Search

Purpose: Lung metastasis is the main cause of death in patients with colorectal carcinoma (CRC). Angiotensin II has been confirmed to facilitate cancer cell progression and metastasis. In this study, the possible anti-metastatic effects of an angiotensin II receptor type 1 (AT1R) antagonist, valsartan, have been investigated in an experimental CRC lung metastasis model. Methods: An animal CRC lung metastasis model was used, involving intravenous injection of CRC cells. The experimental groups included (1) control group; (2) 5-FU (5-fluorouracil) group (5 mg/kg/every other day; ip); (3) valsartan group (40 mg/kg/day; po); and (4) valsartan + 5-FU group (combination group; valsartan 40 mg/kg/day, oral gavage, and 5-FU 5 mg/kg/every other day; ip). After 11 days, macroscopic and histological evaluations of lung tissues have been done for evaluation of lung metastatic nodules. In addition, inflammatory and angiogenic markers and oxidative stress index were measured in lung tissue. Results: Our results showed that administration of valsartan especially in combination with 5-FU significantly reduced lung metastatic nodule and metastatic area (p < 0.05) in macroscopic and histological evaluations stained by hematoxylin-eosin. Measurement of inflammatory, angiogenic, and oxidative/antioxidative markers in lung tissue indicated that the level of IL-6, angiogenic markers (VEGF and VEGFR-1), and antioxidative markers significantly reduced in combination group (p < 0.05) while the MDA as a marker of oxidative stress increased (p < 0.05). Conclusion: These results suggest that valsartan in combination with standard chemotherapeutic agents can have a synergistic effect in treatment of lung metastasis of CRC. [ABSTRACT FROM AUTHOR]

Abstract: Combustion reactions in the Cu–Mo–Si system were investigated. A sample was ignited using electric arc and after completion of the combustion reaction, XRD, SEM and EDS analysis were carried out. The resulting microstructure consisted of almost spherical grains of MoSi2. Also a little amount of Mo-rich silicides (Mo5Si3, Mo3Si) and copper silicides were present at the grain boundaries. For investigating the formation mechanism of this microstructure, another sample was ignited and when the combustion wave was almost in the middle of the sample, the compact was quenched into liquid nitrogen. The results indicated that at the leading edge of combustion front, liquid solution of Cu–Si forms. The Mo particles dissolve in this melt and after that MoSi2 precipitates. By growing MoSi2 particles, remaining melt becomes richer in Cu which finally solidifies in cooling. [Copyright &y& Elsevier]

Oxygen-free radicals have been implicated in the initiation of diabetic complications. Thiazolidinediones (TZDs), known for their antidiabetic properties, also demonstrate notable antioxidant and anti-inflammatory effects. Although a recently developed imidazolyl analogue of pioglitazone (PA9) has exhibited superior glucose-lowering efficacy compared to pioglitazone, its antioxidant effects remain unexplored. Thus, the objective of this study is to evaluate the antioxidant properties of PA9 in animal models with diabetes. Rats were randomly separated into the following four groups: control, diabetic, and two groups treated orally with pioglitazone as a standard drug and PA9 for ten days. Upon completion of the experiment, tissues from the liver, heart, brain, pancreas, spleen, and kidneys were collected to assess oxidant/antioxidant markers and histological alterations. The administration of PA9 resulted in a noteworthy reduction in malondialdehyde (MDA) levels compared to the diabetic group (p < 0.05). The group receiving PA9 displayed elevated levels of three antioxidant markers, catalase (CAT), superoxide dismutase (SOD), and total thiol, in pancreatic tissue compared to diabetic rats (p < 0.05). Furthermore, increased content of CAT was evident in the heart (p < 0.05), spleen (p < 0.001), brain, and kidney tissues in the PA9-treated group, along with augmented thiol content in the spleen compared to the diabetic group. Remarkably, no significant histological changes were observed in the liver, pancreas, heart, brain, spleen, and kidneys of the PA9-treated groups relative to diabetic rats. PA9 effectively mitigates oxidative stress, modulates redox homeostasis, and shows promise in preventing diabetic complications. The proven safety profile of this analogue underscores its potential, warranting comprehensive clinical evaluation to thoroughly understand its therapeutic scope and efficacy in the management of diabetes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Liver cancer, specifically hepatocellular carcinoma (HCC), is the second leading cause of cancer-related deaths, following pancreatic cancer. The 5-year overall survival rate for HCC remains relatively low. Currently, there are multiple treatment options available for HCC, including systemic drugs, minimally invasive local therapies such as radiofrequency ablation, transarterial chemoembolization (TACE), and arterial radioembolization (TARE), as well as surgical interventions like liver resection or transplantation. However, the effectiveness of drug delivery to the cancerous liver is hindered by pathophysiological changes in the organ. In order to address this challenge, lipid-based nanoparticles (LNPs) have emerged as promising platforms for delivering a diverse range of therapeutic drugs. LNPs offer various structural configurations that enhance their physical stability and enable them to accommodate different types of cargo with varying mechanical properties and degrees of hydrophobicity. In this article, we provide a comprehensive review of the current applications of LNPs in the development of anti-HCC therapies. By examining the existing research, we aim to shed light on the potential future directions and advancements in this field., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (©2024 The Author (s).)

Intrauterine adhesion (IUA), also referred to as Asherman's syndrome, is characterized by fibrosis, inflammation, and can cause amenorrhea and infertility due to abnormal endometrial healing. Histological and Molecular methods were used to evaluate the efficacy of EPO, which is traditionally known for its anti-inflammatory and fibrinolytic properties, in preventing the formation of IUA. Oral administration of EPO reduced the formation of adhesion bands and promoted endometrial regeneration. EPO administration decreased extracellular matrix accumulation, evidenced by the down-regulation of tissue COL1A1 and COL3A1 expression. The anti-inflammatory effect of EPO was confirmed by a reduction in oxidants and down-regulation of pro-inflammatory cytokines including TNF-α, IL-6, IFN-γ, and IL-1β. Furthermore, EPO improved embryonic development parameters, including size and weight of embryo, as well as increased embryo count and live embryo percentage in the rat IUA model. EPO also positively enhanced implantation markers, particularly enlargement and mass gain in the placenta of the treated group, consequently improving pregnancy outcomes such as the number of babies, percent of live babies, baby weight and gestation time. Histopathological investigation provides evidence that oral administration of EPO showed no toxicity on the main three organs including liver, kidney and heart. These results showed that EPO can be considered as a safe and natural product with potent anti-inflammatory and fibrinolytic properties without any observed side effects for the treatment of IUA., (© 2024. The Author(s).)

Peptihub (https://bioinformaticscollege.ir/peptihub/) is a meticulously curated repository of cancer-related peptides (CRPs) that have been documented in scientific literature. A diverse collection of CRPs is included in the PeptiHub, showcasing a spectrum of effects and activities. While some peptides demonstrated significant anticancer efficacy, others exhibited no discernible impact, and some even possessed alternative non-drug functionalities, including drug carrier or carcinogenic attributes. Presently, Peptihub houses 874 CRPs, subjected to evaluation across 10 distinct organism categories, 26 organs, and 438 cell lines. Each entry in the database is accompanied by easily accessible 3D conformations, obtained either experimentally or through predictive methodology. Users are provided with three search frameworks offering basic, advanced, and BLAST sequence search options. Furthermore, precise annotations of peptides enable users to explore CRPs based on their specific activities (anticancer, no effect, insignificant effect, carcinogen, and others) and their effectiveness (rate and IC50) under cancer conditions, specifically within individual organs. This unique property facilitates the construction of robust training and testing datasets. Additionally, PeptiHub offers 1141 features with the convenience of selecting the most pertinent features to address their specific research questions. Features include aaindex1 (in six main subcategories: alpha propensities, beta propensity, composition indices, hydrophobicity, physicochemical properties, and other properties), amino acid composition (Amino acid Composition and Dipeptide Composition), and Grouped Amino Acid Composition (Grouped amino acid composition, Grouped dipeptide composition, and Conjoint triad) categories. These utilities not only speed up machine learning-based peptide design but also facilitate peptide classification. Database URL: https://bioinformaticscollege.ir/peptihub/., (© The Author(s) 2024. Published by Oxford University Press.)

One of the main causes of death on the globe is cancer. Peroxisome-proliferator-activated receptors (PPARs) are nuclear hormone receptors, including PPARα, PPARδ and PPARγ, which are important in regulating cancer cell proliferation, survival, apoptosis, and tumor growth. Activation of PPARs by endogenous or synthetic compounds regulates tumor progression in various tissues. Although each PPAR isotype suppresses or promotes tumor development depending on the specific tissues or ligands, the mechanism is still unclear. PPARs are receiving interest as possible therapeutic targets for a number of disorders. Numerous clinical studies are being conducted on PPARs as possible therapeutic targets for cancer. Therefore, this review will focus on the existing and future uses of PPARs agonists and antagonists in treating malignancies. PubMed, Science Direct, and Scopus databases were searched regarding the effect of PPARs on various types of cancers until the end of May 2023. The results of the review articles showed the therapeutic influence of PPARs on a wide range of cancer on in vitro, in vivo and clinical studies. However, further experimental and clinical studies are needed to be conducted on the influence of PPARs on various cancers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Objective: Muscle atrophy due to immobility is a common complication of many diseases and a consequence of therapeutic processes. Immobility and inactivity have been shown to be associated with increased inflammation. The aim of this study was to investigate the therapeutic potential of Wild Bitter Melon (WBM) (Momordica charantia Linn) on muscle atrophy due to immobility in a mouse model., Materials and Methods: This study was performed in two phases of atrophy and recovery on male BALB/c mice which were divided into 3 groups: control, immobilized, and experimental. The treatment period with WBM at a dose of 400 mg/kg daily by gavage was 17 days, including 7 days of being immobilized and 10 days of recovery. At the end of each phase, half of the mice from each group were examined regarding the four limb grip strength, and then histological and biochemical analyses were done., Results: The tissue level of malondialdehyde (MDA) oxidative stress index in the atrophy phase in the atrophy group (5.4567±0.522) nmol/g compared to the control group (3.455±0.065) nmol significantly (p 0.001) <) increased. Also, the tissue level of MDA in the WBM group (3.87±0.035) showed a significant decrease compared to the atrophy group (p<0.01). The strength percentage of four limbs in the mice of the treatment group (-23.46±2.45) was significantly higher than that of the atrophy group (-30.60±3.15) at the end of the atrophy phase., Conclusion: The results suggest that the use of WBM reduces the degree of inflammation, oxidative stress and muscle damage, as well as muscle atrophy, which may improve the muscle atrophy in mice., Competing Interests: The authors have declared that there is no conflict of interest.

Muscle atrophy due to limb immobilization and inactivity is a common consequence of many diseases and treatment processes. One of the systems activated in inflammatory conditions is the renin-angiotensin system (RAS). The present study was conducted with the aim of investigating the effects of one of the angiotensin-converting enzyme (ACE) inhibitors, enalapril, on improving muscle atrophy caused by immobility. The study was conducted in three groups: a control, an atrophy, and an atrophy group treated with enalapril on Balb/c mice. After tying a splint to cause atrophy in one of the legs, daily treatment with enalapril intraperitoneally (dissolved in DMSO) at a dose of 10 mg/kg/day was done for 7 days. On the eighth day, the splint was opened and half of the mice were evaluated. Then, in the recovery phase, treatment with enalapril was continued in the remaining mice for 10 days without a splint. At the end of each phase, the mice were examined for the muscle strength of the lower limb muscles, and histological and biochemical analyses were subsequently carried out. The tissue level of the oxidative stress index MDA was evaluated, which showed a significantly lower level in the enalapril group compared to the atrophy group (*P<0.1). Also, inflammatory factors in the enalapril group showed a decrease compared to the atrophy group. The strength of four limbs in the mice of the treatment group (-18.36 ± 1.70 %) was significantly higher than that of the atrophy group (-30.33 ± 3 %) at the end of the atrophy phase and also after 10 days of recovery. The results suggest that the use of enalapril that reduces the activation of angiotensin II-dependent pro-oxidant and pro-inflammatory pathways may improve the functional disorder and muscle necrosis in the murine model of muscle atrophy., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2024 Seifi et al.)

Background: Several studies have shown that the TGF-β signaling pathway plays a critical role in colorectal cancer (CRC) pathogenesis. The aim of the current study is to investigate the therapeutic potential of Vactosertib (EW-7197), a selective inhibitor of TGF-β receptor type I, either alone or in combination with the standard first-line chemotherapeutic treatment, 5-Fluorouracil (5-FU), in CRC progression in both cellular and animal models., Methods: Real-Time PCR, Zymography, enzyme-linked immunosorbent assay (ELISA), Hematoxylin and Eosin (H&E) tissue staining, and Flow cytometry techniques were applied to determine the anti-tumor properties of this novel TGF-β inhibitor in in vitro (CT-26 cell line) and in vivo (inbred BALB/C mice) samples., Results: Our findings showed that Vactosertib decreased cell proliferation and induced spheroid shrinkage. Moreover, this inhibitor suppressed the cell cycle and its administration either alone or in combination with 5-FU induced apoptosis by regulating the expression of p53 and BAX proteins. It also improved 5-FU anti-cancer effects by decreasing the tumor volume and weight, increasing tumor necrosis, and regulating tumor fibrosis and inflammation in an animal model. Vactosertib also enhanced the inhibitory effect of 5-FU on invasive behavior of CRC cells by upregulating the expression of E-cadherin and inhibiting MMP-9 enzymatic activity., Conclusion: This study demonstrating the potent anti-tumor effects of Vactosertib against CRC progression. Our results clearly suggest that this inhibitor could be a promising agent reducing CRC tumor progression when administered either alone or in combination with standard treatment in CRC patients., (© 2023. The Author(s), under exclusive licence to Tehran University of Medical Sciences.)

The most common type of cancer in the world is lung cancer. Traditional treatments have an important role in cancer therapy. In the present review, the most recent findings on the effects of medicinal plants and their constituents or natural products (NP) in treating lung cancer are discussed. Empirical studies until the end of March 2022 were searched using the appropriate keywords through the databases PubMed, Science Direct and Scopus. The extracts and essential oils tested were all shown to effect lung cancer by several mechanisms including decreased tumour weight and volume, cell viability and modulation of cytokine. Some plant constituents increased expression of apoptotic proteins, the proportion of cells in the G2/M phase and subG0/G1 phase, and Cyt c levels. Also, natural products (NP) activate apoptotic pathways in lung cancer cell including p-JNK, Akt/mTOR, PI3/ AKT\ and Bax, Bcl2, but suppressed AXL phosphorylation. Plant-derived substances altered the cell morphology, reduced cell migration and metastasis, oxidative marker production, p-eIF2α and GRP78, IgG, IgM levels and reduced leukocyte counts, LDH, GGT, 5'NT and carcinoembryonic antigen (CEA). Therefore, medicinal plant extracts and their constituents could have promising therapeutic value for lung cancer, especially if used in combination with ordinary anti-cancer drugs., (© 2023 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Immunosuppressive factors within the tumor microenvironment (TME), such as Transforming growth factor beta (TGF-β), constitute a crucial hindrance to immunotherapeutic approaches in colorectal cancer (CRC). Furthermore, immune checkpoint factors (e.g., programmed death-ligand 1 [PD-L1]) inhibit T-cell proliferation and activation. To cope with the inhibitory effect of immune checkpoints, the therapeutic value of dual targeting PD-L1 and TGF-β pathways via M7824 plus 5-FU in CRC has been evaluated. Integrative-systems biology approaches and RNAseq were used to assess the differential level of genes associated with 88 metastatic-CRC patients. The level of PD-L1 and TGF-β was evaluated in a validation cohort. The anti-proliferative, migratory, and apoptotic effects of PD-L1/TGF-β inhibitor, M7824, were assessed by MTT, wound-healing assay, and flow cytometry. Anti-tumor activity was assessed in a xenograft model, followed by biochemical studies and histological staining, and gene/protein expression analyses by RT-PCR and ELISA/IHC. The result of differentially expressed genes (DEGs) analysis showed 1268 upregulated and 1074 downregulated genes in CRC patients. Among the highest scoring genes and dysregulated pathways associated with CRC, PD-L1, and TGF-β were identified and further validated in 92 CRC patients. Targeting of PD-L1-TGF-β inhibited cell growth and migration, associated with modulation of CyclinD1 and MMP9. Furthermore, M7824 inhibited tumor growth via targeting TGF-β and PD-L1 pathways, resulting in modulation of inflammatory response and fibrosis via TNF-α/IL6/CD4-8 and COL1A1/1A2, respectively. In conclusion, our data illustrated that co-targeting PD-L1 and TGF-β pathways increased the effect of Fluorouracil (5-FU) and reduced the tumor growth in PD-L1/TGF-β expressing tumors, providing a new therapeutic option in the treatment of CRC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The modulating factors within the tumor microenvironment, for example, transforming growth factor beta (TGF-β), may limit the response to chemo and immunotherapy protocols in colorectal cancer (CRC). In the current study, the therapeutic potential of targeting the TGF-β pathway using Pirfenidone (PFD), a TGF-β inhibitor, either alone or in combination with five fluorouracil (5-FU) has been explored in preclinical models of CRC. The anti-proliferative and migratory effects of PFD were assessed by MTT and wound-healing assays respectively. Xenograft models were used to study the anti-tumor activity, histopathological, and side effects analysis. Targeting of TGF-β resulted in suppression of cell proliferation and migration, associated with modulation of survivin and MMP9/E-cadherin. Moreover, the PFD inhibited TGF-β induced tumor progression, fibrosis, and inflammatory response through perturbation of collagen and E-cadherin. Targeting the TGF-β pathway using PFD may increase the anti-tumor effects of 5-FU and reduce tumor development, providing a new therapeutic approach to CRC treatment., (© 2023. Springer Nature Limited.)

Cytochrome P450 (CYP450) enzyme has been shown to be expressed in colorectal cancer (CRC) and its dysregulation is linked to tumor progression and a poor prognosis. Here we investigated the therapeutic potential of targeting CYP450 using lopinavir/ritonavir in CRC. The integrative systems biology method and RNAseq were utilized to investigate the differential levels of genes associated with patients with colorectal cancer. The antiproliferative activity of lopinavir/ritonavir was evaluated in both monolayer and 3-dimensional (3D) models, followed by wound-healing assays. The effectiveness of targeting CYP450 was examined in a mouse model, followed by histopathological analysis, biochemical tests (MDA, SOD, thiol, and CAT), and RT-PCR. The data of dysregulation expressed genes (DEG) revealed 1268 upregulated and 1074 down-regulated genes in CRC. Among the top-score genes and dysregulated pathways, CYPs were detected and associated with poor prognosis of patients with CRC. Inhibition of CYP450 reduced cell proliferation via modulating survivin, Chop, CYP13a, and induction of cell death, as detected by AnnexinV/PI staining. This agent suppressed the migratory behaviors of cells by induction of E-cadherin. Moreover, lopinavir/ritonavir suppressed tumor growth and fibrosis, which correlated with a reduction in SOD/thiol levels and increased MDA levels. Our findings illustrated the therapeutic potential of targeting the CYP450 using lopinavir/ritonavir in colorectal cancer, supporting future investigations on this novel therapeutic approach for the treatment of CRC.

Background: Angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) are mainly known as anti-hypertensive drugs. Recent evidence suggests their anti-tumor potential against renal cancer. More than one-fourth of patients present with metastasis on their first visit., Objective: The purpose of the current study was to examine the potential clinical impact of ACEI/ARB on metastatic renal cell carcinoma (mRCC)., Methods: We searched through several online databases, including Pubmed, Scopus, Web of Science, and Embase, to find clinical studies that have investigated the association between treatment with ACEI/ARB and the survival of patients with mRCC. The hazard ratio (HR) and 95% confidence interval (95% CI) were utilized to assess the strength of the association., Results: A total of 6 studies with a total number of 2,364 patients were found eligible for the final analysis. The HR for the relationship between ACEI/ARB use and overall survival (OS) showed patients undergoing treatment with ACEI/ARB to have higher OS than non-users (HR: 0.664, 95% CI 0.577-0.764, p=0.000). Furthermore, the HR for the relationship between ACEI/ARB use and progression-free survival (PFS) showed patients undergoing treatment with ACEI/ARB to have higher PFS than non-users (HR: 0.734, 95% CI 0.695-0.794, p=0.000)., Conclusion: The results of this review offer ACEI/ARB as a potential therapeutic option associated with improved survival outcomes in patients receiving anti-vascular endothelial growth factor therapy., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Purpose: Lung metastasis is the main cause of death in patients with colorectal carcinoma (CRC). Angiotensin II has been confirmed to facilitate cancer cell progression and metastasis. In this study, the possible anti-metastatic effects of an angiotensin II receptor type 1 (AT1R) antagonist, valsartan, have been investigated in an experimental CRC lung metastasis model., Methods: An animal CRC lung metastasis model was used, involving intravenous injection of CRC cells. The experimental groups included (1) control group; (2) 5-FU (5-fluorouracil) group (5 mg/kg/every other day; ip); (3) valsartan group (40 mg/kg/day; po); and (4) valsartan + 5-FU group (combination group; valsartan 40 mg/kg/day, oral gavage, and 5-FU 5 mg/kg/every other day; ip). After 11 days, macroscopic and histological evaluations of lung tissues have been done for evaluation of lung metastatic nodules. In addition, inflammatory and angiogenic markers and oxidative stress index were measured in lung tissue., Results: Our results showed that administration of valsartan especially in combination with 5-FU significantly reduced lung metastatic nodule and metastatic area (p < 0.05) in macroscopic and histological evaluations stained by hematoxylin-eosin. Measurement of inflammatory, angiogenic, and oxidative/antioxidative markers in lung tissue indicated that the level of IL-6, angiogenic markers (VEGF and VEGFR-1), and antioxidative markers significantly reduced in combination group (p < 0.05) while the MDA as a marker of oxidative stress increased (p < 0.05)., Conclusion: These results suggest that valsartan in combination with standard chemotherapeutic agents can have a synergistic effect in treatment of lung metastasis of CRC., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Adhesion band formation is a common cause of morbidity for patients undergoing surgeries. Anti-inflammatory and anti-fibrotic properties of curcumin, a pharmacologically active component of Curcuma longa, have been investigated in several studies. The aim of this study is to explore the therapeutic potential of curcumin in attenuating post-operative adhesion band (PSAB) formation in both peritoneal and peritendinous surgeries in animal models., Methods: Bio-mechanical, histological and quantitative evaluation of inflammation, and total fibrosis scores were graded and measured in the presence and absence of phytosomal curcumin., Results: Results showed that phytosomal curcumin significantly decreased severity, length, density and tolerance of mobility of peritendinous adhesions as well as incidence and severity of abdominal fibrotic bands post-surgery. Curcumin may decrease inflammation by attenuating recruitment of inflammatory cells and regulating oxidant/anti-oxidant balance in post-operative tissue samples. Moreover, markedly lower fibrosis scores were obtained in the adhesive tissues of phytosomal curcumin-treated groups which correlated with a significant decrease in quantity, quality and grading of fibers, and collagen deposition in animal models., Conclusion: These results suggest that protective effects of phytosomal curcumin against PSAB formation is partially mediated by decreasing inflammation and fibrosis at site of surgery. Further studies are needed to investigate the therapeutic potential of this molecule in preventing PSAB., (© 2023. The Author(s).)

Introduction: Cervical cancer is the leading cause of cancer-related death in women, so novel therapeutic approaches are needed to improve the effectiveness of current therapies or extend their activity. In recent decades, graphene analogs, such as Mxene, an emerging class of two-dimensional (2D) graphene analogs, have been drawing considerable attention based on their intrinsic physicochemical properties and performance as potential candidates for tumor therapy, particularly for therapeutic purposes. Here we explored the targeted drug delivery in cervical cancer in in vivo model. Mxene-based nanocarriers are not able to be precisely controlled in cancer treatment. Method: To solve this problem, the titanium carbide-magnetic core-shell nanocarrier (Ti 3 C 2 -Fe 3 O 4 @SiO 2 -FA) is also developed to provide synergetic anticancer with magnetic controlling ability along with pH-responsive drug release. A xenograft model of the cervix was used to investigate the effects of Cisplatin alone, or in combination with Ti 3 C 2 @FA and Ti 3 C 2 @ Fe 3 O 4 @SiO 2 -FA, on tumor growth following histological staining for evaluation of necrosis. Result and Discussion: A significant tumor-growth suppression effect is shown when the Ti 3 C 2 -Fe 3 O 4 @SiO 2 -FA nanocarrier is magnetically controlled Cisplatin drug release. It reveals a synergistic therapeutic efficacy used in conjunction with pharmaceuticals ( p < .001). According to the in vivo study, the Ti 3 C 2 @FA@Cisplatin nanocomposite exhibits less tumor growth than the drug alone or Ti 3 C 2 @FA@Cisplatin via increasing necrosis effect ( p < .001). Through this study, Mxene nanosheets are expanded for biomedical applications, not only through the fabrication of biocompatible magnetic Mxene nanocomposite but also through the development of functionalization strategies that enable the magnetic Ti 3 C 2 nanocomposite to load high levels of Cisplatin for cervical cancer treatment (242.5%). Hence, Ti 3 C 2 -Fe 3 O 4 @SiO 2 -FA nanocarriers would be promising candidates to improve cancer treatment efficiency., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Darroudi, Elnaz Nazari, Karimzadeh, Asgharzadeh, Khalili-Tanha, Asghari, Ranjbari, Babaei, Rezayi and Khazaei.)

Objectives: Colon cancer is well-known as a life-threatening disease. Since the current treatment modalities for this type of cancer are powerful yet face some limitations, finding novel treatments is required to achieve better outcomes with fewer side effects. Here we investigated the therapeutic potential of Azurin-p28 alone or along with iRGD (Ac-CRGDKGPDC-amide) as a tumor-penetrating peptide and 5-fluorouracil (5-FU) for colon cancer., Materials and Methods: Inhibitory effect of p28 with or without iRGD/5-FU was studied in CT26 and HT29, as well as the xenograft animal model of cancer. The effect of p28 alone or along with iRGD/5-FU on cell migration, apoptotic activity, and cell cycle of the cell lines was assessed. Level of the BAX and BCL2 genes, tumor suppressor genes [(p53 and collagen type-Iα1 (COL1A1), collagen type-Iα2 (COL1A2)] were assessed by quantitative RT-PCR., Results: These findings show that using p28 with or without iRGD and 5-FU raised the level of p53 and BAX but decreased BCL2, compared with control and 5-FU groups in tissues of the tumor, which result in raising the apoptosis., Conclusion: It seems that p28 may be used as a new therapeutic approach in colon cancer therapy that can enhance the anti-tumor effect of 5-FU., Competing Interests: The authors have declared that have no conflicts of interest

Background: Global rise in cannabis abuse during reproductive years has placed a large number of men at risk for the adverse consequences of δ-9-tetrahydrocannabinol (THC), the primary active component of cannabis. It has been reported that THC affects male fertility and causes testicular cell dysfunction and apoptosis. This study aimed to investigate the possible protective role of zinc pretreatment against the toxic effects of THC in cultured mouse Sertoli cells and the underlying mechanism., Methods: The Mus Musculus Sertoli cell line (TM4) was cultured, exposed to THC alone (470 μM, 24 h), co-administered with zinc (8 μM, 48 h), and investigated in three groups: control, THC, and THC + zinc. The MTT was performed to evaluate cell viability. TUNEL assay was also applied for the detection of cell apoptosis and a western blot was performed for measuring protein expression levels of Caspase3, Pro-caspase3, SOD, and PDGF-A., Results: THC significantly decreased cell viability (p < 0.001) and expression levels of SOD, PDGF-A, and pro-caspase3 proteins (p < 0.05 for all), whereas increased Sertoli cells apoptosis (p < 0.001) and expression level of cleaved caspase3 protein (p < 0.001). Pretreatment with zinc reversed THC-induced apoptotic and oxidative effects and reduced cleaved caspase3/pro-caspase3 ratio but could not reverse THC-induced reduction of PDGF-A expression level in TM4 cells., Conclusion: The present data suggest that THC induces Sertoli cell damage through a multitarget mechanism. Zinc was reported to protect against THC-induced Sertoli cell damage due to its antiapoptotic and antioxidant activities, indicating its clinical importance against THC-induced testicular toxicity among addicted men., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: In this study we investigated the therapeutic potential of angiotensin II pathway inhibitors in attenuating post-surgical adhesion band formation in tendon injury., Method: We assigned 30 Wistar albino rats to 5 groups, including negative control, positive control, sham, Telmisartan- and Enalapril-treated groups (n=6). Telmisartan and Enalapril at a dose of 10 mg/kg were administered intraperitoneally for 21 days. Hematoxylin-Eosin, and Masson's trichrome staining were used to measure the inflammatory cell accumulation and collagen deposition in the Achilles tendon tissue sections. Oxidative stress markers were analyzed in tissue samples by spectrophotometric methods. Properties of Achilles tendon adhesions were compared based on Tang and Ishiyama scoring systems in the presence and absence of angiotensin II pathway inhibitors., Results: Telmisartan and Enalapril reduced severity, length, and density of surgical-induced tendon adhesion at site of injury (***p < 0.001). Our results showed that administration of angiotensin II pathway inhibitors decreased infiltration of inflammatory cells to the injured area (*p < 0.05) and suppressed inflammation by regulating oxidative stress markers including MDA (***p < 0.001), total thiol (***p < 0.001), CAT (***p < 0.001), and SOD (***p < 0.001), in post-operative Achilles tendon tissues. Significant lower collagen deposition and formation of fibrotic tissues was seen in Telmisartan- and Enalapril-treated groups as detected by Masson's trichrome staining which correlated with a decrease in quantity (**p < 0.01) and grading of fibrosis score (***p < 0.001), in adhesive tissues. Moreover, inhibition of angiotensin II pathway could also ameliorate mechanical properties including ultimate load (***p < 0.001), and ultimate stress (*p < 0.05) in injured Tendons., Conclusion: Our results showed that ssuppression of inflammation and fibrosis are two mechanisms by which Telmisartan and Enalapril elicit potent protective responses post Achilles tendon injuries., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Mebendazole (MBZ) is an efficacious anthelmintic with known anti-inflammatory and fibrinolytic properties. In this study, we aimed to explore the protective effects of this FDA-approved drug against DSS-induced colitis in a murine model either alone or in combination with Sulfasalazine (SSZ), a standard therapy for ulcerative colitis. We found that MBZ significantly improved colitis disease activity index as assessed by changes in body weight, degree of stool consistency, rectal bleeding, and prolapse. We also found that MBZ ameliorated the colon histopathological score by attenuating crypt loss, mucosal damage, and inflammation score in colitis tissues. Similarly, DSS-induced colon shortening, colon weight loss, and increase in spleen weight were all abrogated in the presence of MBZ. Moreover, MBZ decreased inflammation, possibly by reducing oxidative stress markers, suppressing inflammatory cell infiltration, and down-regulation of inflammatory genes in colon tissues. Furthermore, MBZ potently reduced fibrosis by decreasing collagen deposition and down-regulating pro-fibrotic genes including Col 1a1 and Col 1a2 in colitis tissue homogenates. In conclusion, our study showed that this broad-spectrum anthelminthic could be repurposed as a novel therapy for ulcerative colitis without any observed side effects, however, regarding the concerns about the potential toxicity of MBZ in UC patients, future experiments on MBZ therapy in other models of UC is needed to completely address the toxicity concerns., (© 2022. The Author(s).)

Background: Overexpression of the angiotensin-II receptor and renin-angiotensin system (RAS) has been reported in several malignancies, including colorectal-cancer (CRC), indicating its potential value as a therapeutic target. Here we explored the impact of targeting the RAS using an angiotensin II receptor blocker, valsartan, alone and its combination with Fluorouracil (5-FU) in in vitro and in vivo models of CRC., Methods: Anti-proliferative activity of valsartan was evaluated in 2-/3-dimensional in vitro and in vivo CRC mouse models. The anti-migratory effects of this agent was assessed by wound-healing assay, while apoptosis was studied using 4',6-diamidino-2-phenylindole or DAPI staining, and staining with Annexin-V-fluorescein isothiocyanate with analysis using FACS. Gene-expression was determined at mRNA and protein levels. We further evaluated the anti-inflammatory properties of valsartan by histological analysis and the measurement of oxidative/antioxidant markers. Gelatin zymography was used to measure matrix metalloproteinase-2 and -9 activity (MMP-2 and 9)., Results: Valsartan suppressed CRC cell-growth and synergistically enhanced the anti-tumor-activities of 5-FU by induction of apoptosis, BAX, BCL2, P53 and modulation of the cell cycle. Valsartan inhibited the cell migration by perturbation of MMP2/9. Furthermore, valsartan inhibited tumor-growth, and this was more pronounced when using the valsartan/5-FU combination. The plausible mechanism for this is via the induction of ROS and down-regulation of SOD, thiol/catalase as well as VEGF. Valsartan may protect cells against intestinal fibrosis by modulation of pro-fibrotic and pro-inflammatory factors including interleukins and Col1A1 expression., Conclusions: Our findings demonstrated that targeting RAS pathway using Valsartan interferes with cell-proliferation, induces apoptosis, reduces migration and synergistically interacts with 5-FU, supporting further studies on this new therapeutic approach for colorectal cancer., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in the world. Tumor removal remains the preferred frontline treatment; however, effective non-surgical interventions remain a high priority. 5-fluorouracil (5-FU) is a widely used chemotherapy agent, and molecular hydrogen (H 2 ) has been recognized for its antioxidant and anti-inflammatory effects, with research also suggesting its potential anti-tumor effects. Therefore, H 2 dissolved in water [hydrogen-rich water (HRW)], with or without 5-FU, may present itself as a novel therapeutic for CRC., Aim: To investigate the effects of HRW, with or without 5-FU, as a novel therapeutic for CRC., Methods: CRC was induced in the left flank of inbred Balb/c mice. A total of 24 mice bearing tumors were randomly divided into four groups ( n = 6 per group) and treated as follows: (1) Control group; (2) 5-FU group that received intraperitoneal injection of 5-FU (5 mg/kg) every other day; (3) H 2 group that received HRW, created and delivered via dissolving the H 2 -generating tablet in the animals' drinking water, with 200 μL also delivered by oral gavage; and (4) The combination group, H 2 (administered in same way as for group three) combined with 5-FU administered same way as group two., Results: Administration of HRW + 5-FU significantly improved tumor weight, tumor size, collagen content and fibrosis as compared to the CRC control group. Specifically, HRW attenuated oxidative stress (OS) and potentiated antioxidant activity (AA), whereas 5-FU treatment exacerbated OS and blunted AA. The combination of HRW + 5-FU significantly reduced tumor weight and size, as well as reduced collagen deposition and the degree of fibrosis, while further increasing OS and decreasing AA compared to administration of 5-FU alone., Conclusion: Administration of HRW, with or without 5-FU, may serve as a therapeutic for treating CRC., Competing Interests: Conflict-of-interest statement: Tarnava A is involved in commercial entities with interest in the marketing of hydrogen-rich water; LeBaron TW has received travel reimbursement, honoraria, and speaking and consultancy fees from various academic and commercial entities regarding molecular hydrogen. All other authors report no conflict of interest., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

The incidence of colorectal cancer (CRC) has significantly increased in recent decades, which has made this disease an important global health issue. Despite many efforts, there is no useful prognostic or diagnostic biomarker for CRC. Heat shock protein 27 (Hsp27) is one of the most studied members of the Hsp family. It has attracted particular attention in CRC pathogenesis since it is involved in fundamental cell functions for cell survival. Evidence shows that Hsp27 plays important role in CRC progression and metastasis. Hsp27 overexpression has been observed in CRC and is suggested to be associated with CRC's poor prognosis. In the present review, we focus on the current knowledge of the role of Hsp27 in CRC carcinogenesis and the underlying mechanisms. In addition, we discuss the value of targeting Hsp27 in CRC treatment., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Ovarian cancer is the fifth most common gynecological cancer in women globally. Conventional chemotherapy is the first therapeutic approach in the treatment of ovarian cancer, but its success is limited by severe side effects, transient response, and the high prevalence of relapse. Curcumin is a natural product found in the rhizome extract of Curcuma longa and has been extensively used over the last decades for its unique biological and medicinal properties, which include: having antioxidant, analgesic, anti-inflammation, and anti-tumor activities. Curcumin exerts its anticancer properties against ovarian cancer via multiple mechanisms: interfering with cellular interactions necessary for metastasis and recurrence of OC cells, increasing pro-apoptotic proteins as well as inducing or suppressing generation of different molecules such as cytokines, transcription factors, enzymes, protein kinases, and growth factors. Moreover, curcumin down-regulates various signaling pathways such as PI3K/Akt, Wnt/β-catenin, JAK/STAT3, and MEK/ERK1/2 axes, which at least in part have a role in inhibiting further tumor proliferation, growth, and angiogenesis. In this review, we overview the potential of incorporating curcumin into the treatment of ovarian cancer. In particular, we summarize the preclinical evidence supporting its use in combination with current chemotherapeutic regimens as well as new analogues and formulations under investigation.

The renin-angiotensin system (RAS) has been reported to have a role in carcinogenesis, and therefore it may be of value as a potential therapeutic target in inhibiting tumor growth. It has been shown that inhibition of RAS via angiotensin I-converting enzyme inhibitors (ACEIs) and angiotensin II type-1 receptor (ARBs) inhibitors may have a protective effect against several malignancies. Here, we provide an overview of the potential value of the RAS pathway and targeting via ACE/ARB inhibitors in pancreatic cancer. Whilst the potential role of RAS as a target for the treatment of pancreatic cancer has been reported, the use of candesartan with gemcitabine failed to improve outcomes in pancreatic cancer. Another study of 1-3 years using ARB was found to reduce the risk of pancreatic cancer. In line with these trials, others have demonstrated that the ARBs in combination with gemcitabine might improve clinical outcomes in patients with advanced pancreatic cancer. Prospective trials are warranted to investigate this hypothesis., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Colorectal cancer (CRC) is the third most common cancer worldwide. Despite the enormous amount of effort in the diagnosis and treatment of CRC, the overall survival rate of patients remains low. The precise molecular and cellular basis underlying CRC has not been completely understood yet. Over time, new genes and molecular pathways involved in the pathogenesis of the disease are being identified. The accurate discovery of these genes and signaling pathways are important and urgent missions for the next generation of anticancer therapy research. Chaperone DnaJ, also known as Hsp40 (heat shock protein 40), has been of particular interest in CRC pathogenesis, as it is involved in the fundamental cell activities for maintaining cellular homeostasis. Evidence shows that protein family members of DnaJ/Hsp40 play both roles, enhancing and reducing the growth of CRC cells. In the present review, we focus on the current knowledge of the molecular mechanisms responsible for DnaJ/Hsp40 in CRC carcinogenesis and biology., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Purpose: As the conventional therapeutic approaches were not completely successful in the treatment of colon cancer, there is still a need for finding the most efficient therapeutic agents. Here we investigated the anticancer activity of HPRP-A1 that was derived from the N-terminal region of Helicobacter pylori ribosomal protein L1 (RpL1) alone or in combination with tumor-homing peptide iRGD and 5-Fluorouracil (5FU) on colon cancer cell lines (CT26 and HT29) and isograft models of colon cancer., Method: We assessed the tumor growth inhibitory activity of HPRP-A1 with or without iRGD and 5FU on colon cancer in vitro and in vivo. In the in vitro part, we investigate the effect of HPRP-A1 alone and in combination with iRGD/5FU., Results: Our results demonstrated that co-administration of HPRP-A1 with iRGD increased the apoptosis, while these two peptides in combination with 5FU increased the intracellular level of p53 that upregulate the pro-apoptotic gene BAX and downregulate the anti-apoptotic gene BCL2. HPRP-A1 blocks the cell cycle progression in G0/G1. Co-administration of two peptides significantly reduced the size and weight of the tumors, while the group that received 5FU in combination with the peptides increased the necrotic and decrease the fibrotic area significantly in the tumor tissues, which also disrupt the oxidant/antioxidant balance., Conclusions: Our results indicated that HPRP-A1 could be considered an effective agent toward colon cancer in vitro and in vivo with the ability to enhance the effects of conventional chemotherapy agent 5FU., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Circulating inflammatory factor inorganic polyphosphate (polyP) released from activated platelets could enhance factor XII and bradykinin resulted in increased capillary leakage and vascular permeability. PolyP induce inflammatory responses through mTOR pathway in endothelial cells, which is being reported in several diseases including atherosclerosis, thrombosis, sepsis, and cancer. Systems and molecular biology approaches were used to explore the regulatory role of the AMPK activator, metformin, on polyP-induced hyper-permeability in different organs in three different models of polyP-induced hyper-permeability including local, systemic short- and systemic long-term approaches in murine models. Our results showed that polyP disrupts endothelial barrier integrity in skin, liver, kidney, brain, heart, and lung in all three study models and metformin abrogates the disruptive effect of polyP. We also showed that activation of AMPK signaling pathway, regulation of oxidant/anti-oxidant balance, as well as decrease in inflammatory cell infiltration constitute a set of molecular mechanisms through which metformin elicits it's protective responses against polyP-induced hyper-permeability. These results support the clinical values of AMPK activators including the FDA-approved metformin in attenuating vascular damage in polyP-associated inflammatory diseases., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Chronic use of morphine is associated with reproductive complications, such as hypogonadism and infertility. While the side effects of morphine have been extensively studied in the testis, much less is known regarding the effects of morphine on Sertoli cells and the effects of zinc on morphine-induced testicular injury as well as their underlying mechanisms. Therefore, the purpose of this study was to investigate the effect of morphine (alone and co-administered with zinc) on cell viability and apoptosis of the testicular (Sertoli) cells as well as the tumor suppressor p53 and phosphorylated-protein kinase B (p-Akt) protein levels in both in vitro and in vivo models., Methods: Cultured Sertoli cells were exposed to morphine (23 μM), zinc (8 μM), and zinc prior to morphine and their effects on Sertoli cell viability and apoptosis were investigated. Morphine (3 mg/kg) and zinc (5 mg/kg, 1 h before morphine) were also injected intraperitoneally to rats and then the apoptotic changes in the testis were evaluated., Results: Cell viability and p-Akt protein levels decreased in morphine-treated cells, while apoptosis and p53 protein expression increased in these cells. Pretreatment with zinc recovered morphine-induced apoptotic effects, as well as over-expression of p53 and down-regulation of p-Akt. These findings were supported by a subsequent animal study., Conclusion: The present data indicated the protective effect of zinc against morphine-induced testicular (Sertoli) cell toxicity via p53/Akt pathways in both in vivo and in vitro models and suggested the clinical importance of zinc on infertility among chronic opioid users and addicted men., (Copyright © 2021 Elsevier GmbH. All rights reserved.)

Background: The therapeutic potency of Rigosertib (RGS) in the treatment of the myelodysplastic syndrome has been investigated previously, but little is known about its mechanisms of action., Methods: The present study integrates systems and molecular biology approaches to investigate the mechanisms of the anti-tumor effects of RGS, either alone or in combination with 5-FU in cellular and animal models of colorectal cancer (CRC)., Results: The effects of RGS were more pronounced in dedifferentiated CRC cell types, compared to cell types that were epithelial-like. RGS inhibited cell proliferation and cell cycle progression in a cell-type specific manner, and that was dependent on the presence of mutations in KRAS, or its down-stream effectors. RGS increased both early and late apoptosis, by regulating the expression of p53, BAX and MDM2 in tumor model. We also found that RGS induced cell senescence in tumor tissues by increasing ROS generation, and impairing oxidant/anti-oxidant balance. RGS also inhibited angiogenesis and metastatic behavior of CRC cells, by regulating the expression of CD31, E-cadherin, and matrix metalloproteinases-2 and 9., Conclusion: Our findings support the therapeutic potential of this potent RAS signaling inhibitor either alone or in combination with standard regimens for the management of patients with CRC., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Cerium (IV) oxide (CeO 2 ) exhibit anti-inflammatory activity via scavenge free radicals and decreasing the oxygen species (ROS) production. Here we aimed to exhibit the therapeutic effect of this nanoparticle in experimental colitis models., Methods: Cerium oxide nanoparticles (CeONPs) were synthesized via using UiO-66 as a precursor. We used dextran sodium sulfate (DSS) to induce colitis in experimental models to investigate the anti-inflammatory effect of CeONPs. Colitis models are divided into four groups to receive the treatment, including control, colitis, cerium oxide, and sulfasalazine. We evaluated the therapeutic effects of CeONPs for the increased colitis clinical symptoms and attenuated the histological damage to colon tissue in colitis., Result: This nanoparticle was significantly able to reduce the clinical symptoms of colitis. Moreover, CeONPs can enhance the disease activity index such as body lose weight, diarrhea, rectal bleeding, colon length, and spleen weight. Moreover, CeONPs showed a significant reduction in the histological characteristics of the colitis models., Conclusion: These results suggest that CeONPs can be considered as promising therapeutic agents in treating the ulcerative colitis., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Oxaliplatin is being used in different malignancies and several side effects are reported for patients taking Oxaliplatin, including peripheral neuropathy, nausea and vomiting, diarrhea, mouth sores, low blood counts, fatigue, loss of appetite, etc. Here we have developed a targeted anticancer drug delivery system based on folate-conjugated amine-functionalized UiO-66 for the delivery of oxaliplatin (OX). UiO-66-NH 2 (U) and UiO-66-NH 2 -FA(FU) were pre-functionalized by the incorporation of folic acid (FA) into the structure via coordination of the carboxylate group of FA. The FTIR spectra of drug-loaded U and FU showed the presence of new carboxylic and aliphatic groups of OX and FA. Powder X-ray diffraction (PXRD) patterns were matched accordingly with the reference pattern and FESEM results showed semi-spherical particles (115-128 nm). The evaluated amounts of OX in U and FU were calculated 304.5 and 293 mg/g , respectively. The initial burst release of OX was 15.7% per hour for U(OX) and 10.8% per hour for FU(OX). The final release plateau gives 62.9% and 52.3% for U(OX) and FU(OX). To evaluate the application of the prepared delivery platform, they were tested on colorectal cancer cells (CT-26) via MTT assay, cell migration assay, and spheroid model. IC 50 values obtained from MTT assay were 21.38, 95.50, and 18.20 μg/mL for OX, U(OX), and FU(OX), respectively. After three days of treatment, the CT26 spheroids at two doses of 500 and 50 μg/mL of U(OX) and FU(OX) showed volume reduction. Moreover, the oxidative behavior of the prepared systems within the cell was assessed by total thiol, malondialdehyde, and superoxide dismutase activity. The results showed that FU(OX) had higher efficacy in preventing the growth of CT-26 spheroid, and was more effective than oxaliplation in cell migration inhibition, and induced higher oxidative stress and apoptosis., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Isoniazid (INH) is well known as a first-line anti-tuberculosis, while some studies demonstrate that it has anti-inflammatory activity via a different mechanism such as inhibitionthe production of IL-1, ROS, activation of PPARγ expression, inhibition of the transcriptional regulatory activity of NF-κB and AP-1. The aim of this study, investigate the anti-inflammatory effect of INH and INH combined with Sulfasalazine-loaded nanoparticles (NPs) in the ulcerative colitis mouse model., Methods: To investigate the anti-inflammatory effect of INH and NPs in the ulcerative colitis mice model, we evaluated the effect of INH clinical symptoms and colonic mucosal histology in colitis., Result: The present study demonstrates that combination therapy of INH with sulfasalazine as well as NPs reduces the symptom of ulcerative colitis and improved disease activity index include body lose weight, diarrhea, rectal bleeding, colonic length, spleen weight, and colon histopathological score in DSS-induced colitis mice model., Conclusion: Our results suggest that the nanoforms of INH with sulfasalazine enhances the therapeutic effect of the drugs in the treatment of ulcerative colitis., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Colitis is an inflammatory condition of the bowels associated with abdominal pain, diarrhea, fatigue, and fever. Its etiology is multifactorial but related to the overproduction of inflammatory and oxidative mediators. There is currently no cure for this disease, and drugs used to manage it often have deleterious side effects. H 2 is recognized as having anti-inflammatory and antioxidant effects, which may qualify it as a novel therapeutic for colitis. We induced an acute model of colitis in mice by administering dextran sulfate sodium (DSS) in drinking water for seven days. Mice were divided into five groups (n=6); normal, colitis, H 2 -treated colitis, sulfasalazine-treated colitis, and H 2 plus sulfasalazine-treated colitis. From days three to ten, mice were given H 2 , sulfasalazine, or both. H 2 was administered via dissolving a hydrogen-generating tablet in water to make hydrogen-rich water (HRW), which was ingested ad libitum and via oral gavage (200 μL). The Disease Activity Index (DAI), histological changes, and markers of inflammation and oxidative stress were assessed. HRW and sulfasalazine significantly improved bodyweight, DAI, mucosal damage, crypt loss, and spleen weight compared to control. Both treatments significantly decreased inflammation (high-sensitive C-reactive protein) and restored redox balance (total thiol, superoxide dismutase, catalase activity). There was a trend for the combination treatment to be more effective than either HRW or sulfasalazine alone. Furthermore, HRW tended to be as effective as, and often more effective than, sulfasalazine. HRW may serve as a therapeutic for ameliorating DSS-induced colitis in mice., (Copyright © 2021 LeBaron et al.)

Exocannabinoids such as tetrahydrocannabinol (THC) may alter the physiological function of endocannabinoids in male reproduction and thus affect male fertility. This study aimed to investigate the apoptotic effects of THC via mechanisms related to p53 and AKT signaling pathways on Sertoli cells and seminiferous germinal cells, as well as the possible protective role of selenium pretreatment in both in vitro and in vivo models. The Mus musculus Sertoli cell line, TM4, was used for in vitro experiments. The TM4 cells were cultured and exposed to selenium (2 μM, 48 h) and THC (470 μM, 24 h). The MTT test was performed to evaluate cell viability. Fifteen male Wistar rats (220 ± 20 g) were used for in vivo experiments and divided into three groups: (1) control, (2) tetrahydrocannabinol (THC, 5 mg/kg, dissolved in DMSO 5%, i.p., for 21 consecutive days), and (3) THC + selenium (selenium, 0.5 mg/kg per day, i.p.). At the end of the experiments, Sertoli cells and testis tissue samples were collected for biochemical (AKT, P53), cell apoptosis, and histological analyses. The results of the in vitro study revealed that THC significantly decreases the cell viability (p < 0.001) and expression of the p-AKt protein (p < 0.05) and increases Sertoli cells' apoptosis (p < 0.001) and p53 protein expression (p < 0.001). The in vivo effects of THC were in line with the in vitro results. Pretreatment with selenium (as sodium selenite) significantly decreased the THC-induced Sertoli cell and testicular tissue damages in the rats. Pathological changes were significantly alleviated in the selenium-pretreated rats. Collectively, these data suggest that pretreatment with selenium is able to protect against THC-induced testicular cell damage. The attenuating effect of selenium may be due to its anti-apoptotic activity through the p53 and AKT modulation.

Colorectal cancer (CRC) is an important cause of cancer-related mortality. Aberrant activation of the renin-angiotensin system (RAS) is reported to be associated with poor clinical outcomes in patients with CRC. This study was designed to explore the anti-tumor effects of the angiotensin receptor blocker Candesartan either alone or in combination with 5-FU in in vitro and in vivo models of CRC. The cytotoxic effects of Candesartan were assessed using the MTT assay in two colorectal cancer cell lines (CT-26 and SW-480). To investigate the potential regulatory role of Candesartan on tumor growth, apoptosis, and migration, the expression levels of Cyclin D1, Survivin, MMP3, MMP9, and E-cadherin mRNAs were evaluated. The oxidant/antioxidant balance was also examined by determining the levels of MDA, thiols, SOD, and CAT. We used a xenograft model of colon cancer to investigate the effects of Candesartan alone, or in combination with 5-FU, on tumor growth following histological staining (Hematoxylin & Eosin and Masson trichrome staining) and biochemical studies as well as gene expression analyses by RT-PCR and western blotting. Candesartan suppressed tumor cell proliferation and migration by modulating Cyclin D1, MMP3/9, and E-cadherin. Treatment with Candesartan either alone, or in combination with 5-FU decreased tumor size in the mouse model, and also increased the level of oxidative markers MDA and reduced CAT, SOD, and thiols. Histological evaluation showed that Candesartan increased tumor necrosis, reduced tumor density and attenuated collagen deposition reducing tumor fibrosis in tumor xenograft. Candesartan, an inhibitor of the RAS, when used in combination with 5-FU reduced tumor growth by inhibiting fibrosis and inducing ROS production, supporting further clinical studies on this therapeutic approach for treatment of CRC., (Copyright © 2021 Tabatabai et al.)

Transforming Growth Factor-beta (TGF-β) is dysregulated in colorectal cancer and there is growing evidence that it is associated with a poor prognosis and chemo-resistance in several malignances, including CRC. In this study we have explored the therapeutic potential of targeting TGF-β using Tranilast in colon cancer. The anti-proliferative activity of Tranilast was evaluated in 2- and 3-dimensional cells. We used a xenograft model of colon cancer to investigate the activity of Tranilast alone or in combination with 5-FU on tumor growth using histological staining and biochemical studies, as well as gene expression analyses using RT-PCR and Western blotting. Tranilast alone or in combination with 5-FU inhibited tumor growth and was associated with a reduction of TGF-β expression and CD31 positive endothelial cells. Histological evaluation showed that Tranilast increased tumor necrosis and reduced tumor density and angiogenesis. Tranilast increased MDA and ROS production. It was also found that Tranilast reduced total thiol concentration and reduced SOD and catalase activity. Tranilast plus 5-FU was also found to attenuate collagen deposition, reducing tumor fibrosis in tumor xenografts. Our results show that Tranilast, a TGF inhibitor, in combination with 5-FU reduces tumor growth by inhibiting fibrosis and inducting ROS, thus supporting this therapeutic approach in CRC treatment., (Copyright © 2021 Hashemzehi et al.)

The renin-angiotensin system (RAS) is up-regulated in patients with colorectal cancer (CRC) and is reported to be associated with poor prognosis and chemo-resistance. Here we explored the therapeutic potential of targeting RAS in CRC using Losartan, an angiotensin receptor blocker. An integrative-systems biology approach was used to explore a proteome-level dataset of a gene signature that is modulated by Losartan. The anti-proliferative activity of Losartan was evaluated using 2- and 3-dimensional cell culture models. A xenograft model of colon cancer was used to investigate tumor growth with Losartan alone and in combination with 5-FU followed by histological staining (Hematoxylin & Eosin and Masson trichrome staining), biochemical analyses, gene expression analyses by RT-PCR, western blot/IHC, or MMP Gelatin Zymography studies. Effects on cell cycle and cell death were assessed by flow cytometry. Losartan inhibited cell growth and suppressed cell cycle progression, causing an increase in CRC cells in the G1 phase. Losartan significantly reduced tumor growth and enhanced tumor cell necrosis. An impact on the inflammatory response, including up-regulation of pro-inflammatory cytokines and chemokines in CRC cells are potential mechanisms that could partially explain Losartan's anti-proliferative effects. Moreover, metastasis and angiogenesis were reduced in Losartan-treated mice as observed by inhibited matrix metalloproteinase-2 and -9 activities and decreased tumor vasculature. These data demonstrate the therapeutic potential of combining chemotherapeutic regimens with Losartan to synergistically enhance its activity and target the renin-angiotensin system as a new approach in colorectal cancer treatment., (Copyright © 2021 Hashemzehi et al.)

Inflammatory bowel disease (IBD) is defined by the chronic inflammation of the digestive tract. Ulcerative colitis is one of the most prevalent chronic IBDs. The increase in the mucosal expression of angiotensin II (AT-II) in colitis suggests a possible role of AT-II in colitis-associated inflammation. Here, we examined the potential therapeutic effects of combination therapy regarding valsartan (Val), as an AT-II receptor blocker, with sulfasalazine (SSZ) in a murine colitis model. DSS induced colitis was initiated by the administration of dextran sodium sulfate (DSS) in male C57BL/6 mice for 1 week. Val (160 mg/kg/day, gavage) was given on the third day and continued for seven days. SSZ (100 mg/kg/day) was used as reference drug and also used in combination in one group (Val; 160 mg/kg/day and/or SSZ; 100 mg/kg/day). Colonic mucosal inflammation was evaluated clinically, biochemically, and histologically. The disease activity index in DSS-treated mice, including weight loss, stool consistency, and rectal bleeding, were significantly lower in the group of mice receiving the combination of valsartan and sulfasalazine compared to the DSS-treated group. Valsartan and sulfasalazine treatment was associated with a lower reduction in colon length, diminished colon weight, and high sensitivity C-reactive protein level in mice with DSS-induced colitis. Valsartan and sulfasalazine also reduced markers of oxidative stress after DSS administration. Our findings demonstrate the anti-inflammatory and anti-fibrotic activities of a combination therapy with sulfasalazine and valsartan in experimentally induced colitis, indicating its value as a potential therapeutic option for the treatment of colitis., (Copyright © 2021 Asgharzadeh et al.)

Background: Abdominal adhesions are common and often develop after abdominal surgery. There are currently no useful targeted pharmacotherapies for adhesive disease. Saffron and its active constituents, Crocin and Crocetin, are wildly used in traditional medicine for alleviating the severity of inflammatory or malignant disease., Purpose: The aim of this study was to investigate the therapeutic potential of the pharmacological active component of saffron in attenuating the formation of post-operative adhesion bands using different administration methods in a murine model., Material Method: saffron extract (100 mg/kg), Crocin (100 mg/kg), and Crocetin (100 mg/kg) were administered intraperitoneally and by gavage in various groups of male Wistar rat post-surgery. Also three groups were first treated intra-peritoneally by saffron extract, Crocin, and Crocetin (100 mg/kg) for 10 days and then had surgery. At the end of the experiments, animals sacrificed for biological assessment., Result: A hydro-alcoholic extract of saffron and crocin but not crocetin potently reduced the adhesion band frequency in treatment and pre-treatment groups in the mice given intra-peritoneal (i.p) injections. Following the saffron or crocin administration, histological evaluation and quantitative analysis represented less inflammatory cell infiltration and less collagen composition, compared to control group. Moreover, the oxidative stress was significantly reduced in treatment groups., Conclusion: These findings suggest that a hydro-alcoholic extract of saffron or its active compound, crocin, is a potentially novel therapeutic strategy for the prevention of adhesions formation and might be used as beneficial anti-inflammatory or anti-fibrosis agents in clinical trials., Taxonomy: Abdominal surgeries/post-surgical adhesions., Competing Interests: The authors have no conflicts of interest., (© 2021 Center for Food and Biomolecules, National Taiwan University. Production and hosting by Elsevier Taiwan LLC.)

Coronavirus disease 2019 (SARS-CoV-2) (COVID-19) has recently raised worldwide public health concerns. The available data on COVID-19 in patients with diabetes is limited but generally indicate that there is an increased risk of developing COVID-19 infection in diabetic patients, which ultimately impacts the overall patient's survival. Various aspects might be involved; however, the exact mechanisms and interrelationships between diabetes and the novel COVID-19 have not yet been fully elucidated. This review summarizes the possible mechanisms by which present diabetes predispose individuals to COVID-19 infection, modulates the hostviral interactions and increases the risk of mortality. We hope this review can provide beneficial information for further studies and contribute to improved disease management of diabetic patients with COVID-19., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)