) and (UC + SLZ) groups. Colitis was induced by intra-rectal injection of acetic acid. PSO (0.5ml/200g), ASO (1ml/250g) and SLZ (100 mg/kg) were administered orally once/day for 14 days, 24h after colitis induction. Colitis was evaluated by measuring disease activity index (DAI), colon weight/length ratio and histologic inflammatory score. Vascular endothelial growth factor receptor-2 (VEGFR-2), colonic macrophage migration inhibitory factor (MIF), and malondialdehyde (MDA) were determined. Colonic gene expression of TNF-α, VEGF and heme oxygenase-1 (HO-1) were also estimated. RESULTS: PSO and ASO treatments to UC rats significantly reduced DAI, weight/length ratio, VEGFR-2, and colon histologic inflammatory score versus UC-controls. ASO significantly suppressed MIF levels and TNF-α expression greater than PSO. However, PSO was more significant than ASO in reducing MDA levels and up-regulating HO-1 expression. Both oils significantly down-regulated VEGF expression. The obtained biochemical and histological changes induced by UC were nearly corrected by SLZ. CONCLUSION: The proved beneficial effect of PSO and ASO as anti-inflammatory, anti-angiogenic, and antioxidant in UC rats could be mediated by suppression of TNF-α, VEGF, and MIF and up-regulation of HO-1.

Long noncoding RNAs as regulators of epithelial mesenchymal transition in breast cancer: A recent review.

AIMS: Breast cancer (BC) is the most frequently occurring cancer in women worldwide. BC patients are often diagnosed at advanced stages which are characterized by low survival rates. Distant metastasis is considered a leading cause of mortalities among BC patients. Epithelial-to-mesenchymal transition (EMT) is a transdifferentiation program that is necessary for cancer cells to acquire metastatic potential. In the last decade, long noncoding RNAs (lncRNAs) proved their significant contribution to different hallmarks of cancer, including EMT and metastasis. The primary aim of our review is to analyze recent studies concerning the molecular mechanisms of lncRNAs implicated in EMT regulation in BC. MATERIALS AND METHODS: We adopted a comprehensive search on databases of PubMed, Web of Science, and Google Scholar using the following keywords: lncRNAs, EMT, breast cancer, and therapeutic targeting. KEY FINDINGS: The different roles of lncRNAs in the mechanisms and signaling pathways governing EMT in BC were summarized. LncRNAs could induce or inhibit EMT through WNT/ß-catenin, transforming growth factor-ß (TGF-ß), Notch, phosphoinositide 3-kinase/protein kinase B (PI3K/AKT), signal transducer and activator of transcription 3 (STAT3), and nuclear factor kappa B (NF-κB) pathways as well as via their interaction with histone modifying complexes and miRNAs. SIGNIFICANCE: LncRNAs are key regulators of EMT and BC metastasis, presenting potential targets for therapeutic interventions. Further research is necessary to investigate the practical application of lncRNAs in clinical therapeutics.

Recombinant Human Lactoferrin Augments Epirubicin Chemotherapy in Solid Ehrlich Carcinoma Bearing Mice.

BACKGROUND: Lactoferrin (LF) is a member of the transferrin family, which is known for its immunomodulatory properties. LF has been widely used as an anticancer medication in various cancers including breast cancer. AIMS: The current study aimed to examine the molecular mechanisms underlying the therapeutic potential of recombinant human lactoferrin (rhLF), either alone or combined with epirubicin (EPI), in mice bearing solid Ehrlich carcinoma (SEC). METHODS: SEC-bearing female mice (n=40) were divided into 4 equal groups. Mice were given rhLF orally (100mg/kg/mouse) daily and/or EPI i.p (8mg/kg/mouse). The experiment lasted 14 days, after which samples were collected to measure IL-18 and phosphorylated c-Jun N-terminal kinase (p-JNK) by ELISA and p53 gene expression by real-time PCR. RESULTS: Administration of rhLF, either alone or combined with EPI, markedly decreased the tumor volume and increased tumor inhibition rate as well as survival rate compared to either tumor control group or EPI-mono treated group. In addition, co-administration of rhLF and EPI increased the level of activated JNKs and expression of p53 in tumor tissues compared to the tumor, control group, exhibiting their pro-apoptotic properties. Moreover, the combined treatment with rhLF and EPI elevated IL-18 level in the intestinal mucosa compared to other experimental groups with a possible immune-enhancing effect. CONCLUSION: Recombinant human lactoferrin exhibited potential anticancer and immune-enhancing properties in mice with breast cancer. Co-treatment with rhLF and EPI proved to be a promising strategy in cancer treatment.

Emerging therapeutic strategy for mitigating cancer progression through inhibition of sirtuin-1 and epithelial-mesenchymal transition.

With 8.8 million deaths worldwide, cancer is the major reason for the high rate of fatalities. Malignancy's commencement, progression, development, metastasis, and therapy resistance have all been correlated with the epithelial-to-mesenchymal transition (EMT) pathway. EMT promotes the cancer cells' metastatic spread and starts the development of treatment resistance. Sirtuin-1 (SIRT1) is a histone deacetylase that is important for signaling, cell persistence, and apoptosis. It does this by deacetylating important cell signaling molecules and proteins that are associated with apoptosis. The function of SIRT1 in EMT and cancer progression, as well as the emerging therapeutic strategy of treating cancer through the inhibition of SIRT1 and EMT will be discussed in detail.

Suppression of epithelial-mesenchymal transition and SIRT1/AKT signaling pathway in breast cancer by montelukast.

BACKGROUND: Breast cancer is usually associated with metastatic features, poor prognosis, and high mortality. The epithelial-mesenchymal transition (EMT) process has been implicated in the initiation and metastasis of breast cancer. OBJECTIVE: The study aimed to investigate the possible role of montelukast (Mont), the cysteinyl leukotriene receptor (CystLT1R) antagonist, in mitigating EMT in triple-negative breast cancer (TNBC) (in vitro study) and solid Ehrlich carcinoma (SEC) bearing mice (in vivo study) as well as to clarify the underlying molecular mechanisms in the presence and absence of sirtuin-1 inhibitor (sirtinol; Sirt). METHODS: TNBC MDA-MB-231 cells were treated with either 5 µM Mont or 25 µM Sirt or both for 48 h. Alternatively, SEC cells were inoculated in mice to induce breast cancer. After 12 days, the mice were divided into four groups: Untreated SEC group (vehicle), Sirt group (1 mg/kg), Mont group (10 mg/kg), and cotreatment Sirt/Mont group. The mice groups received the assigned treatment for the consequent 16 days. RESULTS: Mont and/or Sirt decreased cell proliferation, migration and suppressed EMT in both in vitro and in vivo experiments. All treatments downregulated sirtuin-1 and vimentin expression but upregulated E-cadherin expression. Furthermore, all treatments retarded angiogenesis as evidenced by decreased VEGF expression. These findings were associated with suppressing active protein kinase B (p-AKT). CONCLUSION: Cotreatment with Sirt and Mont proved more effective anti-tumor activity in TNBC cell line and in SEC bearing mice than either treatment alone, which could be attributed to the inhibition of sirtuin-1 and AKT- activated pathways, with the subsequent inhibition of EMT.

Upregulation of GLUT4 and PI3K, and downregulation of GSK3 mediate the anti-hyperglycemic effects of proanthocyanidins.

Diabetes mellitus is the most common chronic metabolic disorder worldwide. The present study was designed to investigate the potential role of cinnamon bark extract oligomeric proanthocyanidins (OPCs) in controlling streptozotocin (STZ)-induced hyperglycemia and to clarify the underlying molecular mechanisms underlying its effects. For this purpose, 60 male rats were equally divided into six groups as follows: The normal control group; OPC control group (non-diabetic rats treated with OPC at 300 mg/kg orally for 21 days); the untreated diabetic control group; the wortmannin control group [diabetic rats treated with wortmannin at 1 mg/kg, intraperitoneal (i.p.) on the final day of the experiment]; the OPC diabetic group (diabetic rats treated with OPC at 300 mg/kg orally for 21 days); and the OPC diabetic + wortmannin co-treated group (diabetic rats treated with OPC at 300 mg/kg/day for 21 consecutive days and then 24 h after the final OPC dose treated with a single wortmannin injection at 1 mg/kg, i.p.). The results indicated that OPC ameliorated the diabetic state, as evidenced by a significant decrease in serum glucose levels, and a significant increase in the levels of insulin, amylin, insulin receptor phosphorylation, glycogen and glucose transporter-4 translocation; it also improved the lipid profile in STZ-diabetic rats. On the whole, the findings of the present study provide biochemical evidence that OPC treatment is effective as an anti-diabetic and anti-hyperlipidemic agent by enhancing glucose uptake through the activation of insulin receptor kinase activity and the PI3K/Akt pathway.