Clinical trials of cellular therapies for the treatment of colorectal cancer: a narrative review

Colorectal cancer (CRC) treatment using common chemotherapy approaches has drawbacks such as side effects, costs, and resistance of cancer cells which affects patients’ prolonged survival, and quality of life. The immune cells have pivotal roles in regulating tumor progression in the tumor microenvironment (TME). The most important CRC cellular immunotherapies include the use of tumor-derived cells such as tumor-infiltrating lymphocytes (TILs) and lymph node lymphocytes (LNLs), peripheral blood mononuclear cells (PBMCs), derived cells, including T cells, natural killer (NK) cells, cytokine-induced killer (CIK) cells, and chimeric antigen receptor (CAR) cells. Although adoptive cell therapy has some advantages, some disadvantages have been reported. TILs cells are strictly directed against tumor-specific antigens; however, they are inefficient due to immune editing. CIK cells have a major histocompatibility complex (MHC)-independent cytotoxic effect and need concurrent high-dose interleukin (IL)-2 administration. In addition, chimeric antigen receptor-T cells (CAR-T cells) are MHC-independent that overcome MHC downregulation by the tumor. They are potent in recognizing any cell surface antigen and are applicable to a broad range of patients and T-cell populations. Here, the researchers present the most popular cancer cellular immunotherapy approaches and discuss their clinical relevance by referring to data obtained from CRC clinical trials. To date, clinical experience and efficacy suggest that combining more than one immunotherapy intervention, in combination with other treatments like chemotherapy, radiotherapy, and targeted therapy, is promising for cancer therapy

A single-center non-blinded randomized clinical trial to assess the safety and effectiveness of PhR160 spray in the treatment of COVID-19 pneumonia

7-16COVID-19 is an emerging pandemic that caused a very widespread infection with more than 1000000 cases in Iran within a year. The main cause of mortality among patients with COVID-19 is pulmonary failure. In Iranian Traditional Medicine, essences have been used for curing pulmonary diseases. Pinen-Hydronoplacton-Ribonucleic acid (PHR) is an inhaler spray made of seven different plants, which all are used by humans and have desirable pharmacological features for treating pulmonary symptoms of COVID-19 patients. This study was conducted to assess the safety and effectiveness of PHR160 spray in improving pulmonary symptoms of COVID-19 patients. This was a single-centre, non-blinded randomized clinical trial with two parallel groups in two different wards of Baqiyatallah hospital, Tehran, Iran. Participants were 63 male patients diagnosed with COVID-19 pneumonia, divided into 2 groups of 32 in the intervention group and 31 in the control group. The intervention group received 5 days of PHR160 spray, 10 puffs each day, 300 micrograms in each puff in addition to the routine treatment. Oxygen saturation was measured by a pulse oximeter, every six hours and recorded daily. This study showed that administration of PhR 160 in patients of COVID-19 was safe, and it significantly increased the arterial oxygen saturation percentage in COVID-19 patients. In addition, it decreased hospitalization duration, dyspnea score, and cough score significantly in the patients. The statistical modelling test, with adjusting the age and respiratory rate for baseline and 4 days of the intervention, shows that the oxygen saturation percentage mean was significantly more in the intervention group by 5.14 units (p<0.001)

C-Terminal Domain Deletion Enhances the Protective Activity of cpa/cpb Loaded Solid Lipid Nanoparticles against Leishmania major in BALB/c Mice

Cutaneous leishmaniasis (CL) is the most common form of leishmaniasis with an annual incidence of approximately 2 million cases and is endemic in 88 countries, including Iran. CL's continued spread, along with rather ineffectual treatments and drug-resistant variants emergence has increased the need for advanced preventive strategies. We studied Type II cysteine proteinase (CPA) and Type I (CPB) with its C-terminal extension (CTE) as cocktail DNA vaccine against murine and canine leishmaniasis. However, adjuvants' success in enhancing immune responses to selected antigens led us to refocus our vaccine development programs. Herein, we discuss cationic solid lipid nanoparticles' (cSLN) ability to improve vaccine-induced protective efficacy against CL and subsequent lesion size and parasite load reduction in BALB/c mice. For this work, we evaluated five different conventional as well as novel parasite detection techniques, i.e., footpad imaging, footpad flowcytometry and lymph node flowcytometry for disease progression assessments. Vaccination with cSLN-cpa/cpb-CTE formulation showed highest parasite inhibition at 3-month post vaccination. Immunized mice showed reduced IL-5 level and significant IFN-ã increase, compared to control groups. We think our study represents a potential future and a major step forward in vaccine development against leishmaniasis

Curcuma purpurascens BI. rhizome accelerates rat excisional wound healing: involvement of Hsp70/Bax proteins, antioxidant defense, and angiogenesis activity

Elham Rouhollahi,1 Soheil Zorofchian Moghadamtousi,2 Fatemeh Hajiaghaalipour,3 Maryam Zahedifard,2 Faezeh Tayeby,2 Khalijah Awang,4 Mahmood Ameen Abdulla,3 Zahurin Mohamed1 1Pharmacogenomics Laboratory, Department of Pharmacology, Faculty of Medicine, 2Institute of Biological Sciences, Faculty of Science, 3Department of Biomedical Science, Faculty of Medicine, 4Department of Chemistry, Faculty of Science, University of Malaya, Kuala Lumpur, Malaysia Purpose: Curcuma purpurascens BI. is a member of Zingiberaceae family. The purpose of this study is to investigate the wound healing properties of hexane extract of C. purpurascens rhizome (HECP) against excisional wound healing in rats.Materials and methods: Twenty four rats were randomly divided into 4 groups: A) negative control (blank placebo, acacia gum), B) low dose of HECP, C) high dose of HECP, and D) positive control, with 6 rats in each group. Full-thickness incisions (approximately 2.00 cm) were made on the neck area of each rat. Groups 1&ndash;4 were treated two-times a day for 20 days with blank placebo, HECP (100 mg/kg), HECP (200 mg/kg), and intrasite gel as a positive control, respectively. After 20 days, hematoxylin and eosin and Masson&rsquo;s trichrome stainings were employed to investigate the histopathological alterations. Protein expressions of Bax and Hsp70 were examined in the wound tissues using immunohistochemistry analysis. In addition, levels of enzymatic antioxidants and malondialdehyde representing lipid peroxidation were measured in wound tissue homogenates.Results: Macroscopic evaluation of wounds showed conspicuous elevation in wound contraction after topical administration of HECP at both doses. Moreover, histopathological analysis revealed noteworthy reduction in the scar width correlated with the enhanced collagen content and fibroblast cells, accompanied by a reduction of inflammatory cells in the granulation tissues. At the molecular level, HECP facilitates wound-healing process by downregulating Bax and upregulating Hsp70 protein at the wound site. The formation of new blood vessel was observed in Masson&rsquo;s trichrome staining of wounds treated with HECP (100 and 200 mg/kg). In addition, HECP administration caused a significant surge in enzymatic antioxidant activities and a decline in lipid peroxidation.Conclusion: These findings suggested that HECP accelerated wound-healing process in rats via antioxidant activity, angiogenesis effect and anti-inflammatory responses involving Hsp70/Bax. Keywords: Zingiberaceae, wound closure, immunohistochemistry, antioxidant enzyme activity, inflammatory cell

Synthesis, characterization and apoptotic activity of quinazolinone Schiff base derivatives toward MCF-7 cells via intrinsic and extrinsic apoptosis pathways

The current study investigated the cytotoxic effect of 3-(5-chloro-2-hydroxybenzylideneamino)-2-(5-chloro-2-hydroxyphenyl)-2,3-dihydroquinazolin-41(H)-one (A) and 3-(5-nitro-2-hydroxybenzylideneamino)-2-(5-nitro-2-hydroxyphenyl)-2,3-dihydroquinazolin-4(1H)-one (B) on MCF-7, MDA-MB-231, MCF-10A and WRL-68 cells. The mechanism involved in apoptosis was assessed to evaluate the possible pathways induced by compound A and B. MTT assay results using A and B showed significant inhibition of MCF-7 cell viability, with IC 50 values of 3.27±0.171 and 4.36±0.219μg/mL, respectively, after a 72hour treatment period. Compound A and B did not demonstrate significant cytotoxic effects towards MDA-MB-231, WRL-68 and MCF-10A cells. Acute toxicity tests also revealed an absence of toxic effects on mice. Fluorescent microscopic studies confirmed distinct morphological changes (membrane blebbing and chromosome condensation) corresponding to typical apoptotic features in treated MCF-7 cells. Using Cellomics High Content Screening (HCS), we found that compound A and B could trigger the release of cytochrome c from mitochondria to the cytosol. The release of cytochrome c activated the expression of caspases-9 and then stimulated downstream executioner caspase-3/7. In addition, caspase-8 showed remarkable activity, followed by inhibition of NF-κ B activation in A-and B-treated MCF-7 cells. The results indicated that A and B could induce apoptosis via a mechanism that involves either extrinsic or intrinsic pathways

The antiulcer effect of Cibotium barometz leaves in rats with experimentally induced acute gastric ulcer

Nahla Saeed Al-Wajeeh,1 Maryam Hajrezaie,1 Nawal Al-Henhena,1 Sareh Kamran,1 Elham Bagheri,1 Maryam Zahedifard,1 Kamelia Saremi,1 Suzita Mohd Noor,1 Hapipah Mohd Ali,2 Mahmood Ameen Abdulla11Department of Biomedical Science, Faculty of Medicine, 2Department of Chemistry, Faculty of Science, University of Malaya, Kuala Lumpur, MalaysiaAbstract: Cibotium barometz is a pharmaceutical plant customarily used in traditional medicine in Malaysia for the treatment of different diseases, such as gastric ulcer. The gastroprotective effect of C. barometz leaves against ethanol-induced gastric hemorrhagic abrasions in Sprague Dawley rats has been evaluated in terms of medicinal properties. Seven groups of rats (normal control and ulcerated control groups, omeprazole 20 mg/kg, 62.5, 125, 250, and 500 mg/kg of C. barometz correspondingly) were used in antiulcer experiment and pretreated with 10% Tween&nbsp;20. After 1 hour, the normal group was orally administered 10% Tween 20, whereas absolute alcohol was fed orally to ulcerated control, omeprazole, and experimental groups. Gastric&rsquo;s homogenate were assessed for endogenous enzymes activities. Stomachs were examined macroscopically and histologically. Grossly, the data demonstrated a significant decrease in the ulcer area of rats pretreated with plant extract in a dose-dependent manner with respect to the ulcerated group. Homogenates of the gastric tissue exhibited significantly increased endogenous enzymes activities in rats pretreated with C. barometz extract associated with the ulcerated control group. Histology of rats pretreated with C. barometz extract group using hematoxylin and eosin staining exhibited a moderate-to-mild disruption of the surface epithelium with reduction in submucosal edema and leucocyte infiltration in a dose-dependent manner. In addition, it showed heat shock protein70 protein up-expression and BCL2-associated X protein downexpression. These outcomes might be attributed to the gastroprotective and antioxidative effects of the plant. Keywords: Cibotium barometz leaves, antioxidants, acute toxicity, antiulcer, histolog

A schiff base-derived copper (II) complex is a potent inducer of apoptosis in colon cancer cells by activating the intrinsic pathway

Metal-based drugs with extensive clinical applications hold great promise for the development of cancer chemotherapeutic agents. In the last few decades, Schiff bases and their complexes have become well known for their extensive biological potential. In the present study, we examined the antiproliferative effect of a copper (II) complex on HT-29 colon cancer cells. The Cu(BrHAP)2 Schiff base compound demonstrated a potent tiproliferative effect in HT-29 cells, with an IC50 value of 2.8

Synthesis of Apoptotic New Quinazolinone-Based Compound and Identification of its Underlying Mitochondrial Signalling Pathway in Breast Cancer Cells

The anti-carcinogenic effect of the new quinazolinone compound, named MMD, was tested on MCF-7 human breast cancer cell line. The synthesis of quinazolinone-based compounds attracted strong attention over the past few decades as an alternative mean to produce analogues of natural products. Quinazolinone compounds sharing the main principal core structures are currently introduced in the clinical trials and pharmaceutical markets as anti-cancer agents. Thus, it is of high clinical interest to identify a new drug that could be used to control the growth and expansion of cancer cells. Quinazolinone is a metabolite derivative resulting from the conjugation of 2-aminobenzoyhydrazide and 5-methoxy-2-hydroxybenzaldehyde based on condensation reactions. In the present study, we analysed the influence of MMD on breast cancer adenoma cell morphology, cell cycle arrest, DNA fragmentation, cytochrome c release and caspases activity. MCF-7 is a type of cell line representing the breast cancer adenoma cells that can be expanded and differentiated in culture. Using different in vitro strategies and specific antibodies, we demonstrate a novel role for MMD in the inhibition of cell proliferation and initiation of the programmed cell death. MMD was found to increase cytochrome c release from the mitochondria to the cytosol and this effect was enhanced over time with effective IC50 value of 5.85 ± 0.71 μg/mL detected in a 72-hours treatment. Additionally, MMD induced cell cycle arrest at G0/G1 phase and caused DNA fragmentation with obvious activation of caspase-9 and caspases-3/7. Our results demonstrate a novel role of MMD as an anti-proliferative agent and imply the involvement of mitochondrial intrinsic pathway in the observed apoptosis