Publications by authors named "Milad Ashrafizadeh"

123 Publications

Interplay between SOX9 transcription factor and microRNAs in cancer.

Int J Biol Macromol 2021 May 3;183:681-694. Epub 2021 May 3.

Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein, 2028, South Africa. Electronic address:

SOX transcription factors are critical regulators of development, homeostasis and disease progression and their dysregulation is a common finding in various cancers. SOX9 belongs to SOXE family located on chromosome 17. MicroRNAs (miRNAs) possess the capacity of regulating different transcription factors in cancer cells by binding to 3'-UTR. Since miRNAs can affect differentiation, migration, proliferation and other physiological mechanisms, disturbances in their expression have been associated with cancer development. In this review, we evaluate the relationship between miRNAs and SOX9 in different cancers to reveal how this interaction can affect proliferation, metastasis and therapy response of cancer cells. The tumor-suppressor miRNAs can decrease the expression of SOX9 by binding to the 3'-UTR of mRNAs. Furthermore, the expression of downstream targets of SOX9, such as c-Myc, Wnt, PI3K/Akt can be affected by miRNAs. It is noteworthy that other non-coding RNAs including lncRNAs and circRNAs regulate miRNA/SOX9 expression to promote/inhibit cancer progression and malignancy. The pre-clinical findings can be applied as biomarkers for diagnosis and prognosis of cancer patients.
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http://dx.doi.org/10.1016/j.ijbiomac.2021.04.185DOI Listing
May 2021

Elucidating Role of Reactive Oxygen Species (ROS) in Cisplatin Chemotherapy: A Focus on Molecular Pathways and Possible Therapeutic Strategies.

Molecules 2021 Apr 19;26(8). Epub 2021 Apr 19.

Department of Science in Korean Medicine, College of Korean Medicine, Kyung Hee University, Seoul 02447, Korea.

The failure of chemotherapy is a major challenge nowadays, and in order to ensure effective treatment of cancer patients, it is of great importance to reveal the molecular pathways and mechanisms involved in chemoresistance. Cisplatin (CP) is a platinum-containing drug with anti-tumor activity against different cancers in both pre-clinical and clinical studies. However, drug resistance has restricted its potential in the treatment of cancer patients. CP can promote levels of free radicals, particularly reactive oxygen species (ROS) to induce cell death. Due to the double-edged sword role of ROS in cancer as a pro-survival or pro-death mechanism, ROS can result in CP resistance. In the present review, association of ROS with CP sensitivity/resistance is discussed, and in particular, how molecular pathways, both upstream and downstream targets, can affect the response of cancer cells to CP chemotherapy. Furthermore, anti-tumor compounds, such as curcumin, emodin, chloroquine that regulate ROS and related molecular pathways in increasing CP sensitivity are described. Nanoparticles can provide co-delivery of CP with anti-tumor agents and by mediating photodynamic therapy, and induce ROS overgeneration to trigger CP sensitivity. Genetic tools, such as small interfering RNA (siRNA) can down-regulate molecular pathways such as HIF-1α and Nrf2 to promote ROS levels, leading to CP sensitivity. Considering the relationship between ROS and CP chemotherapy, and translating these findings to clinic can pave the way for effective treatment of cancer patients.
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http://dx.doi.org/10.3390/molecules26082382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8073650PMC
April 2021

Drug Delivery (Nano)Platforms for Oral and Dental Applications: Tissue Regeneration, Infection Control, and Cancer Management.

Adv Sci (Weinh) 2021 04 5;8(8):2004014. Epub 2021 Feb 5.

The Dental College of Georgia Augusta University 1430 John Wesley Gilbert Drive Augusta GA 30192 USA.

The oral cavity and oropharynx are complex environments that are susceptible to physical, chemical, and microbiological insults. They are also common sites for pathological and cancerous changes. The effectiveness of conventional locally-administered medications against diseases affecting these oral milieus may be compromised by constant salivary flow. For systemically-administered medications, drug resistance and adverse side-effects are issues that need to be resolved. New strategies for drug delivery have been investigated over the last decade to overcome these obstacles. Synthesis of nanoparticle-containing agents that promote healing represents a quantum leap in ensuring safe, efficient drug delivery to the affected tissues. Micro/nanoencapsulants with unique structures and properties function as more favorable drug-release platforms than conventional treatment approaches. The present review provides an overview of newly-developed nanocarriers and discusses their potential applications and limitations in various fields of dentistry and oral medicine.
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http://dx.doi.org/10.1002/advs.202004014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8061367PMC
April 2021

Paving the Road Toward Exploiting the Therapeutic Effects of Ginsenosides: An Emphasis on Autophagy and Endoplasmic Reticulum Stress.

Adv Exp Med Biol 2021 ;1308:137-160

Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.

Programmed cell death processes such as apoptosis and autophagy strongly contribute to the onset and progression of cancer. Along with these lines, modulation of cell death mechanisms to combat cancer cells and elimination of resistance to apoptosis is of great interest. It appears that modulation of autophagy and endoplasmic reticulum (ER) stress with specific agents would be beneficial in the treatment of several disorders. Interestingly, it has been suggested that herbal natural products may be suitable candidates for the modulation of these processes due to few side effects and significant therapeutic potential. Ginsenosides are derivatives of ginseng and exert modulatory effects on the molecular mechanisms associated with autophagy and ER stress. Ginsenosides act as smart phytochemicals that confer their effects by up-regulating ATG proteins and converting LC3-I to -II, which results in maturation of autophagosomes. Not only do ginsenosides promote autophagy but they also possess protective and therapeutic properties due to their capacity to modulate ER stress and up- and down-regulate and/or dephosphorylate UPR transducers such as IRE1, PERK, and ATF6. Thus, it would appear that ginsenosides are promising agents to potentially restore tissue malfunction and possibly eliminate cancer.
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http://dx.doi.org/10.1007/978-3-030-64872-5_12DOI Listing
April 2021

Regulation of Nuclear Factor-KappaB (NF-κB) signaling pathway by non-coding RNAs in cancer: Inhibiting or promoting carcinogenesis?

Cancer Lett 2021 Jul 7;509:63-80. Epub 2021 Apr 7.

NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117 600, Singapore. Electronic address:

The nuclear factor-kappaB (NF-κB) signaling pathway is considered as a potential therapeutic target in cancer therapy. It has been well established that transcription factor NF-κB is involved in regulating physiological and pathological events including inflammation, immune response and differentiation. Increasing evidences suggest that deregulated NF-κB signaling can enhance cancer cell proliferation, metastasis and also mediate radio-as well as chemo-resistance. On the contrary, non-coding RNAs (ncRNAs) have been found to modulate NF-κB signaling pathway under different settings. MicroRNAs (miRNAs) can dually inhibit/induce NF-κB signaling thereby affecting the growth and migration of cancer cells. Furthermore, the response of cancer cells to radiotherapy and chemotherapy may also be regulated by miRNAs. Regulation of NF-κB by miRNAs may be mediated via binding to 3-UTR region. Interestingly, anti-tumor compounds can increase the expression of tumor-suppressor miRNAs in inhibiting NF-κB activation and the progression of cancers. Long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) can also effectively modulate NF-κB signaling thus affecting tumorigenesis. It is noteworthy that several studies have demonstrated that lncRNAs and circRNAs can affect miRNAs in targeting NF-κB activation. They can act as competing endogenous RNA (ceRNA) thereby reducing miRNA expression to induce NF-κB activation that can in turn promote cancer progression and malignancy.
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http://dx.doi.org/10.1016/j.canlet.2021.03.025DOI Listing
July 2021

Biological and Therapeutic Effects of Troxerutin: Molecular Signaling Pathways Come into View.

J Pharmacopuncture 2021 Mar;24(1):1-13

Department of Basic Science, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran.

Flavonoids consist a wide range of naturally occurring compounds which are exclusively found in different fruits and vegetables. These medicinal herbs have a number of favourable biological and therapeutic activities such as antioxidant, neuroprotective, renoprotective, anti-inflammatory, anti-diabetic and anti-tumor. Troxerutin, also known as vitamin P4, is a naturally occurring flavonoid which is isolated from tea, coffee and cereal grains as well as vegetables. It has a variety of valuable pharmacological and therapeutic activities including antioxidant, anti-inflammatory, anti-diabetic and anti-tumor. These pharmacological impacts have been demonstrated in in vitro and in vivo studies. Also, clinical trials have revealed the efficacy of troxerutin for management of phlebocholosis and hemorrhoidal diseases. In the present review, we focus on the therapeutic effects and biological activities of troxerutin as well as its molecular signaling pathways.
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http://dx.doi.org/10.3831/KPI.2021.24.1.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010425PMC
March 2021

A review on chemistry, source and therapeutic potential of lambertianic acid.

Z Naturforsch C J Biosci 2021 Apr 6. Epub 2021 Apr 6.

Department of Botany, University of Barishal, Barishal8200, Bangladesh.

Lambertianic acid (LA) is a diterpene bioactive compound mainly purified from different species of . It is an optical isomer of another natural compound daniellic acid and was firstly purified from . LA can be synthesized in laboratory from podocarpic acid. It has been reported to have potential health benefits in attenuating obesity, allergies and different cancers including breast, liver, lung and prostate cancer. It exhibits anticancer properties through inhibiting cancer cell proliferation and survival, and inducing apoptosis, targeting major signalling components including AKT, AMPK, NFkB, COX-2, STAT3, etc. Most of the studies with LA were done using models, thus warranting future investigations with animal models to evaluate its pharmacological effects such as antidiabetic, anti-inflammatory and neuroprotective effects as well as to explore the underlying molecular mechanisms and toxicological profile. This review describes the chemistry, source, purification and therapeutic potentials of LA and it can therefore be a suitable guideline for any future study with LA.
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http://dx.doi.org/10.1515/znc-2020-0267DOI Listing
April 2021

Quercetin and Its Nano-Scale Delivery Systems in Prostate Cancer Therapy: Paving the Way for Cancer Elimination and Reversing Chemoresistance.

Cancers (Basel) 2021 Mar 31;13(7). Epub 2021 Mar 31.

Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, Italy.

Prostate cancer is the second most leading and prevalent malignancy around the world, following lung cancer. Prostate cancer is characterized by the uncontrolled growth of cells in the prostate gland. Prostate cancer morbidity and mortality have grown drastically, and intensive prostate cancer care is unlikely to produce adequate outcomes. The synthetic drugs for the treatment of prostate cancer in clinical practice face several challenges. Quercetin is a natural flavonoid found in fruits and vegetables. Apart from its beneficial effects, its plays a key role as an anti-cancer agent. Quercetin has shown anticancer potential, both alone and in combination. Therefore, the current study was designed to collect information from the literature regarding its therapeutic significance in the treatment of prostate cancer. Studies performed both in vitro and in vivo have confirmed that quercetin effectively prevents prostate cancer through different underlying mechanisms. Promising findings have also been achieved in clinical trials regarding the pharmacokinetics and human applications of quercetin. In the meantime, epidemiological studies have shown a negative correlation between the consumption of quercetin and the incidence of prostate cancer, and have indicated a chemopreventive effect of quercetin on prostate cancer in animal models. The major issues associated with quercetin are its low bioavailability and rapid metabolism, and these require priority attention. Chemoresistance is another main negative feature concerning prostate cancer treatment. This review highlights the chemotherapeutic effect, chemo preventive effect, and chemoresistance elimination potential of quercetin in prostate cancer. The underlying mechanisms for elimination of prostate cancer and eradication of resistance, either alone or in combination with other agents, are also discussed. In addition, the nanoscale delivery of quercetin is underpinned along with possible directions for future study.
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http://dx.doi.org/10.3390/cancers13071602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036441PMC
March 2021

Employing siRNA tool and its delivery platforms in suppressing cisplatin resistance: Approaching to a new era of cancer chemotherapy.

Life Sci 2021 Mar 28;277:119430. Epub 2021 Mar 28.

Department of Pharmacy, Abdul Wali Khan University, Mardan 23200, Pakistan. Electronic address:

Although chemotherapy is a first option in treatment of cancer patients, drug resistance has led to its failure, requiring strategies to overcome it. Cancer cells are capable of switching among molecular pathways to ensure their proliferation and metastasis, leading to their resistance to chemotherapy. The molecular pathways and mechanisms that are responsible for cancer progression and growth, can be negatively affected for providing chemosensitivity. Small interfering RNA (siRNA) is a powerful tool extensively applied in cancer therapy in both pre-clinical (in vitro and in vivo) and clinical studies because of its potential in suppressing tumor-promoting factors. As such oncogene pathways account for cisplatin (CP) resistance, their targeting by siRNA plays an important role in reversing chemoresistance. In the present review, application of siRNA for suppressing CP resistance is discussed. The first priority of using siRNA is sensitizing cancer cells to CP-mediated apoptosis via down-regulating survivin, ATG7, Bcl-2, Bcl-xl, and XIAP. The cancer stem cell properties and related molecular pathways including ID1, Oct-4 and nanog are inhibited by siRNA in CP sensitivity. Cell cycle arrest and enhanced accumulation of CP in cancer cells can be obtained using siRNA. In overcoming siRNA challenges such as off-targeting feature and degradation, carriers including nanoparticles and biological carriers have been applied. These carriers are important in enhancing cellular accumulation of siRNA, elevating gene silencing efficacy and reversing CP resistance.
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http://dx.doi.org/10.1016/j.lfs.2021.119430DOI Listing
March 2021

Nrf2 signaling pathway in cisplatin chemotherapy: Potential involvement in organ protection and chemoresistance.

Pharmacol Res 2021 May 24;167:105575. Epub 2021 Mar 24.

Medical Technology Research Center, Institute of Health Technology, Kermanashah University of Medical Sciences, Kermanshah 6715847141, Iran; Radiology and Nuclear Medicine Department, School of Paramedical Sciences, Kermanshah University of Medical Sciences, Kermanshah, Iran. Electronic address:

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a vital transcription factor and its induction is of significant importance for protecting against oxidative damage. Increased levels of Reactive Oxygen Species (ROS) stimulate Nrf2 signaling, enhancing the activity of antioxidant enzymes such as catalase, superoxide dismutase and glutathione peroxidase. These enzymes are associated with retarding oxidative stress. On the other hand, Nrf2 activation in cancer cells is responsible for the development of chemoresistance due to disrupting oxidative mediated-cell death by reducing ROS levels. Cisplatin (CP), cis-diamminedichloroplatinum(II), is a potent anti-tumor agent extensively used in cancer therapy, but its frequent application leads to the development of chemoresistance as well. In the present study, association of Nrf2 signaling with chemoresistance to CP and protection against its deleterious effects is discussed. Anti-tumor compounds, mainly phytochemicals, retard chemoresistance by suppressing Nrf2 signaling. Upstream mediators such as microRNAs can regulate Nrf2 expression during CP chemotherapy regimens. Protection against side effects of CP is mediated via activating Nrf2 signaling and its downstream targets activating antioxidant defense system. Protective agents that activate Nrf2 signaling, can ameliorate CP-mediated ototoxicity, nephrotoxicity and neurotoxicity. Reducing ROS levels and preventing cell death are the most important factors involved in alleviating CP toxicity upon Nrf2 activation. As pre-clinical experiments advocate the role of Nrf2 in chemoprotection and CP resistance, translating these findings to the clinic can provide a significant progress in treatment of cancer patients.
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http://dx.doi.org/10.1016/j.phrs.2021.105575DOI Listing
May 2021

Injectable hyaluronic acid-based antibacterial hydrogel adorned with biogenically synthesized AgNPs-decorated multi-walled carbon nanotubes.

Prog Biomater 2021 Mar 26;10(1):77-89. Epub 2021 Mar 26.

Regional Centre of Advanced Technologies and Materials, Palacky University, Slechtitelu 27, 783 71, Olomouc, Czech Republic.

Injectable materials have shown great potential in tissue engineering applications. However, bacterial infection is one of the main challenges in using these materials in the field of regenerative medicine. In this study, biogenically synthesized silver nanoparticle-decorated multi-walled carbon nanotubes (Ag/MWCNTs) were deployed for adorning biogenic-derived AgNPs which were subsequently used in the preparation of thermosensitive hydrogels based on hyaluronic acid encompassing these green-synthesized NPs. The antibacterial capacity of AgNPs decorated on MWCNTs synthesized through Camellia sinensis extract in an organic solvent-free medium displayed a superior activity by inhibiting the growth of Gram-negative (E. coli and Klebsiella) and Gram-positive (S. aureus and E. faecalis). The injectable hydrogel nanocomposites demonstrated good mechanical properties, as well. The thermosensitive hyaluronic acid-based hydrogels also exhibited T below the body temperature, indicating the transition from liquid-like behavior to elastic gel-like behavior. Such a promising injectable nanocomposite could be applied as liquid, pomade, or ointment to enter wound cavities or bone defects and subsequently its transition in situ to gel form at human body temperature bodes well for their immense potential application in the biomedical sector.
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http://dx.doi.org/10.1007/s40204-021-00155-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8021662PMC
March 2021

Long non-coding RNAs in the doxorubicin resistance of cancer cells.

Cancer Lett 2021 Jun 22;508:104-114. Epub 2021 Mar 22.

Department of Science in Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea; KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul 02447, Republic of Korea. Electronic address:

Chemotherapy is the main treatment used for cancer patients failing surgery. Doxorubicin (DOX) is a well-known chemotherapeutic agent capable of suppressing proliferation in cancer cells and triggering apoptosis via inhibiting topoisomerase II activity and producing DNA breaks. This activity of DOX restrains mitosis and cell cycle progression. However, frequent application of DOX results in the emergence of resistance in the cancer cells. It seems that genetic and epigenetic factors can provide DOX resistance of cancer cells. Long non-coding RNAs (lncRNAs) are a subcategory of non-coding RNAs with role in the regulation of several cellular processes such as proliferation, migration, differentiation and apoptosis. LncRNA dysregulation has been associated with chemoresistance, and this profile occurs upon DOX treatment of cancer. In the present review, we focus on the role of lncRNAs in mediating DOX resistance and discuss the molecular pathways and mechanisms. LncRNAs can drive DOX resistance via activating pathways such as NF-κB, PI3K/Akt, Wnt, and FOXC2. Some lncRNAs can activate protective autophagy in response to the stress caused by DOX, which mediates resistance. In contrast, there are other lncRNAs involved in the sensitivity of cancer cells to DOX, such as GAS5, PTCSC3 and FENDRR. Some anti-tumor agents such as polydatin can regulate the expression of lncRNAs, enhancing DOX sensitivity. Overall, lncRNAs are potential players in DOX resistance, and their identification and targeting are of importance in chemosensitivity. Furthermore, these findings can be translated into clinical for treatment of cancer patients.
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http://dx.doi.org/10.1016/j.canlet.2021.03.018DOI Listing
June 2021

Small interfering RNA (siRNA) to target genes and molecular pathways in glioblastoma therapy: Current status with an emphasis on delivery systems.

Life Sci 2021 Jun 16;275:119368. Epub 2021 Mar 16.

Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla, 34956 Istanbul, Turkey. Electronic address:

Glioblastoma multiforme (GBM) is one of the worst brain tumors arising from glial cells, causing many deaths annually. Surgery, chemotherapy, radiotherapy and immunotherapy are used for GBM treatment. However, GBM is still an incurable disease, and new approaches are required for its successful treatment. Because mutations and amplifications occurring in several genes are responsible for the progression and aggressive behavior of GBM cells, genetic approaches are of great importance in its treatment. Small interfering RNA (siRNA) is a new emerging tool to silence the genes responsible for disease progression, particularly cancer. SiRNA can be used for GBM treatment by down-regulating genes such as VEGF, STAT3, ELTD1 or EGFR. Furthermore, the use of siRNA can promote the chemosensitivity of GBM cells. However, the efficiency of siRNA in GBM is limited via its degradation by enzymes, and its off-targeting effects. SiRNA-loaded carriers, especially nanovehicles that are ligand-functionalized by CXCR4 or angiopep-2, can be used for the protection and targeted delivery of siRNA. Nanostructures can provide a platform for co-delivery of siRNA plus anti-tumor drugs as another benefit. The prepared nanovehicles should be stable and biocompatible in order to be tested in human studies.
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http://dx.doi.org/10.1016/j.lfs.2021.119368DOI Listing
June 2021

Biomedical application of chitosan-based nanoscale delivery systems: Potential usefulness in siRNA delivery for cancer therapy.

Carbohydr Polym 2021 May 16;260:117809. Epub 2021 Feb 16.

Regional Center of Advanced Technologies and Materials, Palacky University, Šlechtitelů 27, 783 71 Olomouc, Czech Republic. Electronic address:

Gene therapy is an emerging and promising strategy in cancer therapy where small interfering RNA (siRNA) system has been deployed for down-regulation of targeted gene and subsequent inhibition in cancer progression; some issues with siRNA, however, linger namely, its off-targeting property and degradation by enzymes. Nanoparticles can be applied for the encapsulation of siRNA thus enhancing its efficacy in gene silencing where chitosan (CS), a linear alkaline polysaccharide derived from chitin, with superb properties such as biodegradability, biocompatibility, stability and solubility, can play a vital role. Herein, the potential of CS nanoparticles has been discussed for the delivery of siRNA in cancer therapy; proliferation, metastasis and chemoresistance are suppressed by siRNA-loaded CS nanoparticles, especially the usage of pH-sensitive CS nanoparticles. CS nanoparticles can provide a platform for the co-delivery of siRNA and anti-tumor agents with their enhanced stability via chemical modifications. As pre-clinical experiments are in agreement with potential of CS-based nanoparticles for siRNA delivery, and these carriers possess biocompatibiliy and are safe, further studies can focus on evaluating their utilization in cancer patients.
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http://dx.doi.org/10.1016/j.carbpol.2021.117809DOI Listing
May 2021

Small in Size, but Large in Action: microRNAs as Potential Modulators of PTEN in Breast and Lung Cancers.

Biomolecules 2021 02 18;11(2). Epub 2021 Feb 18.

NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore.

MicroRNAs (miRNAs) are well-known regulators of biological mechanisms with a small size of 19-24 nucleotides and a single-stranded structure. miRNA dysregulation occurs in cancer progression. miRNAs can function as tumor-suppressing or tumor-promoting factors in cancer via regulating molecular pathways. Breast and lung cancers are two malignant thoracic tumors in which the abnormal expression of miRNAs plays a significant role in their development. Phosphatase and tensin homolog (PTEN) is a tumor-suppressor factor that is capable of suppressing the growth, viability, and metastasis of cancer cells via downregulating phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling. PTEN downregulation occurs in lung and breast cancers to promote PI3K/Akt expression, leading to uncontrolled proliferation, metastasis, and their resistance to chemotherapy and radiotherapy. miRNAs as upstream mediators of PTEN can dually induce/inhibit PTEN signaling in affecting the malignant behavior of lung and breast cancer cells. Furthermore, long non-coding RNAs and circular RNAs can regulate the miRNA/PTEN axis in lung and breast cancer cells. It seems that anti-tumor compounds such as baicalein, propofol, and curcumin can induce PTEN upregulation by affecting miRNAs in suppressing breast and lung cancer progression. These topics are discussed in the current review with a focus on molecular pathways.
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http://dx.doi.org/10.3390/biom11020304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7922700PMC
February 2021

Flavonoids against the SARS-CoV-2 induced inflammatory storm.

Biomed Pharmacother 2021 Jun 25;138:111430. Epub 2021 Feb 25.

Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia. Electronic address:

The disease severity of COVID-19, especially in the elderly and patients with co-morbidities, is characterized by hypercytokinemia, an exaggerated immune response associated with an uncontrolled and excessive release of proinflammatory cytokine mediators (cytokine storm). Flavonoids, important secondary metabolites of plants, have long been studied as therapeutic interventions in inflammatory diseases due to their cytokine-modulatory effects. In this review, we discuss the potential role of flavonoids in the modulation of signaling pathways that are crucial for COVID-19 disease, particularly those related to inflammation and immunity. The immunomodulatory ability of flavonoids, carried out by the regulation of inflammatory mediators, the inhibition of endothelial activation, NLRP3 inflammasome, toll-like receptors (TLRs) or bromodomain containing protein 4 (BRD4), and the activation of the nuclear factor erythroid-derived 2-related factor 2 (Nrf2), might be beneficial in regulating the cytokine storm during SARS-CoV-2 infection. Moreover, the ability of flavonoids to inhibit dipeptidyl peptidase 4 (DPP4), neutralize 3-chymotrypsin-like protease (3CL) or to affect gut microbiota to maintain immune response, and the dual action of angiotensin-converting enzyme 2 (ACE-2) may potentially also be applied to the exaggerated inflammatory responses induced by SARS-CoV-2. Based on the previously proven effects of flavonoids in other diseases or on the basis of newly published studies associated with COVID-19 (bioinformatics, molecular docking), it is reasonable to assume positive effects of flavonoids on inflammatory changes associated with COVID-19. This review highlights the current state of knowledge of the utility of flavonoids in the management of COVID-19 and also points to the multiple biological effects of flavonoids on signaling pathways associated with the inflammation processes that are deregulated in the pathology induced by SARS-CoV-2. The identification of agents, including naturally occurring substances such as flavonoids, represents great approach potentially utilizable in the management of COVID-19. Although not clinically investigated yet, the applicability of flavonoids against COVID-19 could be a promising strategy due to a broad spectrum of their biological activities.
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http://dx.doi.org/10.1016/j.biopha.2021.111430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906511PMC
June 2021

The role of SOX family transcription factors in gastric cancer.

Int J Biol Macromol 2021 Mar 1;180:608-624. Epub 2021 Mar 1.

Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein 2028, South Africa. Electronic address:

Gastric cancer (GC) is a leading cause of death worldwide. GC is the third-most common cause of cancer-related death after lung and colorectal cancer. It is also the fifth-most commonly diagnosed cancer. Accumulating evidence has revealed the role of signaling networks in GC progression. Identification of these molecular pathways can provide new insight into therapeutic approaches for GC. Several molecular factors involved in GC can play both onco-suppressor and oncogene roles. Sex-determining region Y (Sry)-box-containing (SOX) family members are transcription factors with a well-known role in cancer. SOX proteins can bind to DNA to regulate cellular pathways via a highly conserved domain known as high mobility group (HMG). In the present review, the roles of SOX proteins in the progression and/or inhibition of GC are discussed. The dual role of SOX proteins as tumor-promoting and tumor-suppressing factors is highlighted. SOX members can affect upstream mediators (microRNAs, long non-coding RNAs and NF-κB) and down-stream mediators (FAK, HIF-1α, CDX2 and PTEN) in GC. The possible role of anti-tumor compounds to target SOX pathway members in GC therapy is described. Moreover, SOX proteins may be used as diagnostic or prognostic biomarkers in GC.
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http://dx.doi.org/10.1016/j.ijbiomac.2021.02.202DOI Listing
March 2021

Nrf2 Signaling Pathway in Chemoprotection and Doxorubicin Resistance: Potential Application in Drug Discovery.

Antioxidants (Basel) 2021 Feb 26;10(3). Epub 2021 Feb 26.

Cancer Science Institute of Singapore, Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore.

Doxorubicin (DOX) is extensively applied in cancer therapy due to its efficacy in suppressing cancer progression and inducing apoptosis. After its discovery, this chemotherapeutic agent has been frequently used for cancer therapy, leading to chemoresistance. Due to dose-dependent toxicity, high concentrations of DOX cannot be administered to cancer patients. Therefore, experiments have been directed towards revealing underlying mechanisms responsible for DOX resistance and ameliorating its adverse effects. Nuclear factor erythroid 2-related factor 2 (Nrf2) signaling is activated to increase levels of reactive oxygen species (ROS) in cells to protect them against oxidative stress. It has been reported that Nrf2 activation is associated with drug resistance. In cells exposed to DOX, stimulation of Nrf2 signaling protects cells against cell death. Various upstream mediators regulate Nrf2 in DOX resistance. Strategies, both pharmacological and genetic interventions, have been applied for reversing DOX resistance. However, Nrf2 induction is of importance for alleviating side effects of DOX. Pharmacological agents with naturally occurring compounds as the most common have been used for inducing Nrf2 signaling in DOX amelioration. Furthermore, signaling networks in which Nrf2 is a key player for protection against DOX adverse effects have been revealed and are discussed in the current review.
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http://dx.doi.org/10.3390/antiox10030349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996755PMC
February 2021

Anti-Inflammatory Activity of Melatonin: a Focus on the Role of NLRP3 Inflammasome.

Inflammation 2021 Mar 2. Epub 2021 Mar 2.

Noncommunicable Diseases Research Center, Neyshabur University of Medical Sciences, Neyshabur, Iran.

Melatonin is a hormone of the pineal gland that contributes to the regulation of physiological activities, such as sleep, circadian rhythm, and neuroendocrine processes. Melatonin is found in several plants and has pharmacological activities including antioxidant, anti-inflammatory, hepatoprotective, cardioprotective, and neuroprotective. It also has shown therapeutic efficacy in treatment of cancer and diabetes. Melatonin affects several molecular pathways to exert its protective effects. The NLRP3 inflammasome is considered a novel target of melatonin. This inflammasome contributes to enhanced level of IL-1β, caspase-1 activation, and pyroptosis stimulation. The function of NLRP3 inflammasome has been explored in various diseases, including cancer, diabetes, and neurological disorders. By inhibiting NLRP3, melatonin diminishes inflammation and influences various molecular pathways, such as SIRT1, microRNA, long non-coding RNA, and Wnt/β-catenin. Here, we discuss these molecular pathways and suggest that melatonin-induced inhibition of NLRP3 should be advanced in disease therapy.
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http://dx.doi.org/10.1007/s10753-021-01428-9DOI Listing
March 2021

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition).

Autophagy 2021 Jan 8;17(1):1-382. Epub 2021 Feb 8.

University of Crete, School of Medicine, Laboratory of Clinical Microbiology and Microbial Pathogenesis, Voutes, Heraklion, Crete, Greece; Foundation for Research and Technology, Institute of Molecular Biology and Biotechnology (IMBB), Heraklion, Crete, Greece.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
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http://dx.doi.org/10.1080/15548627.2020.1797280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996087PMC
January 2021

Curcumin Efficacy in a Serum/glucose Deprivation-induced Neuronal PC12 Injury Model.

Curr Mol Pharmacol 2021 Feb 3. Epub 2021 Feb 3.

Noncommunicable Diseases Research Center, Neyshabur University of Medical Sciences, Neyshabur, . Iran.

Background: Glucose/serum deprivation (GSD), has been used for understanding molecular mechanisms of neuronal damage during ischemia. It has been suggested that curcumin may improve neurodegenerative diseases.

Aim: In this study, the protective effects of curcumin and its underlying mechanisms were investigated in PC12 cells upon GSD-induced stress.

Methods: PC12 cells were cultured in DMEM overnight and then incubated in GSD condition for either 6 or 12h. GSD-treated cells were pretreated with various concentrations of curcumin (10, 20, and 40 M) for 5h. The cell viability, apoptosis, reactive oxygen species (ROS) level, oxidative stress, expression of apoptosis-related genes, and IL-6 were determined.

Results: Curcumin increased cell viability and caused an anti-apoptotic effect in PC12 cells exposed for 12h to GSD . Curcumin also increased antioxidant enzyme expression, suppressed lipid peroxidation, and decreased interleukin-6 secretion in PC12 cells subjected to GSD. In addition, pretreatment with curcumin down-regulated pro-apoptotic (Bax), and up-regulated antiapoptotic (Bcl2) mediators.

Conclusion: Curcumin mitigates many of the adverse effects of ischemia, and therefore, should be considered as an adjunct therapy in ischemic patients.
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http://dx.doi.org/10.2174/1874467214666210203211312DOI Listing
February 2021

Crosstalk of long non-coding RNAs and EMT: Searching the missing pieces of an incomplete puzzle for lung cancer therapy.

Curr Cancer Drug Targets 2021 Feb 2. Epub 2021 Feb 2.

Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla, 34956, Istanbul. Turkey.

Background: Lung cancer is considered to be the first place among the cancer-related deaths worldwide and demands novel strategies in the treatment of this life-threatening disorder. The aim of this review is to explore regulation of epithelial-to-mesenchymal transition (EMT) by long non-coding RNAs (lncRNAs) in lung cancer.

Introduction: LncRNAs can be considered as potential factors for targeting in cancer therapy, since they regulate a bunch of biological processes, e.g. cell proliferation, differentiation and apoptosis. The abnormal expression of lncRNAs occurs in different cancer cells. On the other hand, epithelial-to-mesenchymal transition (EMT) is a critical mechanism participating in migration and metastasis of cancer cells.

Method: Different databases including Googlescholar, Pubmed and Sciencedirect were used for collecting articles using keywords such as "LncRNA", "EMT", and "Lung cancer".

Result: There are tumor-suppressing lncRNAs that can suppress EMT and metastasis of lung cancer cells. Expression of such lncRNAs undergoes down-regulation in lung cancer progression and restoring their expression is of importance in suppressing lung cancer migration. There are tumor-promoting lncRNAs triggering EMT in lung cancer and enhancing their migration.

Conclusion: LncRNAs are potential regulators of EMT in lung cancer, and targeting them, both pharmacologically and genetically, can be of importance in controlling migration of lung cancer cells.
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http://dx.doi.org/10.2174/1568009621666210203110305DOI Listing
February 2021

Recent advances and future directions in anti-tumor activity of cryptotanshinone: A mechanistic review.

Phytother Res 2021 Jan 10;35(1):155-179. Epub 2020 Aug 10.

Radiology and Nuclear Medicine Department, School of Paramedical Sciences, Kermanshah University of Medical Sciences, Kermanshah, Iran.

In respect to the enhanced incidence rate of cancer worldwide, studies have focused on cancer therapy using novel strategies. Chemotherapy is a common strategy in cancer therapy, but its adverse effects and chemoresistance have limited its efficacy. So, attempts have been directed towards minimally invasive cancer therapy using plant derived-natural compounds. Cryptotanshinone (CT) is a component of salvia miltiorrihiza Bunge, well-known as Danshen and has a variety of therapeutic and biological activities such as antioxidant, anti-inflammatory, anti-diabetic and neuroprotective. Recently, studies have focused on anti-tumor activity of CT against different cancers. Notably, this herbal compound is efficient in cancer therapy by targeting various molecular signaling pathways. In the present review, we mechanistically describe the anti-tumor activity of CT with an emphasis on molecular signaling pathways. Then, we evaluate the potential of CT in cancer immunotherapy and enhancing the efficacy of chemotherapy by sensitizing cancer cells into anti-tumor activity of chemotherapeutic agents, and elevating accumulation of anti-tumor drugs in cancer cells. Finally, we mention strategies to enhance the anti-tumor activity of CT, for instance, using nanoparticles to provide targeted drug delivery.
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http://dx.doi.org/10.1002/ptr.6815DOI Listing
January 2021

Novel strategy in breast cancer therapy: Revealing the bright side of ginsenosides.

Curr Mol Pharmacol 2021 Jan 20. Epub 2021 Jan 20.

Department of Pharmacy, Abdul Wali Khan University, Mardan, 23200. Pakistan.

Breast cancer is one of the leading causes of death worldwide. Breast cancer cells demonstrate uncontrolled proliferation, and high metastatic capacity. They can obtain resistance to chemotherapy and radiotherapy. This has resulted in troublesome problems in its treatment. Nature as a rich source of plant derived-natural products with anti-tumor activity can be of interest in breast cancer therapy. Ginsenosides are triterpenoid saponins and considered as secondary metabolites exclusively found in Panax species. From immemorial times, ginsenosides have been applied in treatment of various disorders such as diabetes, inflammatory diseases, neurological disorders, and particularly, cancer. In the present review, we highlight anti-tumor activity of ginsenosides against breast cancer cells. Ginsenosides are able to induce apoptosis and cell cycle arrest. They interfere with breast cancer metastasis via inhibiting epithelial-to-mesenchymal transition, matrix metalloproteinase proteins and angiogenesis. Ginsenosides can promote efficacy of chemotherapy via suppressing migration and proliferation. Molecular pathways such as phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt), insulin-like growth factor-1, Wnt, microRNAs and long non-coding RNAs are affected by ginsenosides in suppressing breast cancer malignancy. Consequently, ginsenosides are versatile compounds in breast cancer therapy by suppressing growth, and invasion, as well as promoting their sensitivity to chemotherapy.
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http://dx.doi.org/10.2174/1874467214666210120153348DOI Listing
January 2021

Anti-tumor activity of resveratrol against gastric cancer: a review of recent advances with an emphasis on molecular pathways.

Cancer Cell Int 2021 Jan 21;21(1):66. Epub 2021 Jan 21.

Noncommunicable Diseases Research Center, Neyshabur University of Medical Sciences, Neyshabur, 9318614139, Iran.

Gastric cancer (GC) is one of the most common cancers with high malignancy. In spite of the great development in diagnostic tools and application of anti-tumor drugs, we have not witnessed a significant increase in the survival time of patients with GC. Multiple studies have revealed that Wnt, Nrf2, MAPK, and PI3K/Akt signaling pathways are involved in GC invasion. Besides, long non-coding RNAs and microRNAs function as upstream mediators in GC malignancy. GC cells have acquired resistance to currently applied anti-tumor drugs. Besides, combination therapy is associated with higher anti-tumor activity. Resveratrol (Res) is a non-flavonoid polyphenol with high anti-tumor activity used in treatment of various cancers. A number of studies have demonstrated the potential of Res in regulation of molecular pathways involved in cancer malignancy. At the present review, we show that Res targets a variety of signaling pathways to induce apoptotic cell death and simultaneously, to inhibit the migration and metastasis of GC cells.
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http://dx.doi.org/10.1186/s12935-021-01773-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818776PMC
January 2021

Curcumin and cardiovascular diseases: Focus on cellular targets and cascades.

Biomed Pharmacother 2021 Apr 12;136:111214. Epub 2021 Jan 12.

Noncommunicable Diseases Research Center, Neyshabur University of Medical Sciences, Neyshabur, Iran. Electronic address:

Cardiovascular diseases (CVDs) are one of the leading causes of the most considerable mortality globally, and it has been tried to find the molecular mechanisms and design new drugs that triggered the molecular target. Curcumin is the main ingredient of Curcuma longa (turmeric) that has been used in traditional medicine for treating several diseases for years. Numerous investigations have indicated the beneficial effect of Curcumin in modulating multiple signaling pathways involved in oxidative stress, inflammation, apoptosis, and proliferation. The cardiovascular protective effects of Curcumin against CVDs have been indicated in several studies. In the current review study, we provided novel information on Curcumin's protective effects against various CVDs and potential molecular signaling targets of Curcumin. Nonetheless, more studies should be performed to discover the exact molecular target of Curcumin against CVDs.
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http://dx.doi.org/10.1016/j.biopha.2020.111214DOI Listing
April 2021

The role of microRNA-338-3p in cancer: growth, invasion, chemoresistance, and mediators.

Life Sci 2021 Mar 6;268:119005. Epub 2021 Jan 6.

Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein 2028, South Africa. Electronic address:

Cancer still remains as one of the leading causes of death worldwide. Metastasis and proliferation are abnormally increased in cancer cells that subsequently, mediate resistance of cancer cells to different therapies such as radio-, chemo- and immune-therapy. MicroRNAs (miRNAs) are endogenous short non-coding RNAs that can regulate expression of target genes at post-transcriptional level and capable of interaction with mRNA-coding genes. Vital biological mechanisms including apoptosis, migration and differentiation are modulated by these small molecules. MiRNAs are key players in regulating cancer proliferation and metastasis as well as cancer therapy response. MiRNAs can function as both tumor-suppressing and tumor-promoting factors. In the present review, regulatory impact of miRNA-338-3p on cancer growth and migration is discussed. This new emerging miRNA can regulate response of cancer cells to chemotherapy and radiotherapy. It seems that miRNA-338-3p has dual role in cancer chemotherapy, acting as tumor-promoting or tumor-suppressor factor. Experiments reveal anti-tumor activity of miRNA-338-3p in cancer. Hence, increasing miRNA-338-3p expression is of importance in effective cancer therapy. Long non-coding RNAs, circular RNAs and hypoxia are potential upstream mediators of miRNA-338-3p in cancer. Anti-tumor agents including baicalin and arbutin can promote expression of miRNA-338-3p in suppressing cancer progression. These topics are discussed to shed some light on function of miRNA-338-3p in cancer cells.
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http://dx.doi.org/10.1016/j.lfs.2020.119005DOI Listing
March 2021

Dual relationship between long non-coding RNAs and STAT3 signaling in different cancers: New insight to proliferation and metastasis.

Life Sci 2021 Apr 6;270:119006. Epub 2021 Jan 6.

Department of Pharmacy, Abdul Wali Khan University, Mardan 23200, Pakistan. Electronic address:

Uncontrolled growth and metastasis of cancer cells is an increasing challenge for overcoming cancer, and improving survival of patients. Complicated signaling networks account for proliferation and invasion of cancer cells that need to be elucidated for providing effective cancer therapy, and minimizing their malignancy. Long non-coding RNAs (lncRNAs) are RNA molecules with a length of more than 200 nucleotides. They participate in cellular events, and their dysregulation in a common phenomenon in different cancers. Noteworthy, lncRNAs can regulate different molecular pathways, and signal transducer and activator of transcription 3 (STAT3) is one of them. STAT3 is a tumor-promoting factors in cancers due to its role in cancer proliferation (cell cycle progression and apoptosis inhibition) and metastasis (EMT induction). LncRNAs can function as upstream mediators of STAT3 pathway, reducing/enhancing its expression. This dual relationship is of importance in affecting proliferation and metastasis of cancer cells. The response of cancer cells to therapy such as chemotherapy and radiotherapy is regulated by lncRNA/STAT3 axis. Tumor-promoting lncRNAs including NEAT1, SNHG3 and H19 induces STAT3 expression, while tumor-suppressing lncRNAs such as MEG3, PTCSC3 and NKILA down-regulate STAT3 expression. Noteworthy, upstream mediators of STAT3 such as microRNAs can be regulated by lncRNAs. These complicated signaling networks are mechanistically described in the current review.
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http://dx.doi.org/10.1016/j.lfs.2020.119006DOI Listing
April 2021

Flavonoids Targeting HIF-1: Implications on Cancer Metabolism.

Cancers (Basel) 2021 Jan 3;13(1). Epub 2021 Jan 3.

Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia.

Tumor hypoxia is described as an oxygen deprivation in malignant tissue. The hypoxic condition is a consequence of an imbalance between rapidly proliferating cells and a vascularization that leads to lower oxygen levels in tumors. Hypoxia-inducible factor 1 (HIF-1) is an essential transcription factor contributing to the regulation of hypoxia-associated genes. Some of these genes modulate molecular cascades associated with the Warburg effect and its accompanying pathways and, therefore, represent promising targets for cancer treatment. Current progress in the development of therapeutic approaches brings several promising inhibitors of HIF-1. Flavonoids, widely occurring in various plants, exert a broad spectrum of beneficial effects on human health, and are potentially powerful therapeutic tools against cancer. Recent evidences identified numerous natural flavonoids and their derivatives as inhibitors of HIF-1, associated with the regulation of critical glycolytic components in cancer cells, including pyruvate kinase M2(PKM2), lactate dehydrogenase (LDHA), glucose transporters (GLUTs), hexokinase II (HKII), phosphofructokinase-1 (PFK-1), and pyruvate dehydrogenase kinase (PDK). Here, we discuss the results of most recent studies evaluating the impact of flavonoids on HIF-1 accompanied by the regulation of critical enzymes contributing to the Warburg phenotype. Besides, flavonoid effects on glucose metabolism via regulation of HIF-1 activity represent a promising avenue in cancer-related research. At the same time, only more-in depth investigations can further elucidate the mechanistic and clinical connections between HIF-1 and cancer metabolism.
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http://dx.doi.org/10.3390/cancers13010130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794792PMC
January 2021

Artemisia species as a new candidate for Diabetes therapy: A Comprehensive Review.

Curr Mol Med 2021 Jan 1. Epub 2021 Jan 1.

Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan,. Iran.

Diabetes mellitus (DM) is a chronic disease and threatening problem for world health. Allopathic medications are not efficient enough in controlling DM and its complications. Therefore, much attention has been directed towards the traditional medicine system. Plant derived-natural compounds with medicinal properties play an essential role in DM management and treatment. Artemisia is a varied and widespread genus of the family Asteraceae, which has more than 500 species with beneficial economic and therapeutic significance. Electronic databases such as Science Direct, Scopus, Pubmed, Web of Science, medRixv and Wiley were used to search scientific literatures. In folklore medicine, Artemisia species have been widely utilized for diabetes management. Molecular investigations have revealed that the NF-κB suppression, Notch 1 inhibition, cell cycle stop at S+G2/M-phase, enhanced Bax protein concentrations, mitochondrial membrane potential attenuation, activation of p53 and caspase, Bcl-2 regulation, and ROS formation are crucial mechanisms that could be targeted via various Artemisia species. Anti-diabetic effects of single or multiple doses of alcoholic and aqueous extracts of Artemisia species are due to presence of bioactive compounds, and they are completely efficient in lowering levels of blood glucose in experimental examinations. In spite of available anti-diabetic drugs, therapeutic agents obtained from mentioned plants have been used for the treatment of this disease and its complications with less adverse impacts. Taken together, multiple line of evidences indicated that Artemisia species could be introduced as potential therapeutic candidate in the treatment and management of diabetes.
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http://dx.doi.org/10.2174/1566524020999210101234317DOI Listing
January 2021