Tumoricidal properties of thymoquinone on human colorectal adenocarcinoma cells via the modulation of autophagy.

Colorectal cancer (CRC) is deadly anaplastic changes in the gastrointestinal tract with high-rate mortality. In recent years, the application of phytocompounds has been extended along with different therapeutic protocols. Here, we monitored the effects of Thymoquinone (TQ) on autophagy via mitochondrial function after modulation of the Wnt/ß-catenin signaling pathway.Human colorectal adenocarcinoma HT-29 cells were treated with TQ (60 µM) and 15 µM Wnt3a inhibitor (LGK974) for 48 h. The survival rate was evaluated using an MTT assay. The expression of Wnt-related factors (c-Myc, and Axin), angiogenesis (VE-Cadherin), and mitophagy-related factors (PINK1, OPTN) was assessed using real-time PCR assay. Protein levels of autophagy factors (Beclin-1, LC3, and P62) were monitored using western blotting. Using flow cytometry analysis, the intracellular accumulation of Rhodamine 123 was evaluated. The migration properties were analyzed using a scratch wound healing assay.Data indicated that TQ can reduce the viability of HT-29 cells compared to the control cells (p < 0.05). The expression of VE-Cadherin was inhibited while the expression of PINK1 was induced in treated cells (p < 0.05). Both LGK974 and TQ-treated cells exhibited activation of autophagy flux (Beclin-1↑, LC3II/I↑, and p62↓) compared to the control group (p < 0.05). TQ can increase intracellular accumulation of Rhodamine 123, indicating the inhibition of efflux mechanisms in cancer cells. Along with these changes, the migration of cells was also reduced (p < 0.05).TQ is a potential phytocompound to alter the dynamic growth of human colorectal HT-29 cells via the modulation of autophagy, and mitophagy-related mechanisms.

Role of autophagy in angiogenic potential of vascular pericytes.

The vasculature system is composed of a multiplicity of juxtaposed cells to generate a functional biological barrier between the blood and tissues. On the luminal surface of blood vessels, endothelial cells (ECs) are in close contact with circulating cells while supporting basal lamina and pericytes wrap the abluminal surface. Thus, the reciprocal interaction of pericytes with ECs is a vital element in the physiological activity of the vascular system. Several reports have indicated that the occurrence of pericyte dysfunction under ischemic and degenerative conditions results in varied micro and macro-vascular complications. Emerging evidence points to the fact that autophagy, a conserved self-digestive cell machinery, can regulate the activity of several cells like pericytes in response to various stresses and pathological conditions. Here, we aim to highlight the role of autophagic response in pericyte activity and angiogenesis potential following different pathological conditions.

Mitochondria-loaded alginate-based hydrogel accelerated angiogenesis in a rat model of acute myocardial infarction.

Here, mitochondria were isolated from mesenchymal stem cells (MSCs) after being treated with mitochondria-stimulating substrates, 50 µM metformin (Met), and 40 µM dichloroacetic acid (DCA). The isolated mitochondria (2 × 107 particles) were characterized and encapsulated inside 100 µl hydrogel composed of alginate (3 % w/v; Alg)/gelatin (Gel; 1 % w/v) enriched with 1 µM pyrrole (Pyr) solidified in the presence of 0.2 M FeCl3. The physicochemical properties and cytocompatibility of prepared hydrogels were assessed using FTIR, swelling, biodegradation, porosity assays, and scanning electron microscopy (SEM). The mitochondria-bearing hydrogel was injected into the ischemic area of rat hearts. FTIR absorption bands represented that the addition of FeCl3 led to polypyrrole (PPy) formation, polysaccharide oxidation, and interaction between Alg and Gel. SEM images exhibited porous structure and the size of pores was reduced in Alg/Gel + PPy group compared to Alg + PPy hydrogel. Based on the data, both Alg + PPy and Alg/Gel + PPy hydrogels can preserve the integrity and morphology of loaded mitochondria. It was noted that Alg/Gel + PPy hydrogel possessed a higher swelling ratio, degradation, and porosity compared to Alg + PPy group. Data confirmed that Alg/Gel + PPy hydrogel containing 1 µM Pyr yielded the highest survival rate compared to groups with 2 and 4 µM Pyr (p < 0.05). Injection of mitochondria-loaded Alg/Gel + PPy hydrogel yielded significant restoration of left ventricle thickness compared to the infarction, mitochondria, and Alg/Gel + PPy hydrogel groups 14 days post-injection (p < 0.05). Histological analyses revealed a significant increase of vWF+ capillaries and α-SMA+ arterioles in the mitochondria-loaded Alg/Gel + PPy hydrogel group (p < 0.05). Immunofluorescence imaging revealed the ability of rat cardiomyocytes to uptake mitochondria alone or after being loaded into Alg/Gel + PPy hydrogel. These effects were evident in the Alg/Gel + PPy group. Taken together, electroconductive Alg-based hydrogels are suitable platforms for the transplantation of cells and organelles and the regeneration of ischemic heart changes.

Prokaryotic microvesicles Ortholog of eukaryotic extracellular vesicles in biomedical fields.

Every single cell can communicate with other cells in a paracrine manner via the production of nano-sized extracellular vesicles. This phenomenon is conserved between prokaryotic and eukaryotic cells. In eukaryotic cells, exosomes (Exos) are the main inter-cellular bioshuttles with the potential to carry different signaling molecules. Likewise, bacteria can produce and release Exo-like particles, namely microvesicles (MVs) into the extracellular matrix. Bacterial MVs function with diverse biological properties and are at the center of attention due to their inherent therapeutic properties. Here, in this review article, the comparable biological properties between the eukaryotic Exos and bacterial MVs were highlighted in terms of biomedical application. Video Abstract.

Angiogenic activity of mitochondria; beyond the sole bioenergetic organelle.

Angiogenesis is a complex process that involves the expansion of the pre-existing vascular plexus to enhance oxygen and nutrient delivery and is stimulated by various factors, including hypoxia. Since the process of angiogenesis requires a lot of energy, mitochondria play an important role in regulating and promoting this phenomenon. Besides their roles as an oxidative metabolism base, mitochondria are potential bioenergetics organelles to maintain cellular homeostasis via sensing alteration in oxygen levels. Under hypoxic conditions, mitochondria can regulate angiogenesis through different factors. It has been indicated that unidirectional and bidirectional exchange of mitochondria or their related byproducts between the cells is orchestrated via different intercellular mechanisms such as tunneling nanotubes, extracellular vesicles, and gap junctions to maintain the cell homeostasis. Even though, the transfer of mitochondria is one possible mechanism by which cells can promote and regulate the process of angiogenesis under reperfusion/ischemia injury. Despite the existence of a close relationship between mitochondrial donation and angiogenic response in different cell types, the precise molecular mechanisms associated with this phenomenon remain unclear. Here, we aimed to highlight the possible role of mitochondria concerning angiogenesis, especially the role of mitochondrial transport and the possible relation of this transfer with autophagy, the housekeeping phenomenon of cells, and angiogenesis.

The Beneficial and Adverse Effects of Autophagic Response to Caloric Restriction and Fasting.

Each cell is equipped with a conserved housekeeping mechanism, known as autophagy, to recycle exhausted materials and dispose of injured organelles via lysosomal degradation. Autophagy is an early-stage cellular response to stress stimuli in both physiological and pathological situations. It is thought that the promotion of autophagy flux prevents host cells from subsequent injuries by removing damaged organelles and misfolded proteins. As a correlate, the modulation of autophagy is suggested as a therapeutic approach in diverse pathological conditions. Accumulated evidence suggests that intermittent fasting or calorie restriction can lead to the induction of adaptive autophagy and increase longevity of eukaryotic cells. However, prolonged calorie restriction with excessive autophagy response is harmful and can stimulate a type II autophagic cell death. Despite the existence of a close relationship between calorie deprivation and autophagic response in different cell types, the precise molecular mechanisms associated with this phenomenon remain unclear. Here, we aimed to highlight the possible effects of prolonged and short-term calorie restriction on autophagic response and cell homeostasis.

Applications of engineered exosomes in drugging noncoding RNAs for cancer therapy.

Noncoding RNAs (ncRNAs) are engaged in key cell biological and pathological events, and their expression alteration is connected to cancer progression both directly and indirectly. A huge number of studies have mentioned the significant role of ncRNAs in cancer prevention and therapy that make them an interesting subject for cancer therapy. However, there are several limitations, including delivery, uptake, and short half-life, in the application of ncRNAs in cancer treatment. Exosomes are introduced as promising options for the delivery of ncRNAs to the target cells. In this review, we will briefly discuss the application and barriers of ncRNAs. After that we will focus on exosome-based ncRNAs delivery and their advantages as well as the latest achievements in drugging ncRNAs with exosomes.

CRISPR/Cas9 gene editing: a new approach for overcoming drug resistance in cancer.

The CRISPR/Cas9 system is an RNA-based adaptive immune system in bacteria and archaea. Various studies have shown that it is possible to target a wide range of human genes and treat some human diseases, including cancers, by the CRISPR/Cas9 system. In fact, CRISPR/Cas9 gene editing is one of the most efficient genome manipulation techniques. Studies have shown that CRISPR/Cas9 technology, in addition to having the potential to be used as a new therapeutic approach in the treatment of cancers, can also be used to enhance the effectiveness of existing treatments. Undoubtedly, the issue of drug resistance is one of the main obstacles in the treatment of cancers. Cancer cells resist anticancer drugs by a variety of mechanisms, such as enhancing anticancer drugs efflux, enhancing DNA repair, enhancing stemness, and attenuating apoptosis. Mutations in some proteins of different cellular signaling pathways are associated with these events and drug resistance. Recent studies have shown that the CRISPR/Cas9 technique can be used to target important genes involved in these mechanisms, thereby increasing the effectiveness of anticancer drugs. In this review article, studies related to the applications of this technique in overcoming drug resistance in cancer cells will be reviewed. In addition, we will give a brief overview of the limitations of the CRISP/Cas9 gene-editing technique.

MicroRNAs and osteosarcoma: Potential targets for inhibiting metastasis and increasing chemosensitivity.

Osteosarcoma (OS) is the third most common cancer in young adults after lymphoma and brain cancer. Metastasis, like other cellular events, is dependent on signaling pathways; a series of changes in some proteins and signaling pathways pave the way for OS cells to invade and migrate. Ezrin, TGF-ß, Notch, RUNX2, matrix metalloproteinases (MMPs), Wnt/ß-catenin, and phosphoinositide 3-kinase (PI3K)/AKT are among the most important of these proteins and signaling pathways. Despite the improvements in treating OS, the overall survival of patients suffering from the metastatic disease has not experienced any significant change after surgical treatments and chemotherapy and 5-years overall survival in patients with metastatic OS is about 20%. Studies have shown that overexpression or inhibition of some microRNAs (miRNAs) has significant effects in limiting the invasion and migration of OS cells. The results of these studies highlight the potential of the clinical application of some miRNA mimics and miRNA inhibitors (antagomiRs) to inhibit OS metastasis in the future. In addition, some studies have shown that miRNAs are associated with the most important drug resistance mechanisms in OS, and some miRNAs are highly effective targets to increase chemosensitivity. The results of these studies suggest that miRNA mimics and antagomiRs may be helpful to increase the efficacy of conventional chemotherapy drugs in the treatment of metastatic OS. In this article, we discussed the role of various signaling pathways and the involved miRNAs in the metastasis of OS, attempting to provide a comprehensive review of the literature on OS metastasis and chemosensitivity.

Zinc and Respiratory Viral Infections: Important Trace Element in Anti-viral Response and Immune Regulation.

Influenza viruses, respiratory syncytial virus (RSV), and SARS-COV2 are among the most dangerous respiratory viruses. Zinc is one of the essential micronutrients and is very important in the immune system. The aim of this narrative review is to review the most interesting findings about the importance of zinc in the anti-viral immune response in the respiratory tract and defense against influenza, RSV, and SARS-COV2 infections. The most interesting findings on the role of zinc in regulating immunity in the respiratory tract and the relationship between zinc and acute respiratory distress syndrome (ARDS) are reviewed, as well. Besides, current findings regarding the relationship between zinc and the effectiveness of respiratory viruses' vaccines are reviewed. The results of reviewed studies have shown that zinc and some zinc-dependent proteins are involved in anti-viral defense and immune regulation in the respiratory tract. It seems that zinc can reduce the viral titer following influenza infection. Zinc may reduce RSV burden in the lungs. Zinc can be effective in reducing the duration of viral pneumonia symptoms. Zinc may enhance the effectiveness of hydroxychloroquine in reducing mortality rate in COVID-19 patients. Besides, zinc has a positive effect in preventing ARDS and ventilator-induced lung damage. The relationship between zinc levels and the effectiveness of respiratory viruses' vaccines, especially influenza vaccines, is still unclear, and the findings are somewhat contradictory. In conclusion, zinc has anti-viral properties and is important in defending against respiratory viral infections and regulating the immune response in the respiratory tract.

Zinc and Selenium in Inflammatory Bowel Disease: Trace Elements with Key Roles?

Inflammatory bowel disease (IBD) is a chronic inflammatory condition that may emerge at a young age and often lasts for life. It often goes through phases of recurrence and remission and has a devastating effect on quality of life. The exact etiology of the disease is still unclear, but it appears that an inappropriate immune response to intestinal flora bacteria in people with a genetic predisposition may cause the disease. Managing inflammatory bowel disease is still a serious challenge. Oxidative stress and free radicals appear to be involved in the pathogenesis of this disease, and a number of studies have suggested the use of antioxidants as a therapeutic approach. The antioxidant and anti-inflammatory properties of some trace elements have led some of the research to focus on studying these trace elements in inflammatory bowel disease. Zinc and selenium are among the most important trace elements that have significant anti-inflammatory and antioxidant properties. Some studies have shown the importance of these trace elements in inflammatory bowel disease. In this review, we have attempted to provide a comprehensive overview of the findings of these studies and to gather current knowledge about the association of these trace elements with the inflammatory process and inflammatory bowel disease.