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1.
Promising Anti-Mitochondrial Agents for Overcoming Acquired Drug Resistance in Multiple Myeloma.
Innao, V, Rizzo, V, Allegra, AG, Musolino, C, Allegra, A
Cells. 2021;(2)
Abstract
Multiple myeloma (MM) remains an incurable tumor due to the high rate of relapse that still occurs. Acquired drug resistance represents the most challenging obstacle to the extension of survival and several studies have been conducted to understand the mechanisms of this phenomenon. Mitochondrial pathways have been extensively investigated, demonstrating that cancer cells become resistant to drugs by reprogramming their metabolic assessment. MM cells acquire resistance to proteasome inhibitors (PIs), activating protection programs, such as a reduction in oxidative stress, down-regulating pro-apoptotic, and up-regulating anti-apoptotic signals. Knowledge of the mechanisms through which tumor cells escape control of the immune system and acquire resistance to drugs has led to the creation of new compounds that can restore the response by leading to cell death. In this scenario, based on all literature data available, our review represents the first collection of anti-mitochondrial compounds able to overcome drug resistance in MM. Caspase-independent mechanisms, mainly based on increased oxidative stress, result from 2-methoxyestradiol, Artesunate, ascorbic acid, Dihydroartemisinin, Evodiamine, b-AP15, VLX1570, Erw-ASNase, and TAK-242. Other agents restore PIs' efficacy through caspase-dependent tools, such as CDDO-Im, NOXA-inhibitors, FTY720, GCS-100, LBH589, a derivative of ellipticine, AT-101, KD5170, SMAC-mimetics, glutaminase-1 (GLS1)-inhibitors, and thenoyltrifluoroacetone. Each of these substances improved the efficacy rates when employed in combination with the most frequently used antimyeloma drugs.
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2.
Inositol Hexaphosphate (IP6) and Colon Cancer: From Concepts and First Experiments to Clinical Application.
Vucenik, I, Druzijanic, A, Druzijanic, N
Molecules (Basel, Switzerland). 2020;(24)
Abstract
Multiple human health-beneficial effects have been related to highly phosphorylated inositol hexaphosphate (IP6). This naturally occurring carbohydrate and its parent compound, myo-inositol (Ins), are abundantly present in plants, particularly in certain high-fiber diets, but also in mammalian cells, where they regulate important cellular functions. However, the striking and broad-spectrum anticancer activity of IP6, consistently demonstrated in different experimental models, has been in a spotlight of the scientific community dealing with the nutrition and cancer during the last several decades. First experiments were performed in colon cancer 30 years ago. Since then, it has been shown that IP6 reduces cell proliferation, induces apoptosis and differentiation of malignant cells with reversion to normal phenotype, affecting several critical molecular targets. Enhanced immunity and antioxidant properties also contribute to the tumor cell destruction. Although Ins possesses a modest anticancer potential, the best anticancer results were obtained from the combination of IP6 + Ins. Here we review the first experimental steps in colon cancer, when concepts and hypotheses were put together almost without real knowledge and present clinical studies, that were initiated in colon cancer patients. Available as a dietary supplement, IP6 + Ins has been shown to enhance the anticancer effect of conventional chemotherapy, controls cancer metastases, and improves quality of life in cancer patients. Emerging clinical and still vast amount of experimental data suggest its role either as an adjuvant or as an "alternative" to current chemotherapy for cancer.
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3.
Apoptosis in Autoimmunological Diseases, with Particular Consideration of Molecular Aspects of Psoriasis.
Krawczyk, A, Miśkiewicz, J, Strzelec, K, Wcisło-Dziadecka, D, Strzalka-Mrozik, B
Medical science monitor : international medical journal of experimental and clinical research. 2020;:e922035
Abstract
Apoptosis is a natural physiological process involving programmed cell death. Thanks to this process, it is possible to maintain the homeostasis of the body and the immune system. Dysfunctions of this mechanism lead to development of autoimmune diseases such as psoriasis; these diseases are chronic and treatment is extremely difficult. In psoriasis (a skin disease), apoptosis disorders are manifested by keratinocyte proliferation dysfunction. Autoimmune diseases coexisting with psoriasis include multiple sclerosis, autoimmune thyroid disease, and diabetes, but the common pathogenesis of these diseases is not fully understood. Given the heterogenous nature and chronic and recurrent course of psoriasis, the selection of an effective therapeutic strategy is still a problem. This literature review was focused on the process of apoptosis as a factor in the development of autoimmune diseases, with particular emphasis on psoriasis. The work also includes a review of therapeutic methods of psoriasis based on the latest literature.
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4.
MicroRNAs play an essential role in autophagy regulation in various disease phenotypes.
Zhao, Y, Wang, Z, Zhang, W, Zhang, L
BioFactors (Oxford, England). 2019;(6):844-856
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Free full text
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Abstract
Autophagy is a highly conserved catabolic process and fundamental biological process in eukaryotic cells. It recycles intracellular components to provide nutrients during starvation and maintains quality control of organelles and proteins. In addition, autophagy is a well-organized homeostatic cellular process that is responsible for the removal of damaged organelles and intracellular pathogens. Moreover, it also modulates the innate and adaptive immune systems. Micro ribonucleic acids (microRNAs) are a mature class of post-transcriptional modulators that are widely expressed in tissues and organs. And, it can suppress gene expression by targeting messenger RNAs for translational repression or, at a lesser extent, degradation. Research indicates that microRNAs regulate autophagy through different pathways, playing an essential role in the treatment of various diseases. It is an important regulator of fundamental cellular processes such as proliferation, autophagy, and cell apoptosis. In this review article, we first review the current knowledge of autophagy and the function of microRNAs. Then, we summarize the mechanism of autophagy and the signaling pathways related to autophagy by citing at least the main proteins involved in the different phases of the process. Second, we introduce other members of RNA and report some examples in various pathologies. Finally, we review the current literature regarding microRNA-based therapies for cancer, atherosclerosis, cardiac disease, tuberculosis, and viral diseases. MicroRNAs can cause autophagy upregulation or downregulation by targeting genes or affecting autophagy-related signaling pathways. Therefore, the microRNAs have a huge potential in autophagy regulation, and it is the function as diagnostic and prognostic markers.
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5.
Cathepsin D primes caspase-8 activation by multiple intra-chain proteolysis.
Conus, S, Pop, C, Snipas, SJ, Salvesen, GS, Simon, HU
The Journal of biological chemistry. 2012;(25):21142-51
Abstract
During the resolution of inflammatory responses, neutrophils rapidly undergo apoptosis. A direct and fast activation of caspase-8 by cathepsin D was shown to be crucial in the initial steps of neutrophil apoptosis. Nevertheless, the activation mechanism of caspase-8 remains unclear. Here, by using site-specific mutants of caspase-8, we show that both cathepsin D-mediated proteolysis and homodimerization of caspase-8 are necessary to generate an active caspase-8. At acidic pH, cathepsin D specifically cleaved caspase-8 but not the initiator caspase-9 or -10 and significantly increased caspase-8 activity in dimerizing conditions. These events were completely abolished by pepstatin A, a pharmacological inhibitor of cathepsin D. The cathepsin D intra-chain proteolysis greatly stabilized the active site of caspase-8. Moreover, the main caspase-8 fragment generated by cathepsin D cleavage could be affinity-labeled with the active site probe biotin-VAD-fluoromethyl ketone, suggesting that this fragment is enzymatically active. Importantly, in an in vitro cell-free assay, the addition of recombinant human caspase-8 protein, pre-cleaved by cathepsin D, was followed by caspase-3 activation. Our data therefore indicate that cathepsin D is able to initiate the caspase cascade by direct activation of caspase-8. As cathepsin D is ubiquitously expressed, this may represent a general mechanism to induce apoptosis in a variety of immune and nonimmune cells.
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6.
Insights into the monomers and single drugs of Chinese herbal medicine on myocardial preservation.
Yuan, SM, Jing, H
African journal of traditional, complementary, and alternative medicines : AJTCAM. 2011;(2):104-27
Abstract
Chinese herbal drugs have been proved to be effective agents in myocardial protection by preventing ischemia-reperfusion injury. The underlying mechanisms as to how these agents work were however poorly elucidated. Studies on the monomers or on the single drugs have highlighted the possible rationales, leading to a better understanding of the pharmaceutical effects of the active parts of the herbs. These agents have been found to be structure-sensitive while they play the role of a protective ingredient. Polysaccharides of Chinese herbal medicine have pharmaceutical effects in immune modulation, anti-inflammation, anti-virus, anti-tumor, anti-aging mechanisms, with an anti-oxidative effect being a commonly recognized mechanism. Saponins are prone to alleviate calcium overload. As bioflavonoids commonly contain active phenolic hydroxy group, they have good anti-oxidant property. Those containing effective lignanoids and essential oils can result in a reduced nitric oxide secretion of the endothelial cells and an increased intercellular cell adhesion molecule-1 expression. Alkaloids may resist free radical injuries. Most importantly, modern in-depth research revealed that myocardial infarction is typically associated with apoptosis, and herbal medicine containing carbohydrates and glycosides showed cardioprotective effects by way of inhibiting apoptosis of myocytes. As a supplement to cardioplegia, some Chinese herbal drugs have become especially valuable in myocardial protection in open heart surgery by preserving metabolic energy. In conclusion, the classification of Chinese herbal medicine made according to their main active ingredients has facilitated the expression of their functioning mechanisms. Chinese herbal drugs play an important role in cardioprotection via many different mechanisms, the most recent and important finding being the inhibition of apoptosis.
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7.
Effect of Bifidobacterium infantis on Interferon- gamma- induced keratinocyte apoptosis: a potential therapeutic approach to skin immune abnormalities.
Cinque, B, Di Marzio, L, Della Riccia, DN, Bizzini, F, Giuliani, M, Fanini, D, De Simone, C, Cifone, MG
International journal of immunopathology and pharmacology. 2006;(4):775-86
Abstract
Current management of atopic dermatitis is mainly directed to the reduction of cutaneous inflammation. Since patients with atopic dermatitis show abnormalities in immunoregulation, a therapy aimed to adjust their immune function could represent an alternative approach, particularly in the severe form of the disease. Indeed, T-lymphocytes constitute a large population of cellular infiltrate in atopic/allergic inflammation and a dysregulated T-cell induced keratinocyte apoptosis appears to be an important pathogenetic factor of the eczematous disease. In recent years, attention has been focused on the interaction between host and probiotics which may have anti-inflammatory properties and immunomodulatory activities. The aim of the present work is to investigate the effect of a selected probiotic extract, the Bifidobacterium infantis extract, on a human keratinocyte cell line (HaCaT) abnormal apoptosis induced by activated-T-lymphocyte. An in vitro model of atopic dermatitis was used to assess the ability of the probiotic extract to protect HaCaT from apoptosis induced by soluble factors (IFN-gamma and CD95 ligand) released by human T-lymphocytes in vitro activated with anti-CD3/CD28 mAbs or Phytohemoagglutinin. Evidence is given that the bacterial extract treatment was able to totally prevent T lymphocyte-induced HaCaT cell apoptosis in vitro. The mechanism underlying this inhibitory effect has been suggested to depend on the ability of the bacterial extract to significantly reduce anti-CD3/CD28 mAbs and mitogen-induced T-cell proliferation, IFN-gamma generation and CD95 ligand release. These preliminary results may represent an experimental basis for a potential therapeutic approach mainly targeting the skin disorders-associated immune abnormalities.
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8.
Lymphocyte apoptosis after exhaustive and moderate exercise.
Mooren, FC, Blöming, D, Lechtermann, A, Lerch, MM, Völker, K
Journal of applied physiology (Bethesda, Md. : 1985). 2002;(1):147-53
Abstract
Apoptosis or programmed cell death is a process of fundamental importance for regulation of the immune response. Several reasons suggest that apoptosis is involved in exercise-induced alterations of the immune system such as postexercise lymphocytopenia. Healthy volunteers performed two treadmill exercise tests; the first was performed at 80% maximal oxygen uptake until exhaustion (exhaustive exercise) and the second 2 wk later at 60% maximal oxygen uptake with the identical running time (moderate exercise). Blood samples were taken before, immediately after, and 1 h after the test. Lymphocytes were analyzed for apoptotic and necrotic cells by using FITC-labeled annexin V-antibodies and nuclear propidium iodide uptake, respectively. In addition, apoptotic/necrotic cells were measured after a 24-h incubation of lymphocytes in the presence of camptothecin or phytohemagglutinin. Finally, plasma membrane expression of CD95-receptor and CD95-receptor ligand was investigated. Immediately after the exhaustive exercise, the percentage of apoptotic cells increased significantly, whereas it remained unchanged after the moderate exercise. Similar results were obtained after 24-h incubation of lymphocytes in medium alone or in the presence of camptothecin, but not with phytohemagglutinin. We found an upregulation of CD95-receptor expression after both exercise tests. However, only after exhaustive exercise a characteristic shift in CD95 expression profile toward cells with a high receptor density was observed. Expression of the CD95-receptor ligand remained unchanged after both exhaustive and moderate exercise. These results suggest that apoptosis may contribute to the regulation of the immune response after exhaustive exercise. Whether this mechanism can be regarded either as beneficial, i.e., deletion of autoreactive cells, or harmful, i.e., suppression of the immune response, awaits further investigations.