Emerging role of natural lipophagy modulators in metabolic dysfunction-associated steatotic liver disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), is a seriously increasing liver disorder affecting nearly 32% of adults globally. Hepatic triglycerides (TG) accumulation is the hallmark of MASLD, which results from dysregulated lipid and fatty acid uptake, increased de novo lipogenesis (DNL), and decreased lipid removal. More recently, selective autophagy of lipid droplets (LDs), termed lipophagy, has emerged to be closely associated with disrupted hepatic lipid homeostasis. Recent studies have indicated that a series of natural products have shown promise as an alternative approach in attenuating MASLD via regulating lipophagy in vivo and in vitro. Therefore, lipophagy could be a new approach for natural products to be used to improve MASLD. This article aims to provide a comprehensive overview on the interrelationship between dysregulated lipid metabolism, lipophagy, and MASLD pathogenesis. In addition, the role of some natural products as lipophagy modulators and their impact on MASLD will be discussed.

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.

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.

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.

Hemin versus erythropoietin: Possible role in Nrf2/HO-1 signaling pathway in rats with nephrotoxicity.

BACKGROUND AND AIM: Gentamycin-induced nephrotoxicity is related to stimulation of oxidative stress and inflammatory cascades leading to apoptotic renal damage. Heme oxygenase-1 (HO-1) induction considered to be an adaptive response against oxidative tissue damage. Our study aimed to investigate the possible nephroprotective role of HO-1 inducers (hemin and erythropoietin (EPO)) and elucidate their potential underlying molecular mechanisms by assessing their antioxidant, anti-apoptotic, and anti-inflammatory properties. METHODS: Kidney function markers (urea and creatinine), lipid peroxidation and antioxidant markers (MDA and GPx), inflammation and apoptotic markers (IL-6 and Bcl-2), and the relative gene expression levels of Nrf2 and HO-1 were assessed. Histopathological changes of the kidney were examined. RESULTS: Nephrotoxic rats pretreated with hemin showed significant decrease in serum level of urea, creatinine, and MDA, compared to non-treated group. The kidney tissues also showed significant elevation of Bcl2 level, but significant decrease of IL-6, compared to non-treated group. Moreover, hemin pre-treatment significantly upregulated gene expression of Nrf2 and HO-1 in kidney tissue to near the normal control group. On the other hand, pretreatment with EPO showed significant upregulation of HO-1 gene expression but didn't show significant difference in Nrf2 gene expression compared to control group. The histopathological examination of kidney supported the biochemical results. CONCLUSION: The current results proved that hemin rather than EPO, showed reno-protective effects in rats, which was mediated by activation of Nrf2 signaling pathway. This could be also attributed to the observed anti-inflammatory, antioxidant, and anti-apoptotic properties of hemin. In this regard, EPO showed lower potency.

Blocking of The Prostaglandin E2 Receptor as a Therapeutic Strategy for Treatment of Breast Cancer: Promising Findings in a Mouse Model.

OBJECTIVE: The study aimed to investigate the anticancer effect of E-prostanoid receptor 1 (EP1) antagonist, SC19220, alone or in combination with the COX-2 inhibitor Celecoxob(CXB)® in mice bearing solid Ehrlich carcinoma (SEC). METHODS: The tumors were induced in 40 female mice, which were divided randomly into four equal groups (n= 10 in each group): Tumor control, CXB, EP1 antagonist, and co-treatment. CXB (10mg/kg) and EP1 antagonist (2mg/kg) were given intraperitoneally every three days, six times in total, then tissue was extracted and prepared for histopathology and measurement of weight, PGE2, and gene expression of EP1 and ß 1 integrin. RESULTS: Both inhibitors, alone or in combination, showed a significant (p<0.001) antitumorigenic effect by decreasing, significantly (p<0.001), each of the tumor weights, tumor volumes, PGE2 levels, EP1 and ß1-integrin gene expression along with increasing, significantly (p<0.001), the P53 tumor suppressor protein. The survival rate was improved from 80% in the control group to reach 100% in the treated groups. The co-treatment by CXB and EP1 antagonist showed a marked decrease in tumor weights and volumes as compared with the single treatment. In parallel, the histopathological findings showed enhanced apoptosis and diminished necrosis in the co-treated group. CONCLUSION: EP1 antagonist proved an antitumorigenic effect alone or combined with CXB and could play a new therapeutic strategy against breast cancer.

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.

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.

Comparative Efficacy and Safety Study of Darbepoetin Alfa versus Epoetin Alfa in Management of Anemia Associated with ESRD in Egyptian Hemodialysis Patients.

BACKGROUND: Anemia is one of the most common complications of Chronic Kidney Disease (CKD). The vast majority of Egyptian CKD patients are interchangeably treated with Darbepoetin Alfa (DPA) and Epoetin Alfa (EPA) to achieve and maintain target hemoglobin levels. Our study aimed to compare the efficacy and safety of DPA versus EPA for managing anemia amongst Egyptian patients with CKD undergoing dialysis. METHODS: A multicenter, open label, randomized, prospective, parallel study was conducted. Patients with CKD undergoing dialysis with Hb level < 10 g/dl were enrolled. The primary efficacy endpoint was the change in hemoglobin concentration at the evaluation period (weeks 20-24). Prespecified adverse events of interest following administration, including blood transfusions requirement, blood pressure and hemoglobin excursions, the relationship between C - Reactive Protein (CRP) and hemoglobin, were assessed. RESULTS: Only 98 of 104 enrolled patients completed the study, fifty patients received EPA, and 48 patients received DPA. Our results showed that a significantly higher percentage of patients who achieved target Hb level ≥ 11 g/dL in DPA treated group vs. EPA as well as the meantime to achieve Hb level ≥ 10 g/dL was shorter in DPA treated group. Safety profiles of both treatments were similar. A negative correlation was observed between serum CRP and hemoglobin level in hemodialysis patients. CONCLUSION: Our study showed that DPA was more effective and well tolerated in achieving and maintaining Hb levels with lower dosing frequency compared to EPA. Furthermore, CRP is recommended to be routinely measured where patients with higher CRP require high ESA doses.

Inhibition of PKC/MEK pathway suppresses ß1-integrin and mitigates breast cancer cells proliferation.

Prostaglandin E2 (PGE2) and ß1-integrin have been correlated with breast cancer, where both could enhance progression and metastasis. Protein kinase C (PKC) and MEK have played a vital role in breast cancer development. Our study was conducted to elucidate the effect of inhibition of E-prostanoid receptor 1 (EP1)/ PKC/ MEK/ ß1-integrin pathway in mitigating breast cancer progression and to evaluate the role of the intermediate signals FOXC2, E2F1, NF-Ò¡B and survivin. MCF7 cells were treated with 17 -PT-PGE2, an EP1 agonist, for 24 h, and ß1-integrin was measured. To MCF7 cells treated with 17-PT-PGE2, inhibitors of either EP1, MEK, PKC or NF-Ò¡B were added followed by measurement of ß1-integrin gene expression and cell proliferation in each case. Addition of 17- PT-PGE2 to MCF7 cells showed enhancement of both cell proliferation, and cell cycle transition from G1 to S phase. In addition, activation of EP1 receptor increased ß1-integrin expression. On the contrary, inhibition of EP1 receptor showed a decrease in the cell proliferation, ß1-integrin expression and cells transition to S phase, but increased cell count in apoptotic phase. Selective inhibition of each of MEK, PKC, and NF-Ò¡B suppressed 17 -PT-PGE2-mediated ß1-integrin expression as well as cell proliferation. Furthermore, FOXC2, phosphorylated NF-Ò¡B, E2F1, and survivin levels were upregulated with 17- PT-PGE2 and suppressed by MEK, PKC and NF-Ò¡B inhibitors. Targeting the biochemical mediators of PKC/MEK pathway may be of value in developing new chemical entities for cancer treatment.

Amelioration of lithiatic injury to renal tissue by candesartan and sodium thiosulfate in a rat model of nephrolithiasis.

AIM: Nephrolithiasis is a chronic metabolic condition affecting 10% of population worldwide. The present study aimed to investigate the possible protective role of candesartan (CAND) and sodium thiosulfate (STS) in ameliorating ethylene glycol (EG) induced nephrolithiasis. METHODS: One hundred male Wistar rats were divided into five groups: Normal control group, nephrolithiasis (EG) group (1% EG in drinking water), Cystone (CYS) group (EG + 750 mg/kg CYS, orally, once daily), STS group (EG + 0.4 gm/kg STS, intraperitoneally, 3 times/week) and CAND group (EG + 70 µg/mL CAND in drinking water). Treatments and EG administration commenced on the same day and continued for 28 days. CYS was used as reference drug. Urine, blood, and renal tissues were collected at the end of the experiment for assessment of kidney function tests (serum creatinine and urea), urinary (8-hydroxydeoxyguanosine (8-OHdG), calcium and oxalate), inflammatory and oxdative stress biomarkers (transforming growth factor beta (TGF-ß), osteopontin (OPN) and ratio of reduced glutathione to oxidized glutathione (GSH/GSSG)) in renal tissue. RESULTS: Serum (creatinine and urea), urinary (8-OHdG and oxalate) and renal (OPN and TGF-ß) were significantly reduced in CAND and STS groups compared to EG group. Furthermore, renal GSH/GSSG and urinary calcium were significantly increased in CAND and STS groups compared to EG group. Histopathological results support the biochemical findings; CAND and STS groups showed less retention of crystals and necrotic damage in kidney. Also, microscopic examination of urine revealed less crystal for CAND and STS groups. CONCLUSION: Candesartan and sodium thiosulfate exhibited protective effect against nephrolithiasis.

The plausible mechanisms of tramadol for treatment of COVID-19.

Currently, no single medication has been approved for the management of coronavirus disease-2019 (COVID-19) caused by the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Therefore, drug repositioningby investigating the use of existing drugs for management of COVID-19 patients is considered a desperate need. Tramadol is a commonly prescribed analgesic drug for treatment of moderate to severe pain with less potential for dependence and respiratory depression. Multiple evidence support that tramadol is a promising drug for treatment of COVID-19 patients. Herein, we discuss the possible beneficial effects of using tramadol against SARS-CoV-2 infection and their underlying mechanism of action. The anti-inflammatory effect of tramadol may help to suppress the COVID-19 related cytokine storm through decreasing interleukin (IL)-6, tumor necrosis factor-alpha (TNF-α), and C-reactive protein (CRP). Besides, tramadol activates natural killer (NK) and T-cells and enhances IL-2 secretion, which produce immune-enhancing effect against SARS-CoV-2. Recent studies confirmed that COVID-19 patients with acute respiratory failure showed increased fibrin formation and polymerization that may lead to thrombosis. Tramadol owing to its hypocoagulable effect may protect against venous thromboembolism in these patients. Moreover, tramadol can exert a cardioprotective effect via decreasing lactate dehydrogenase (LDH) level which is elevated in most of patients with COVID-19. Furthermore, the severity and mortality of COVID-19 have been correlated with old age patients, which may be due to the lack of antioxidant mechanisms and increased oxidative damage. Tramadol could protect COVID-19 patient from disease complications by increases the antioxidant enzymes superoxide dismutase and glutathione peroxidase while diminished malondialdehyde. More interestingly, tramadol as an effective analgesic and antitussive may have a beneficial effect on COVID-19 patients suffering from cough, headache, ache, and pain. The tramadol anti-psychotic effect may also protect against psychiatric disorders associated with SARS-CoV-2 infection. Moreover, tramadol has bactericidal activity against a wide range of pathogens including Pseudomonas aeruginosa which is common in severe COVID-19 patients leading to pneumonia with worse clinical outcomes. Therefore, we hypothesize that tramadol might be a promising adjuvant therapeutic option against SARS-CoV-2 infection. Based on that, tramadol should be considered as adjuvant therapy for COVID-19 clinical trials.

Immunosuppressive role of Benzo[a]pyrene in induction of lung cancer in mice.

AIM: Benzo[a]pyrene [BP] is one of the major carcinogenic precursors of cigarette smoke that primary affects the lung at its first proximity. The goal of the current research was to elucidate new mechanisms underlying the tumorigenic impact of oral BP in the lung of mice, with focus on immunosuppressive effects and cancer stemming properties. METHODS: Female albino mice (n = 44) were divided into 2 groups: normal control and BP group. BP was administered orally to mice (50 mg/kg body weight), twice a week for four weeks in succession. At the end of experiment (22 weeks), gene expression were measured for transforming growth factor-ß (TGF-ß), cytotoxic T lymphocyte antigen-4 (CTLA-4), programmed death ligand 1(PD-L1), forkhead box protein P3 (FOXP3) and interleukin 12 (IL-12) and CD83+, CD8+ and CD166+ cell percentage were measured in lung tissue. RESULTS: The results indicated the tumorigenic role of BP in the lung which was evidenced by histopathological examination. BP group also showed immunosuppressive role which evidenced by increased expression of lung TGF-ß, CTLA-4, PD-L1, FOXP3 genes and decreased expression of lung IL-12 gene compared with normal control group. BP group also showed decreased CD83+ cells, CD8+ cells and increased number of CD166+ cells. CONCLUSION: Our findings indicated that BP has immunosuppressive role in lung cancer besides increasing the percentage of cancer stem like cells.

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.

TNM staging for GIT cancers is correlated with the level of MMPs and TGF-ß1.

Gastrointestinal (GIT) cancers represent the third common cancers worldwide, characterized by rapid progression and higher mortality rate. Matrix metalloproteinases (MMPs) play an important role in cancer metastases. The present study was conducted to estimate and evaluate the role of MMP-7, -9, -10 and -12 and TGF ß1 along with conventional biomarkers (CEA and CA19-9) in gastric (GC), pancreatic (PC) and colorectal cancer (CRC) staging system according to tumor size (T), included lymph node (N) and metastasis (M). Seventy-five patients were divided into GC group (n = 25), PC group (n = 25), CRC group (n = 25) and twenty-five healthy subjects (control group). Serum levels of MMP-7, -10 and -12 were assayed simultaneously using luminex multiplex technique. Also, MMP-9, TGF-ß1, CA19-9 and CEA were determined by ELISA. MMP-7,-9,-10, -12, TGF-ß1 and CEA levels were significantly (p < 0.001) higher in GIT cancer groups compared with control. CA19-9 was significantly (p < 0.001) higher in PC and CRC groups compared with control. MMP-9 was positively correlated with TNM staging in PC patients. MMP-12 was negatively correlated with T in PC and positively correlated with M in CRC group. CA 19-9 was positively correlated with M grade in CRC. Depending on the estimated cutoff values of area under receiver curve; CA19-9 and MMP-7 were excellent diagnostic markers in PC, CEA and MMP-7 were excellent in CRC, and MMP-7 and MMP-9 were excellent in GC. Our findings indicated the clinical utility of MMPs in diagnosis and TNM staging of GIT cancers along with CEA and CA19-9.

Inhibition of lovastatin- and docosahexaenoic acid-initiated autophagy in triple negative breast cancer reverted resistance and enhanced cytotoxicity.

AIMS: Autophagy plays a complex role in breast cancer by suppressing or improving the efficiency of treatment. Triple-negative breast cancer (TNBC) cell line (MDA-MB-231) is associated with aggressive response and developing therapy resistance. MDA-MB-231 cells depend on autophagy for survival. Also, the potential benefits of autophagy inhibition in ameliorating developed chemotherapy resistance towards MDA-MB-231 remains to be elucidated. Despite showing anti-tumorigenic activities, the use of lovastatin and docosahexaenoic acid (DHA) for treating different types of cancers is still limited. We aimed to investigate the protective effect of autophagy inhibition by chloroquine (CQ) in MDA-MB-231 cells resistance treated with lovastatin or DHA. MAIN METHODS: MDA-MB-231 cells were treated with 30 µM lovastatin and/or 100 µM DHA for 48 h plus 20 µM CQ. Autophagic flux was assessed in association with the expression of multidrug resistance gene 1 (MDR1), transforming growth factor beta 1 gene (TGF-ß1), and autophagy-related 7 gene (ATG7). KEY FINDINGS: Both drugs exhibited dose-dependent cytotoxicity, enhanced the autophagic flux represented by increased LC3BII protein concentration and decreased p62 protein concentration, and up-regulated the expression of MDR1, TGF-ß1, and ATG7 genes. CQ addition enhanced the cytotoxicity of drugs and inhibited the autophagic flux which is detected by higher levels of LC3BII and p62 correlated with the reverted MDR1, TGF-ß1 and ATG7 genes expression. SIGNIFICANCE: Autophagy inhibition by CQ showed an ameliorative effect on lovastatin- and DHA-induced resistance and enhanced their cytotoxicity, providing a promising strategy in breast cancer therapy.