Effects of Echinacoside on Ehrlich Carcinoma in Rats by Targeting Proliferation, Hypoxia and Inflammation.

Background and objectives Ehrlich solid carcinoma (ESC) is a type of tumor originating from a spontaneous mammary adenocarcinoma in mice. It is highly aggressive and fast-growing and can create a solid undifferentiated mass when inserted under the skin. This makes it an ideal model for assessing cancer biology and tumor immunology. Echinacoside is a natural phenylethanoid glycoside with anti-inflammatory, anti-endoplasmic reticulum stress, anti-oxidative stress, and other beneficial properties. This study explored the potential anti-cancer benefits of echinacoside in rats with ESC. The study also analyzed its effects on tumor cell proliferation, differentiation, motility, and inflammation. Methods The study involved injecting rats with tumors in their left hind limb using an intramuscular injection of 2×106 cells. After 14 days, some rats were given a daily intraperitoneal dose of 30 mg/kg echinacoside for three weeks. Muscle samples were then analyzed under an electron microscope. In addition, gene expression and protein levels of various factors such as phosphoinositide 3-kinases (PI3K), mammalian target of rapamycin (mTOR), hypoxia-inducible factor (HIF)-1α, cyclin D1, cyclin-dependent kinase 2 (CDK2), tumor necrosis factor (TNF)-α, and nuclear factor (NF)κB were evaluated in another part of the muscle samples. Results After being treated with echinacoside, the ESC rats experienced a significant increase in their mean survival time from 27 days to 48 days. This treatment also resulted in a decrease in the volume and weight of the tumor. Upon examining the tumor tissue under an electron microscope, signs of damage such as pleomorphic cells, necrosis, nuclear fragmentation, membrane damage with cytoplasmic content spilling, and loss of cellular junction were observed. However, the treatment with echinacoside was effective in improving these effects. Furthermore, the expression of PI3K, mTOR, HIF-1α, cyclin D1, CDK2, TNF-α, and NFκB was significantly reduced due to the echinacoside treatment. Conclusions Our research found that echinacoside has antitumor properties that resulted in a substantial decrease in tumor size and weight, leading to an increase in the average survival time of rats and an improvement in muscle structure. Additionally, echinacoside was shown to ameliorate hypoxia by suppressing HIF-1α, reduce inflammation by decreasing NFκB and TNF-α, decrease proliferation by reducing PI3K, and block cyclin D1 and CDK2 to inhibit differentiation.

Arctiin Inhibits Inflammation, Fibrosis, and Tumor Cell Migration in Rats With Ehrlich Solid Carcinoma.

BACKGROUND AND OBJECTIVES: ESC or Ehrlich solid carcinoma is a type of tumor originating from a spontaneous mammary adenocarcinoma in mice. It is a highly aggressive and fast-growing carcinoma that can create a solid mass when inserted under the skin. Its solid, undifferentiated form makes it an ideal model for researching cancer biology, tumor immunology, and testing various anti-cancer treatments. Additionally, arctiin has multiple beneficial properties, such as anti-proliferative, anti-oxidative, anti-adipogenic, and anti-bacterial. This study aimed to explore the potential anti-cancer benefits of arctiin in rats with ESC while also analyzing its effects on cell fibrosis markers, tumor cell migration, and inflammasome pathways. METHODS: Rats were given a tumor in their left hind limb via an intramuscular injection consisting of 2×106 cells. After eight days, some of the rats received a daily oral dose of 30 mg/kg of arctiin for three weeks. Muscle samples were observed under an electron microscope or stained with hematoxylin/eosin. Additionally, gene expression and protein levels of toll-like receptor 4 (TLR4), NLR family pyrin domain containing 3 (NLRP3), signal transducer and activator of transcription 3 (STAT3), transforming growth factor (TGF)-ß, endothelial growth factor (VEGF), and cyclin D1 were assessed in another part of the muscle samples. RESULTS: When ESC rats were given arctiin as a treatment, their mean survival time increased and their tumor volume and weight decreased. Additionally, when tumor tissue was examined under an electron microscope, it showed signs of pleomorphic cells, necrosis, nuclear fragmentation, membrane damage with cytoplasmic content spilling, and loss of cellular junction. The stained sections with hematoxylin/eosin showed a dense cellular mass and compressed, degenerated, and atrophied muscle. However, treatment with arctiin improved all these effects. Finally, the expression of TLR4, NLRP3, STAT3, TGF-ß, VEGF, and cyclin D1 was significantly reduced with arctiin treatment. CONCLUSIONS: Through the use of arctiin, tumor size and weight were effectively reduced, leading to an increase in the average survival time of rats and an improvement in muscle structure. Additional research has shown that arctiin is able to suppress inflammation, fibrosis, and the migration of tumor cells by inhibiting STAT3, TGF-ß1, TLR4, NLRP3, VEGF, and cyclin D1.

Novel topoisomerase II/EGFR dual inhibitors: design, synthesis and docking studies of naphtho[2',3':4,5]thiazolo[3,2-a]pyrimidine hybrids as potential anticancer agents with apoptosis inducing activity.

Topoisomerases II are ubiquitous enzymes with significant genotoxic effects in many critical DNA processes. Additionally, epidermal growth factor receptor (EGFR) plays pivotal role in tumour growth and angiogenesis. A novel series of naphtho[2',3':4,5]thiazolo[3,2-a]pyrimidine hybrids have been designed, synthesised and evaluated for their topo IIα/EGFR inhibitory and apoptotic inducer activities. Cytotoxicity of the synthesised hybrids was evaluated against MCF-7, A549 and HCT-116 cell lines. Of the synthesised hybrids, 6i, 6a and 6c experienced superior cytotoxic activity compared to doxorubicin and erlotinib against the tested cancer cells. The molecular mechanism of these hybrids revealed their ability to successfully inhibit topo IIα and EGFR activities in micromolar concentration and may serve as topo II catalytic inhibitor. Moreover, these hybrids significantly arrested cell cycle at G2/M phase together with increased p53, caspae-7, caspase-9 levels and Bax/Bcl-2 ratio. The synthesised hybrids showed efficient binding pattern in molecular docking study and have acceptable drug likeness characters.

A novel therapeutic combination of dapagliflozin, Lactobacillus and crocin attenuates diabetic cardiomyopathy in rats: Role of oxidative stress, gut microbiota, and PPARγ activation.

AIMS: Diabetic cardiomyopathy is diagnosed by the development of abnormality in the structure and performance of myocardium in diabetic mellitus (DM) patients. Recent studies reported the association between altered gut microbiota and metabolic disorders like diabetes and cardiovascular diseases. Here, we aimed to investigate the gut-heart axis in an experimental animal model where we developed a novel therapeutic combination of dapagliflozin, crocin prebiotic and Lactobacilli probiotic to correct induced diabetic cardiomyopathy. MATERIALS AND METHODS: Diabetes mellitus was induced by Intraperitoneal (i.p) streptozotocin in male rats. The experimental design includes the administration of the tested drugs (Crocin, Dapagliflozin) solely and with Lactobacillus, or in combination therapy with and without Lactobacillus to the diabetic rats for six weeks. Clinical and microscopic evaluation scoring for cardiac tissues were determined. Biochemical markers including blood glucose level, adiponectin, resistin, cardiac injury markers, lipid profile, antioxidant enzymes, pro and anti-inflammatory markers were assessed. In addition, quantitative relative expression of PPARγ and TXINP genes and capsase-3 levels were measured. The change in the microbiota abundance was investigated using real-time PCR. KEY FINDINGS: This study demonstrated the synergistic effect of the triple combination; dapagliflozin, crocin prebiotic, and Lactobacillus fermentum and Lactobacillus delbrueckii probiotic in treating diabetic cardiomyopathy in rats. The triple combination significantly reduced the oxidative, inflammatory, apoptotic activities induced by streptozotocin STZ and helped in restoring the symbiotic gut microbiota. SIGNIFICANCE: It is worthy to perform this study in clinical trials as a primary step to include crocin and Lactobacilli in the therapeutic protocols of diabetic cardiomyopathy.

Effect of Diacerein on HOTAIR/IL-6/STAT3, Wnt/ß-Catenin and TLR-4/NF-κB/TNF-α axes in colon carcinogenesis.

Colorectal cancer (CRC) is a common malignancy with high mortality and poor prognosis. Diacerein (DIA) is an anti-inflammatory used for treatment of osteoarthritis. We delineated some underlying molecular mechanisms of DIA's anti-carcinogenic effect in CRC using in vivo and in vitro models. Human Caco-2 cells were treated with DIA followed by MTT and Annexin V assays and CRC was experimentally induced using 1,2-dimethylhydrazine. DIA (50 mg/kg/day, orally) was administrated for 8 weeks. The MTT assay confirmed cytotoxic effect of DIA in vitro and Annexin V confirmed its apoptotic effect. DIA resulted in regression of tumour lesions with reduced colonic TLR4, NF-κB and TNF-α protein levels and down-regulated VEGF expression, confirming anti-angiogenic impact. DIA triggered caspase-3 expression and regulated Wnt/ß-Catenin pathway, by apparently interrupting the IL-6/STAT3/ lncRNA HOTAIR axis. In conclusion, DIA disrupted IL-6/STAT3/ lncRNA HOTAIR axis which could offer an effective therapeutic strategy for the management of CRC.

Nifuroxazide-loaded cubosomes exhibit an advancement in pulmonary delivery and attenuate bleomycin-induced lung fibrosis by regulating the STAT3 and NF-κB signaling: A new challenge for unmet therapeutic needs.

Pulmonary fibrosis (PF) is a chronic progressive disease that portends a very poor prognosis. It has been suggested that STAT3 is a potential target in PF. This study highlights the importance of cubosomes as a drug delivery system in enhancing the bioavailability of nifuroxazide (NXZD), a poorly soluble STAT3 inhibitor. NXZD-loaded cubosomes (NXZD-LC) were in vitro and in vivo evaluated. In vitro, cubosomes presented a poly-angular nanosized particles with a mean size and zeta potential of 223.73 ± 4.73 nm and - 20.93 ± 2.38 mV, respectively. The entrapment efficiency of nifuroxazide was 90.56 ± 4.25%. The in vivo pharmacokinetic study and the lung tissue accumulation of NXZD were performed by liquid chromatography-tandem mass spectrometry after oral administration to rats. The nanoparticles exhibited a two-fold increase and 1.33 times of bioavailability and lung tissue concentration of NXZD compared to NXZD dispersion, respectively. In view of this, NXZD-LC effectively attenuated PF by targeting STAT3 and NF-κB signals. As a result, NXZD-LC showed a potential anti-inflammatory effect as revealed by the significant decrease in MCP-1, ICAM-1, IL-6, and TNF-α and suppressed fibrogenic mediators as indicated by the significant reduction in TGF-ß, TIMP-1, and PDGF-BB in lung tissues. Besides, NXZD-LC improved antioxidant defense mechanisms and decreased LDH and BALF total protein. These effects contributed to decreased collagen deposition. To conclude, cubosomes represent an advantageous pharmaceutical delivery system for enhancing pulmonary delivery of poorly soluble drugs. Additionally, repurposing NXZD as an antifibrotic agent is a promising challenge and new therapeutic approach for unmet therapeutic needs.

Chemopreventive and hepatoprotective effects of genistein via inhibition of oxidative stress and the versican/PDGF/PKC signaling pathway in experimentally induced hepatocellular carcinoma in rats by thioacetamide.

OBJECTIVE: Genistein is a recognized isoflavone present in soybeans with antioxidant, anti-inflammatory, antiangiogenic and antitumor activities. This study aimed to test ability of genistein in modulating versican/platelet derived growth factor (PDGF) axis in HCC. METHODS: HCC was experimentally induced in male Sprague-Dawley rats then treated with 25 or 75 mg/kg genistein. Antioxidant activities of genistein was assessed by measuring the gene expression of Nrf2 and the hepatic levels of malondialdehyde (MDA), superoxide dismutase (SOD) and reduced glutathione. Expression of versican, PDGF, protein kinase C (PKC) and ERK-1 protein was assessed by Western blotting and immunostaining. RESULTS: HCC induced an elevation in oxidative stress, PDGF, versican, PKC and ERK protein expression levels. Genistein significantly reduced an HCC-induced increase in oxidative stress. Moreover, genistein dose-dependently reduced HCC-induced elevation of PDGF, versican, PKC and ERK protein expression levels. Moreover, genistein helped retain a normal hepatocyte structure and reduced fibrous tissue deposition, especially in high dose. CONCLUSIONS: Genistein exerted antitumor and antioxidant effects and therefore suppress HCC development via inhibition of the PDGF/versican bidirectional axis, suppressing both ERK1 and PKC as downstream regulators. Therefore, genistein is a potential novel therapeutic candidate for improving the outcome of patients with HCC.

Berberine-loaded nanostructured lipid carriers mitigate warm hepatic ischemia/reperfusion-induced lesion through modulation of HMGB1/TLR4/NF-κB signaling and autophagy.

OBJECTIVE: Berberine (BBR) is a known alkaloid that has verified its protective effects against ischemia/reperfusion (I/RN) lesion in multiple organs but its poor oral bioavailability limited its use. Despite the previous works, its possible impact on the warm hepatic I/RN-induced lesion is not clear. Accordingly, a nanostructured lipid carrier of BBR (NLC BBR) was developed for enhancing its efficiency and to inspect its protective mechanistic against warm hepatic I/RN. METHODS: NLC BBR formula was evaluated pharmaceutically. Wistar rats were orally pre-treated with either BBR or NLC BBR (100 mg/kg) for 2 weeks followed by hepatic I/RN (30 min/24 h). Biochemical, ELISA, qPCR, western blot, histopathological, and immunohistochemical studies were performed. KEY FINDINGS: Optimized NLC BBR was prepared with a particle size of 130 ± 8.3 nm. NLC BBR divulged its aptitude to safeguard the hepatic tissues partly due to anti-inflammatory capacity through downsizing the HMGB1/TLR4/NF-κB trajectory with concomitant rebating of TNF-α, iNOS, COX-2, and MPO content. Furthermore, NLC BBR antiapoptotic trait was confirmed by boosting the prosurvival protein (Bcl-2) and cutting down the pro-apoptotic marker (Bax). Moreover, its antioxidant nature was confirmed by TAC uplifting besides MDA subsiding. On the other hand, NLC BBR action embroiled autophagy flux spiking merit exemplified in Beclin-1 and LC3-II enhancement. Finally, NLC BBR administration ascertained its hepatocyte guarding action by recovering the histopathological ailment and diminishing serum transaminases. CONCLUSION: NLC BBR purveyed reasonable shielding mechanisms and subsided incidents contemporaneous to warm hepatic I/RN lesion in part, by moderating HMGB1/TLR4/NF-κB inflammatory signaling, autophagy, and apoptosis.

A novel role of pirfenidone in attenuation acetic acid induced ulcerative colitis by modulation of TGF-ß1 / JNK1 pathway.

Colon diseases are a major health burden, particularly ulcerative colitis, in both men and women worldwide. Environmental and genetic factors in various colonic pathologies influence the onset and outcome of diseases. As the evidence from recent research is considered, the importance of inflammation in the onset, progression, and outcome is gaining more traction. The goal of this study was to see if pirfenidone could treat ulcerative colitis (UC) and if so, what mechanisms were involved. By intracolonic instillation [2 ml, 3 percent v/v acetic acid (AA)], ulcerative colitis was induced. Pirfenidone was administered to rats in different experimental groups (125 or 250 and 500 mg/kg, orally) for two weeks. Compared to normal group, the AA group showed an increase in colon weight, length, body weight, clinical evaluation, and macroscopic scoring of UC, serum lactate dehydrogenase, C-reactive protein, malondialdehyde, while decreasing serum total antioxidant capacity. Significant increases in colon Jun N terminal kinase1 (JNK1), transforming growth factor-beta (TGF-ß1), interleukin 1 beta (IL1ß), and Caspase-3 content. Furthermore, immunohistochemical staining revealed increased nuclear factor kappa B (NF-κB) expression along with histopathological changes. Pirfenidone inhibited inflammatory biomarkers release and restored oxidants/antioxidants hemostasis. In a dose-dependent manner, pirfenidone treatment showed a significantly decrease in all of these parameters. In addition, pirfenidone has significantly preserved the histopathological architecture of tissues. Current data demonstrate that Pirfenidone protects against AA-induced UC by modulating the TGF-ß1/JNK1 and Caspase-3 pathways. Pirfenidone's antioxidant, anti-inflammatory, and anti-apoptotic properties are thought to be responsible for its therapeutic benefit.

Anti-inflammatory/anti-apoptotic impact of betulin attenuates experimentally induced ulcerative colitis: An insight into TLR4/NF-kB/caspase signalling modulation.

Ulcerative colitis (UC) is an inflammatory bowel disease with limited therapeutic management approaches. The present study evaluated the potential therapeutic impact of betulin on acetic acid (AA)-induced UC in rats. UC was induced by intracolonic instillation of AA (3% v/v). Rats were treated with betulin (8 mg/kg, I.P., once daily) four days post AA instillation and for 14 consecutive days. Betulin attenuated AA-induced UC as evidenced by retracted macroscopic scores, serum CRP titre and LDH activity, attenuated histopathological hallmarks of UC including mucosal necrosis, haemorrhage, congestion and inflammatory cells infiltration. Moreover, betulin dampened UC-associated colonic inflammatory load with modulation of TLR4/NF-kB axis and reduction in colonic inflammatory cytokines; TNF-α, IL1ß and IL-6. Nevertheless, betulin suppressed colonic apoptosis with reduced colonic caspase-3 and caspase-8 expression. The current findings confirm a beneficial therapeutic impact of betulin against UC. The prospective underlying mechanisms include down-regulation of TLR4/NF-κB and the subsequent downstream signalling pathways.

Albendazole-loaded cubosomes interrupt the ERK1/2-HIF-1α-p300/CREB axis in mice intoxicated with diethylnitrosamine: A new paradigm in drug repurposing for the inhibition of hepatocellular carcinoma progression.

Hepatocellular carcinoma (HCC) is a leading cause of cancer related deaths worldwide. It was suggested that albendazole (ABZ) is a powerful inhibitor of several carcinoma types. However, the bioavailability of ABZ is very poor. Additionally, the mechanisms underlying the antitumor effects of ABZ may go beyond its tubulin-inhibiting activity. Therefore, we aimed to examine the effects of ABZ suspension (i.p. and p.o.) and ABZ-loaded cubosomes (LC) on the diethylnitrosamine-induced HCC in mice. ABZ-loaded nanoparticles exhibited a mean particle size of 48.17 ± 0.65 nm and entrapped 93.26 ± 2.48% of ABZ. The in vivo absorption study confirmed a two-fold improvement in the relative bioavailability compared with aqueous ABZ suspension. Furthermore, the oral administration of ABZ cubosomal dispersion demonstrated regression of tumor production rates that was comparable with ABZ (i.p.). ABZ relieved oxidative stress, improved liver function, and decreased necroinflammation score. The antiangiogenic activity was evident as ABZ effectively downregulated tissue expression of CD34, mRNA expression of CD309 and VEGF at the protein expression level. Besides, lower levels of MMP-9 and CXCR4 indicated antimetastatic activity. ABZ showed a considerable level of apoptotic activity as indicated by increased mRNA expression level of p53 and the increased Bax/BCL-2 ratio and active caspase-3. Additionally, Ki-67 expression levels were downregulated showing an antiproliferative potential. These protective effects contributed to increasing survival rate of diethylnitrosamine-treated mice. These effects found to be mediated via interrupting ERK1/2-HIF-1α-p300/CREB interactions. Therefore, our findings revealed that disrupting ERK1/2-HIF-1α-p300/CREB interplay might create a novel therapeutic target for the management of HCC.

Phenethyl isothiocyanate attenuates diabetic nephropathy via modulation of glycative/oxidative/inflammatory signaling in diabetic rats.

Diabetic nephropathy (DN) is a diabetic complication characterized by disruption of renal microvasculature, reactive oxygen species accumulation and increased inflammation, all of which contribute to renal injury. Phenethyl isothiocyanate (PEITC) is a naturally occurring isothiocyanate well known for its antioxidant and anti-inflammatory effects, yet its reno-preventive effects against DN has not been investigated. The current study looked into the in vivo reno-protective effects of PEITC in STZ-induced DN in rats. PEITC (3, 10 and 30 mg/kg) was administered orally for 8 weeks post DM establishment. PEITC treatment significantly improved kidney and liver functions, renal histopathological features, tissue fibrosis, macrophage infiltration and blood glucose levels compared to DN control. Mechanistically, PEITC treatment alleviated DN-induced renal damage via modulating glycation and oxidative stresses and inflammatory response. As such, PEITC activated glyoxalase 1 (GLO1) that induced a retraction in renal tissue expression of advanced glycation end products (AGEs) and its receptor (RAGE). PEITC activated nuclear erythroid 2-related factor 2 (Nrf2) and increased expression of its downstream targets, hemeoxygenase-1 (HO-1) and gamma glutamate-cysteine (γ-GCS). Additionally, PEITC treatment decreased the expression of Nrf2 repressor protein, keap1. The anti-inflammatory effect of PEITC was driven, at least in part, via reducing the NLRP3 inflammasome activation as indicated by down regulation of NLRP3, TXNIP, capsase-1 and IL-1ß, TNF-alpha and IL-6. In conclusion; PEITC attenuated DN progression in a dose dependent manner mainly via interruption of AGE/RAGE and NLPR3/TXNIP/NrF2 crosstalk.

The therapeutic role of lactobacillus and montelukast in combination with metformin in diabetes mellitus complications through modulation of gut microbiota and suppression of oxidative stress.

Male reproductive dysfunction is one of the overlooked findings of diabetes mellitus (DM) that deserves greater scientific attention. This study is designed to explore the therapeutic potential of metformin and montelukast, in combination with Lactobacillus, for modulation of intestinal flora and suppression of oxidative stress in testicular and liver damage in diabetic male rats. A DM model was induced by streptozotocin (STZ)which caused functional, biochemical, and inflammatory injuries to the testicular and liver tissues. The experimental panel included nine rat groups: normal control, normal control plus metformin, normal control plus montelukast, DM control, DM plus montelukast, DM plus a combination of metformin and Lactobacillus, DM plus a combination of montelukast and Lactobacillus, and DM plus a combination of metformin and montelukast. In parallel, clinical evaluation of microscopic examination scoring, and hepatic and testicular injuries, were evaluated. Biochemical markers including glucose level, lipid profile, inflammatory markers (tumor necrosis factor- (TNF-α) and interleukin-17 (IL-17), Caspase-3, and Bax proteins expressions were measured. The change in the microbiota abundance was investigated using conventional and real-time PCR. The current study revealed a significant difference in the relative abundance of microbiota, where DM is associated with an enormous increase of Bacteroides spp., Clostridium spp., E. coli, and Fusobacterium spp., and a significant decrease in Bifidobacteria spp., and Lactobacillus spp., in contrast with normal control. Metformin and montelukast, in combination with Lactobacillus, significantly reversed the testicular and liver damage caused by STZ. Moreover, the drugs significantly reduced the oxidative, inflammatory, and apoptotic activities induced by STZ.

A Novel Combination Therapy Using Rosuvastatin and Lactobacillus Combats Dextran Sodium Sulfate-Induced Colitis in High-Fat Diet-Fed Rats by Targeting the TXNIP/NLRP3 Interaction and Influencing Gut Microbiome Composition.

Inflammasome targeting and controlling dysbiosis are promising therapeutic approaches to control ulcerative colitis. This report is the first to investigate the mechanisms underlying the coloprotective effects of rosuvastatin and Lactobacillus and their combined therapy on dextran sodium sulfate (DSS)-induced colitis in high-fat diet (HFD)-fed rats. Our results demonstrate the aggravation of intestinal inflammation as a consequence of an HFD following DSS administration. An association between dyslipidemia, LDL oxidation, CD36 expression, ROS generation, thioredoxin-interacting protein (TXNIP) upregulation, and NLRP3 inflammasome activation was demonstrated by DSS exposure in HFD-fed rats. We demonstrated that rosuvastatin/Lactobacillus significantly suppressed the DSS/HFD-induced increase in colon weight/length ratio, DAI, MDI, and myeloperoxidase, as well as corrected dysbiosis and improved histological characteristics. Additionally, caspase-1 activity and IL-1ß-driven pyroptotic activity was significantly reduced. Rosuvastatin/Lactobacillus showed prominent anti-inflammatory effects as revealed by the IL-10/IL-12 ratio and the levels of TNF-α and IL-6. These latter effects may be attributed to the inhibition of phosphorylation-induced activation of NF-κB and a concomitant reduction in the expression of NLRP3, pro-IL-1ß, and pro-IL-18. Furthermore, rosuvastatin/Lactobacillus reduced Ox-LDL-induced TXNIP and attenuated the inflammatory response by inhibiting NLRP3 inflammasome assembly. To conclude, rosuvastatin/Lactobacillus offers a safe and effective strategy for the management of ulcerative colitis.

Novel Potent and Selective DPP-4 Inhibitors: Design, Synthesis and Molecular Docking Study of Dihydropyrimidine Phthalimide Hybrids.

BACKGROUND: Dipeptidyl peptidase-4 (DPP-4) inhibitors have emerged as anti-hyperglycemic agents that improve glycemic control in type 2 diabetic patients, either as monotherapy or in combination with other antidiabetic drugs. METHODS: A novel series of dihydropyrimidine phthalimide hybrids was synthesized and evaluated for their in vitro and in vivo DPP-4 inhibition activity and selectivity using alogliptin as reference. Oral glucose tolerance test was assessed in type 2 diabetic rats after chronic treatment with the synthesized hybrids ± metformin. Cytotoxicity and antioxidant assays were performed. Additionally, molecular docking study with DPP-4 and structure activity relationship of the novel hybrids were also studied. RESULTS: Among the synthesized hybrids, 10g, 10i, 10e, 10d and 10b had stronger in vitro DPP-4 inhibitory activity than alogliptin. Moreover, an in vivo DPP-4 inhibition assay revealed that 10g and 10i have the strongest and the most extended blood DPP-4 inhibitory activity compared to alogliptin. In type 2 diabetic rats, hybrids 10g, 10i and 10e exhibited better glycemic control than alogliptin, an effect that further supported by metformin combination. Finally, 10j, 10e, 10h and 10d had the highest radical scavenging activity in DPPH assay. CONCLUSIONS: Hybrids 10g, 10i and 10e are potent DPP-4 inhibitors which may be beneficial for T2DM treatment.

Fucoidan Ameliorates Hepatocellular Carcinoma Induced in Rats: Effect on miR143 and Inflammation.

Fucoidan is sulfated polysaccharide of brown seaweed. It offers various pharmacological actions like anti-inflammatory, anti-bacterial and anti-tumor activities. Therefore, we aimed to investigate the effect of targeting microRNA-143 and inflammatory pathway by Fucoidan on experimentally induced hepatocellular carcinoma (HCC) in rats. HCC is experimentally induced in Sprague Dawley by thioacetamide. Rats were treated with 100 mg/kg and 200 mg/kg Fucoidan. Hepatic sections were stained with hematoxylin/esosin for investigation of cell integrity. Moreover, hepatic sections were immunohistochemically stained with antibodies for ki67, TNF-α, and IL-1ß. Finally, hepatic tissues were investigated for expression of miR-143, NF-κB, TNF-α, and IL-1ß. We found that treating HCC with Fucoidan significantly reduced HCC-induced elevation in oxidative stress. Moreover, Fucoidan reduced HCC-induced in expression of miR-143, NF-κB, TNF-α, and IL-1ß. Finally, Fucoidan attenuated pseudohepatic lobules, broad fibrous septa and vacuolar to ballooning degeneration associated with reduction of immunostaining of ki67, TNF-α, and IL-1ß. Fucoidan elevated the survival of HCC rats and reduced their serum AFP. In addition, Fucoidan treatment revealed reduction in the expression of miR-143 associated with antioxidant and anti-inflammatory activities in HCC rats.

A Novel Role of Dapagliflozin in Mitigation of Acetic Acid-Induced Ulcerative Colitis by Modulation of Monocyte Chemoattractant Protein 1 (MCP-1)/Nuclear Factor-Kappa B (NF-κB)/Interleukin-18 (IL-18).

Colon illnesses, particularly ulcerative colitis, are considered a major cause of death in both men and women around the world. The present study investigated the underlying molecular mechanisms for the potential anti-inflammatory effect of Dapagliflozin (DAPA) against ulcerative colitis (UC) induced by intracolonic instillation of 3% v/v acetic acid (AA). DAPA was administered to rats (1 mg/kg, orally) for two weeks during the treatment regimen. Interestingly, compared to the normal group, a marked increase in the index of colon/body weight, colon weight/colon length ratio, serum lactate dehydrogenase (LDH), and C-reactive protein (CRP), besides decrease in the serum total antioxidant capacity (TAC), were reported in the AA control group (p ˂ 0.05). Elevation in colon monocyte chemoattractant protein (MCP1), Interleukin 18 (IL-18), and inflammasome contents were also reported in the AA control group in comparison with the normal group. In addition, colon-specimen immunohistochemical staining revealed increased expression of nuclear factor-kappa B (NF-κB) and Caspase-3 with histopathological changes. Moreover, DAPA significantly (p ˂ 0.05) reduced the colon/body weight index, colon weight/colon length ratio, clinical evaluation, and macroscopic scoring of UC, and preserved the histopathological architecture of tissues. The inflammatory biomarkers, including colon MCP1, IL-18, inflammasome, Caspase-3, and NF-κB, were suppressed following DAPA treatment and oxidants/antioxidants hemostasis was also restored. Collectively, the present data demonstrate that DAPA represents an attractive approach to ameliorating ulcerative colitis through inhibiting MCP1/NF-κB/IL-18 pathways, thus preserving colon function. Antioxidant, anti-inflammatory, and anti-apoptotic properties of DAPA are implicated in its observed therapeutic benefits.

ß-Blockers bearing hydroxyethylamine and hydroxyethylene as potential SARS-CoV-2 Mpro inhibitors: rational based design, in silico, in vitro, and SAR studies for lead optimization.

The global COVID-19 pandemic became more threatening especially after the introduction of the second and third waves with the current large expectations for a fourth one as well. This urged scientists to rapidly develop a new effective therapy to combat SARS-CoV-2. Based on the structures of ß-adrenergic blockers having the same hydroxyethylamine and hydroxyethylene moieties present in the HIV-1 protease inhibitors which were found previously to inhibit the replication of SARS-CoV, we suggested that they may decrease the SARS-CoV-2 entry into the host cell through their ability to decrease the activity of RAAS and ACE2 as well. Herein, molecular docking of twenty FDA-approved ß-blockers was performed targeting SARS-CoV-2 Mpro. Results showed promising inhibitory activities especially for Carvedilol (CAR) and Nebivolol (NEB) members. Moreover, these two drugs together with Bisoprolol (BIS) as an example from the lower active ones were subjected to molecular dynamics simulations at 100 ns. Great stability across the whole 100 ns timeframe was observed for the top docked ligands, CAR and NEB, over BIS. Conformational analysis of the examined drugs and hydrogen bond investigation with the pocket's crucial residues confirm the great affinity and confinement of CAR and NEB within the Mpro binding site. Moreover, the binding-free energy analysis and residue-wise contribution analysis highlight the nature of ligand-protein interaction and provide guidance for lead development and optimization. Furthermore, the examined three drugs were tested for their in vitro inhibitory activities towards SARS-CoV-2. It is worth mentioning that NEB achieved the most potential anti-SARS-CoV-2 activity with an IC50 value of 0.030 µg ml-1. Besides, CAR was found to have a promising inhibitory activity with an IC50 of 0.350 µg ml-1. Also, the IC50 value of BIS was found to be as low as 15.917 µg ml-1. Finally, the SARS-CoV-2 Mpro assay was performed to evaluate and confirm the inhibitory effects of the tested compounds (BIS, CAR, and NEB) towards the SARS-CoV-2 Mpro enzyme. The obtained results showed very promising SARS-CoV-2 Mpro inhibitory activities of BIS, CAR, and NEB (IC50 = 118.50, 204.60, and 60.20 µg ml-1, respectively) compared to lopinavir (IC50 = 73.68 µg ml-1) as a reference standard.

A novel role of nifuroxazide in attenuation of sepsis-associated acute lung and myocardial injuries; role of TLR4/NLPR3/IL-1ß signaling interruption.

Acute lung injury (ALI) and the subsequent multi-system organ failure is a serious health problem with devastating impacts on the health care systems. Indeed, the world has been facing an un-preceded situation in the past couple of months following COVID-19 infestation and the associated high-mortality rates mainly attributed to sepsis and the associated multiple organ failures of particular concern; acute respiratory distress syndrome post lung injury. The current study provides evidence on the ameliorative impact of nifuroxazide, and FDA approved antidiarrheal drug in attenuation of lipopolysaccharide (LPS)-induced ALI and myocarditis when administrated either in prophylactic or curative regimens. Nifuroxazide administration was associated with a significant improvement in lung and heart histopathological characteristics and architecture with retraction of LPS-induced inflammatory-infiltration. This was associated with retraction in serum biomarkers of cellular injury of which; LDH, CK-MB, and ALP. Nifuroxazide administration was associated with a significant improvement in both lung and heart oxidative status. Such positive outcomes were underlined by a significant inhibitory effect of nifuroxazide on lung and heart contents of toll-like receptor (4) (TLR4)/the inflammasome NALPR3/interleukin- 1ß (IL-1ß). In conclusion: Nifuroxazide attenuates LPS-induced ALI and myocardial injury via interruption of TLR4/NALPR3/IL-1ß signaling. Thus it can offer a potential approach for attenuation of sepsis in critically ill patients.