Andrographolide reverts multidrug resistance in KBChR 8-5 cells through AKT signaling pathway.

Multidrug resistance (MDR) is a major obstacle in cancer chemotherapy. P-glycoprotein (P-gp) one of the ATP-binding cassette (ABC) transporters plays an important role in MDR. In this study, we examined the sensitizing property of andrographolide (Andro) to reverse MDR in the drug-resistant KBChR 8-5 cells. Andro exhibited increased cytotoxicity in a concentration-dependent manner in the P-gp overexpressing KBChR 8-5 cells. Furthermore, Andro showed synergistic interactions with PTX and DOX in this drug-resistant cells. Andro co-administration enhanced PTX- and DOX-induced cytotoxicity and reduced cell proliferation in the MDR cancer cells. Moreover, reactive oxygen species (ROS) were elevated with a decrease in the mitochondrial membrane potential (MMP) during Andro and chemotherapeutic drugs combination treatment in the drug-resistant cells. Furthermore, Andro and PTX-induced cell cycle arrest was observed in the drug-resistant cell. We also noticed that the expression of ABCB1 and AKT were downregulated during Andro (4 µM) treatment. Furthermore, Andro treatment enhanced the expression of caspase 3 and caspase 9 in the combinational groups that support the enhanced apoptotic cell death in drug-resistant cancer cells. Therefore, the results reveal that Andro plays a role in the reversal of P-gp-mediated MDR in KBChR 8-5 cells which might be due to regulating ABCB1/AKT signaling pathway.

Natural medicinal compounds target signal transduction pathways to overcome ABC drug efflux transporter-mediated multidrug resistance in cancer.

ATP-binding cassette (ABC) transporters such as ABCB1, ABCG2, and ABCC1 are the major players in drug efflux-mediated multidrug resistance (MDR), which severely affects the efficacy of chemotherapy. Several synthetic compounds block the drug transport by ABC transporters; however, they exhibit a narrow therapeutic window, and produce side effects in non-target normal tissues. Conversely, the downregulation of the expression of ABC drug transporters seems to be a promising strategy to reverse MDR in cancer cells. Several signaling pathways, such as NF-κB, STAT3, Gli, NICD, YAP/TAZ, and Nrf2 upregulate the expression of ABC drug transporters in drug-resistant cancers. Recently, natural medicinal compounds have gained importance to overcome the ABC drug-efflux pump-mediated MDR in cancer. These compounds target transcription factors and the associated signal transduction pathways, thereby downregulating the expression of ABC transporters in drug-resistant cancer cells. Several potent natural compounds have been identified as lead candidates to synergistically enhance chemotherapeutic efficacy, and a few of them are already in clinical trials. Therefore, modulation of signal transduction pathways using natural medicinal compounds for the reversal of ABC drug transporter-mediated MDR in cancer is a novel approach for improving the efficiency of the existing chemotherapeutics. In this review, we discuss the modulatory role of natural medicinal compounds on cellular signaling pathways that regulate the expression of ABC transporters in drug-resistant cancer cells.

Antiproliferative effect of Solanum nigrum L. water extract on breast can-cer cells: potential roles of apoptosis and oxidative stress.

Breast cancer is the most progressive cancer among women worldwide. The currently available chemotherapeutic agents induce severe unacceptable adverse effects in breast cancer patients. In this context, natural medicinal herbs are gaining importance to find non-toxic effective anticancer drugs. Solanum nigrum is one of the major traditional medicinal plants widely used in Ayurveda for the treatment of various diseases. This study investigated the anticancer effect of Solanum nigrum water extract (SNWE) against MCF-7 and triple-negative MDA-MB-231 breast cancer cell lines. SNWE significantly induced oxidative stress-mediated apoptotic cell death in a concentration-dependent manner. Real-time PCR results illustrated the upregulation of proapoptotic genes and downregulation of antiapoptotic genes after SNWE treatment in MCF-7 and MDA-MB-231 cell lines. Immunofluorescence analysis showed increased expressions of apoptotic markers like p53, Caspase3 and BAX by SNWE treatment. In conclusion, the findings of this study indicate the antiproliferative effect and apoptosis-inducing property of SNWE in both cell lines. Further studies are warranted on testing the anticancer activity of S. nigrum L. using animal models of cancer.

Preventive effect of andrographolide against ultraviolet-B radiation-induced oxidative stress and apoptotic signaling in human dermal fibroblasts.

Ultraviolet radiation induces oxidative photoaging in the skin cells. In this study, we investigated the ability of andrographolide (ADP) to protect human dermal fibroblasts (HDFa) from UVB radiation-induced oxidative stress and apoptosis. The HDFa cells were exposed to UVB (19.8 mJ/cm2 ) radiation in the presence or absence of ADP (7 µM) and then oxidative stress and apoptotic protein expression were analyzed. UVB exposure resulted in a significant decline in the activity of antioxidant enzymes and altered mitochondrial membrane potential (MMP). Furthermore, UVB-irradiation causes increased intracellular reactive oxygen species (ROS) production, apoptotic morphological changes, and lipid peroxidation levels in the HDFa. Moreover, the pretreatment with ADP reduced the UVB-induced cytotoxicity, ROS production, and increased antioxidant enzymes activity. Further, the ADP pretreatment prevents the UVB-induced loss of MMP and apoptotic signaling in HDFa cells. Therefore, the present results suggest that ADP protects HDFa cells from UVB-induced oxidative stress and apoptotic damage.

Auranofin sensitizes breast cancer cells to paclitaxel chemotherapy by disturbing the cellular redox system.

The intrinsic redox status of cancer cells limits the efficacy of chemotherapeutic drugs. Auranofin, a Food and Drug Administration-approved gold-containing compound, documented with effective pharmacokinetics and safety profiles in humans, has recently been repurposed for anticancer activity. This study examined the paclitaxel-sensitizing effect of auranofin by targeting redox balance in the MDA-MB-231 and MCF-7 breast cancer cell lines. Auranofin treatment depletes the activities of superoxide dismutase, catalase, and glutathione peroxidase and alters the redox ratio in the breast cancer cell lines. Furthermore, it has been noticed that auranofin augmented paclitaxel-mediated cytotoxicity in a concentration-dependent manner in both MDA-MB-231 and MCF-7 cell lines. Moreover, auranofin increased the levels of intracellular reactive oxygen species (observed using 2, 7-diacetyl dichlorofluorescein diacetate staining) and subsequently altered the mitochondrial membrane potential (rhodamine-123 staining) in a concentration-dependent manner. Further, the expression of apoptotic marker p21 was found to be higher in auranofin plus paclitaxel-treated breast cancer cells compared to paclitaxel-alone treatment. Thus, the present results illustrate the chemosensitizing property of auranofin in MDA-MB-231 and MCF-7 breast cancer cell lines via oxidative metabolism. Therefore, auranofin could be considered a chemosensitizing agent during cancer chemotherapy.

The regulation of necroptosis and perspectives for the development of new drugs preventing ischemic/reperfusion of cardiac injury.

In the last 10 years, mortality from acute myocardial infarction (AMI) has not significantly decreased. This situation is associated with the absence in clinical practice of highly effective drugs capable of preventing the occurrence of reperfusion injury of the heart. Necroptosis inhibitors may become prototypes for the creation of highly effective drugs that increase cardiac tolerance to ischemic/reperfusion (I/R) and reduce the mortality rate in patients with AMI. Necroptosis is involved in I/R cardiac injury and inhibition of RIPK1 or RIPK3 contributes to an increase in cardiac tolerance to I/R. Necroptosis could also be involved in the development of adverse remodeling of the heart. It is unclear whether pre- and postconditioning could inhibit necroptosis of cardiomyocytes and endothelial cells. The role of necroptosis in coronary microvascular obstruction and the no-reflow phenomenon also needs to be studied. MicroRNAs and LncRNAs can regulate necroptotic cell death. Ca2+ overload and reactive oxygen species could be the triggers of necroptosis. Activation of kinases (p38, JNK1, Akt, and mTOR) could promote necroptotic cell death. The interaction of necroptosis, apoptosis, autophagy, ferroptosis, and pyroptosis is discussed. The water-soluble necroptosis inhibitors may be highly effective drugs for treatment of AMI or stroke. It is possible that microRNAs may become the basis for creating drugs for treatment of diseases triggered by I/R of organs.

The preventive effect of linalool on acute and chronic UVB-mediated skin carcinogenesis in Swiss albino mice.

In this study, we evaluated the role of linalool in acute ultraviolet-B (UVB; 280-320 nm) radiation-induced inflammation and chronic UVB-mediated photocarcinogenesis in mouse skin. Acute UVB-irradiation (180 mJ cm(-2)) causes hyperplasia, edema formation, lipid peroxidation, antioxidant depletion, and overexpression of cyclooxygenase-2 (COX-2) and ornithine decarboxylase (ODC) in mouse skin. Topical or intraperitoneal (i.p.) treatment of linalool prevented acute UVB-induced hyperplasia, edema formation, lipid peroxidation, and antioxidant depletion in mouse skin. Further, linalool treatment prevented UVB-induced overexpression of COX-2 and ODC in mouse skin. In the chronic study, mice were subjected to UVB-exposure thrice weekly for 30 weeks. Chronic UVB-exposure induced tumor incidence and expression of proliferative markers such as NF-κB, TNF-α, IL-6, COX-2, VEGF, TGF-ß1, Bcl-2 and mutated p53 in mouse skin. Treatment with linalool before each UVB-exposure significantly prevented the expression of these proliferative markers and subsequently decreased the tumor incidence in mice skin. Histopathological studies confirmed the development of dysplasia and squamous cell carcinoma (SCC) in the chronic UVB-exposed mouse skin; and this was prevented by both topical and i.p. linalool treatment. Therefore, linalool may be considered as a photochemopreventive agent against UVB radiation induced skin carcinogenesis.

Synthesis of a Novel Gold(I) Complex and Evaluation of Its Anticancer Properties in Breast Cancer Cells.

BACKGROUND: Platinum complexes are commonly used for cancer chemotherapy; however, they are not only highly-priced but also have various side effects. It is, therefore, important to design affordable anticancer drugs with minimal side effects. METHODS: We synthesized a new gold(I) complex, PF6{(BDPEA)(TPPMS) digold(I)} (abbreviated as PBTDG) and tested its cytotoxicity in MCF-7 breast cancer cells. We also evaluated the effects of PBTDG on mitochondrial membrane potential, generation of reactive oxygen species (ROS) and apoptosis in breast cancer cells. RESULTS: The IC50 values for PBTDG and sorafenib were found to be 1.48 µM and 4.45 µM, respectively. Exposure to PBTDG caused significant and concentration-dependent depletion of ATP and disruption of mitochondrial membrane potential. PBTDG induced 2.6, 3.6, and 5.7-fold apoptosis for 1 µM, 3 µM, and 10 µM concentrations, respectively. The induction of apoptosis by the same concentrations of sorafenib was 1.2, 1.3, and 1.6-fold, respectively. The low concentration of PBTDG (1 µM) induced the generation of ROS by 99.83%, which was significantly higher than the ROS generation caused by the same concentration of sorafenib (73.76%). The ROS induction caused by higher concentrations (5 µM) of PBTDG and sorafenib were 104.95% and 122.11%, respectively. CONCLUSION: The lower concentration of PBTDG produced similar cytotoxicity and apoptotic effects that were caused by a comparatively higher concentration of known anticancer drug (sorafenib). The anticancer effects of PBTDG are attributed to its tendency to disrupt mitochondrial membrane potential, induction of apoptosis and generation of ROS. Further studies are warranted to test the anticancer effects of PBTDG in animal models of cancer.

Effect of Cold Adaptation on the State of Cardiovascular System and Cardiac Tolerance to Ischemia/Reperfusion Injury.

Despite the unconditional success achieved in the treatment and prevention of AMI over the past 40 years, mortality in this disease remains high. Hence, it is necessary to develop novel drugs with mechanism of action different from those currently used in clinical practices. Studying the molecular mechanisms involved in the cardioprotective effect of adapting to cold could contribute to the development of drugs that increase cardiac tolerance to the impact of ischemia/reperfusion. An analysis of the published data shows that the long-term human stay in the Far North contributes to the occurrence of cardiovascular diseases. At the same time, chronic and continuous exposure to cold increases tolerance of the rat heart to ischemia/ reperfusion. It has been demonstrated that the cardioprotective effect of cold adaptation depends on the activation of ROS production, stimulation of the ß2-adrenergic receptor and protein kinase C, MPT pore closing, and KATP channel.

Dysprosium-containing cobalt sulfide nanoparticles as anticancer drug carriers.

BACKGROUND: Among various materials designed for anticancer drug transport, sulfide nanoparticles are uniquely intriguing owing to their spectral characteristics. Exploration of newer nanoscale copper sulfide particles with dysprosium doping is reported herein. It leads to a change in the physicochemical properties of the sulfide nanoparticles and hence the difference in drug release and cytotoxicity. OBJECTIVE: We intend to purport the suitably engineered cobalt sulfide and dysprosium-doped cobalt sulfide nanoparticles that are magnetic and NIR-absorbing, as drug delivery vehicles. The drug loading and release are based on the supramolecular drug complex formation on the surface of the nanoparticles. METHOD: The nanomaterials are synthesized employing hydrothermal procedures, coated with a biocompatible poly-ß-cyclodextrin, and characterized using the methods of diffractometry, microscopy, spectroscopy, thermogravimetry and magnetometry. The sustained drug release is investigated in vitro. 5-Fluorouracil is loaded in the nanocarriers. The empty and 5-fluorouracil-loaded nanocarriers are screened for their anti-breast cancer activity in vitro on MCF-7 cells. RESULTS: The size of the nanoparticles is below 10 nm. They show soft ferromagnetic characteristics. Further, they show broad NIR absorption bands extending up to 1200 nm, with the dysprosium-doped material displaying greater absorbance. The drug 5-fluorouracil is encapsulated in the nanocarriers and released sustainably, with the expulsion duration extending over 10 days. The IC50 of the blank and the drug-loaded cobalt sulfide are 16.24 ± 3.6 and 12.2 ± 2.6 µg mL-1, respectively. For the drug-loaded, dysprosium-doped nanocarrier, the IC50 value is 9.7 ± 0.3 µg mL-1. CONCLUSION: The ultrasmall nanoparticles possess a size suitable for drug delivery and are dispersed well in the aqueous medium. The release of the loaded 5-fluorouracil is slow and sustained. The anticancer activity of the drug-loaded nanocarrier shows an increase in efficacy, and the cytotoxicity is appreciable due to the controlled release. The nanocarriers show multi-functional characteristics, i.e., magnetic and NIR-absorbing, and are promising drug delivery agents.

The Role of Mitochondrial Dysfunction in Cytotoxic Effects of Solanum nigrum Water Extract on MCF-7 and MDA-MB-231 Breast Cancer Cells.

BACKGROUND: Recent studies suggest that numerous naturally occurring agents have the potential to kill cancer cells via mitochondrial dysfunction. Solanum nigrum is a herb widely used in alternative medical systems. This study aimed to investigate the cytotoxic effect of Solanum nigrum water extract (SNWE) against Michigan Cancer Foundation-7 (MCF-7) and MD Anderson-Metastatic Breast Cancer-231 (MDA-MB-231) cells. METHODS: We used an MTT reduction assay for cytotoxicity analysis. To explore the mode of action, the cellular adenosine triphosphate (ATP) levels and mitochondrial membrane potential were analyzed using a colorimetric ATP assay and Rhodamine-123 fluorescent staining, respectively, during SNWE treatment for 72 h. RESULTS: The cytotoxic effect was significant in both cell lines, with IC50 values of 4.26 µg/mL and 5.30 µg/mL in MCF-7 and MDA-MB-231 cells, respectively. The 24, 48, and 72 h treatments of 100 µg/mL SNWE showed 0.85 ± 0.07, 0.38 ± 0.1, and 0.20 ± 0.1 nM ATP in MCF-7 cells and 0.94 ± 0.07, 0.84 ± 0.2 and 0.46 ± 0.2 nM in MDA-MB-231 cells, respectively. The SNWE treatment altered the mitochondrial membrane potential (ΔΨm) in a concentration-dependent manner in both the breast cancer cell lines, to 29.6 ± 4.1% in MCF-7 and 28.7 ± 4.17% in MDA-MB-231 cells, when compared with healthy mitochondria (100% ΔΨm). CONCLUSIONS: The cytotoxic effects of Solanum nigrum against breast cancer cells are associated with energy metabolism. Additional studies are warranted to test the anticancer effect of Solanum nigrum using an animal model of breast cancer.

The Infarct-Reducing Effect of the δ2 Opioid Receptor Agonist Deltorphin II: The Molecular Mechanism.

The search for novel drugs for the treatment of acute myocardial infarction and reperfusion injury of the heart is an urgent aim of modern pharmacology. Opioid peptides could be such potential drugs in this area. However, the molecular mechanism of the infarct-limiting effect of opioids in reperfusion remains unexplored. The objective of this research was to study the signaling mechanisms of the cardioprotective effect of deltorphin II in reperfusion. Rats were subjected to coronary artery occlusion (45 min) and reperfusion (2 h). The ratio of infarct size/area at risk was determined. This study indicated that the cardioprotective effect of deltorphin II in reperfusion is mediated via the activation of peripheral δ2 opioid receptor (OR), which is most likely localized in cardiomyocytes. We studied the role of guanylyl cyclase, protein kinase Cδ (PKCδ), phosphatidylinositol-3-kinase (PI3-kinase), extracellular signal-regulated kinase-1/2 (ERK1/2-kinase), ATP-sensitive K+-channels (KATP channels), mitochondrial permeability transition pore (MPTP), NO synthase (NOS), protein kinase A (PKA), Janus 2 kinase, AMP-activated protein kinase (AMPK), the large conductance calcium-activated potassium channel (BKCa-channel), reactive oxygen species (ROS) in the cardioprotective effect of deltorphin II. The infarct-reducing effect of deltorphin II appeared to be mediated via the activation of PKCδ, PI3-kinase, ERK1/2-kinase, sarcolemmal KATP channel opening, and MPTP closing.

KATP channels are regulators of programmed cell death and targets for the creation of novel drugs against ischemia/reperfusion cardiac injury.

BACKGROUND: The use of percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI) is associated with a mortality rate of 5%-7%. It is clear that there is an urgent need to develop new drugs that can effectively prevent cardiac reperfusion injury. ATP-sensitive K+ (KATP ) channel openers (KCOs) can be classified as such drugs. RESULTS: KCOs prevent irreversible ischemia and reperfusion injury of the heart. KATP channel opening promotes inhibition of apoptosis, necroptosis, pyroptosis, and stimulation of autophagy. KCOs prevent the development of cardiac adverse remodeling and improve cardiac contractility in reperfusion. KCOs exhibit antiarrhythmic properties and prevent the appearance of the no-reflow phenomenon in animals with coronary artery occlusion and reperfusion. Diabetes mellitus and a cholesterol-enriched diet abolish the cardioprotective effect of KCOs. Nicorandil, a KCO, attenuates major adverse cardiovascular event and the no-reflow phenomenon, reduces infarct size, and decreases the incidence of ventricular arrhythmias in patients with acute myocardial infarction. CONCLUSION: The cardioprotective effect of KCOs is mediated by the opening of mitochondrial KATP (mitoKATP ) and sarcolemmal KATP (sarcKATP ) channels, triggered free radicals' production, and kinase activation.

Apigenin ameliorates gamma radiation-induced cytogenetic alterations in cultured human blood lymphocytes.

The aim of the present study was to assess the protective effect of apigenin, a dietary flavone, against cytogenetic alterations in human peripheral blood lymphocytes (HPBL) induced by Cobalt-60 radiation (3Gy). Results of MTT [3-(4, 5-dimethyl-2-thiaozolyl)-2,5-diphenyl-2H tetrazolium bromide] assay revealed that 37.2µM of apigenin was found to be non-toxic in HPBL. At this dose (37.2µM) of apigenin, the LD(50) radiation dose of HPBL increased from 2.9Gy to 3.4Gy, which resulted in a DMF of 1.17. Apigenin (37.2µM) treatment 1h before irradiation significantly (p<0.05) reduced DNA damage in irradiated HPBL as measured by comet assay (% tail DNA, tail length, tail moment, and olive tail moment). Moreover, apigenin treatment significantly decreased the frequencies of dicentric (DC), acentric fragments (AF), and acentric rings (AR) in irradiated HPBL. Apigenin pretreatment also reduced the radiation-induced CBMN (cytokinesis blocked micronuclei) anomalies such as micronuclei (MNi), nucleoplasmic bridges (NPB) and nuclear buds (NBUD) in HPBL. These results also showed that there was a significant correlation between NPB and DC frequencies and MNi and AF+AR. Treatment with apigenin alone had no significant effect on DNA damage and chromosomal aberrations in HPBL. Thus, the current studies indicate that apigenin protects HPBL from radiation-induced cytogenetic alterations.

Redox status and metabolomic profiling of thioredoxin reductase inhibitors and 4 kGy ionizing radiation-exposed Deinococcus radiodurans.

The gram-positive bacterium Deinococcus radiodurans can survive under extreme ionizing radiation environment. This study aims to rationalize the role of redox balance, antioxidant status, and metabolite content on the radiation survival of D. radiodurans. We found that the TrxR inhibitors, i.e., ebselen, auranofin, and epigallocatechin gallate (EGCG) (10 µM) treatment affects the radiation survival of D. radiodurans. The TrxR inhibitors treatment affects the redox status, activities of antioxidant enzymes, increases the intracellular ROS levels and protein carbonylation upon 4 kGy ionizing radiation treatments. Moreover, the alteration in cellular redox status affects the metabolites content of the organism. In addition, we noticed differential metabolomic profiles in sham control, radiation control (4 kGy), and TrxR inhibitors plus radiation-treated D. radiodurans. The TrxR inhibitors plus radiation treated groups exhibit more variation compare to sham control and 4 kGy radiation-exposed D. radiodurans. Further, some novel metabolites can possess the high antioxidant property and involved in vital cellular metabolism were found in sham control and radiation treated cells of D. radiodurans. Thus, the results illustrate the role of intracellular redox status in the survival and metabolomic profile of D. radiodurans.

The effect of an adaptation to hypoxia on cardiac tolerance to ischemia/reperfusion.

The acute myocardial infarction (AMI) and sudden cardiac death (SCD), both associated with acute cardiac ischemia, are one of the leading causes of adult death in economically developed countries. The development of new approaches for the treatment and prevention of AMI and SCD remains the highest priority for medicine. A study on the cardiovascular effects of chronic hypoxia (CH) may contribute to the development of these methods. Chronic hypoxia exerts both positive and adverse effects. The positive effects are the infarct-reducing, vasoprotective, and antiarrhythmic effects, which can lead to the improvement of cardiac contractility in reperfusion. The adverse effects are pulmonary hypertension and right ventricular hypertrophy. This review presents a comprehensive overview of how CH enhances cardiac tolerance to ischemia/reperfusion. It is an in-depth analysis of the published data on the underlying mechanisms, which can lead to future development of the cardioprotective effect of CH. A better understanding of the CH-activated protective signaling pathways may contribute to new therapeutic approaches in an increase of cardiac tolerance to ischemia/reperfusion.

Pharmacological Approaches to Limit Ischemic and Reperfusion Injuries of the Heart: Analysis of Experimental and Clinical Data on P2Y12 Receptor Antagonists.

Ischemic and reperfusion injuries of the heart underlie the pathogenesis of acute myocardial infarction (AMI) and sudden cardiac death. The mortality rate is still high and is 5-7% in patients with ST-segment elevation myocardial infarction. The review is devoted to pharmacological approaches to limitation of ischemic and reperfusion injuries of the heart. The article analyzes experimental evidence and the clinical data on the effects of P2Y12 receptor antagonists on the heart's tolerance to ischemia/reperfusion in animals with coronary artery occlusion and reperfusion and also in patients with AMI. Chronic administration of ticagrelor prevented adverse remodeling of the heart. There is evidence that sphingosine-1-phosphate is the molecule that mediates the infarct-reducing effect of P2Y12 receptor antagonists. It was discussed a role of adenosine in the cardioprotective effect of ticagrelor.

Reperfusion Cardiac Injury: Receptors and the Signaling Mechanisms.

It has been documented that Ca2+ overload and increased production of reactive oxygen species play a significant role in reperfusion injury (RI) of cardiomyocytes. Ischemia/reperfusion induces cell death as a result of necrosis, necroptosis, apoptosis, and possibly autophagy, pyroptosis and ferroptosis. It has also been demonstrated that the NLRP3 inflammasome is involved in RI of the heart. An increase in adrenergic system activity during the restoration of coronary perfusion negatively affected cardiac resistance to RI. Toll-like receptors are involved in RI of the heart. Angiotensin II and endothelin-1 aggravated ischemic/reperfusion injury of the heart. Activation of neutrophils, monocytes, CD4+ T-cells and platelets contributes to cardiac ischemia/reperfusion injury. Our review outlines the role of these factors in reperfusion cardiac injury.

Phytochemicals reverse P-glycoprotein mediated multidrug resistance via signal transduction pathways.

P-glycoprotein, encoded by ATP-binding cassette transporters B1 gene (ABCB1), renders multidrug resistance (MDR) during cancer chemotherapy. Several synthetic small molecule inhibitors affect P-glycoprotein (P-gp) transport function in MDR tumor cells. However, inhibition of P-gp transport function adversely accumulates chemotherapeutic drugs in non-target normal tissues. Moreover, most small-molecule P-gp inhibitors failed in the clinical trials due to the low therapeutic window at the maximum tolerated dose. Therefore, downregulation of ABCB1-gene expression (P-gp) in tumor tissues seems to be a novel approach rather than inhibiting its transport function for the reversal of multidrug resistance (MDR). Several plant-derived phytochemicals modulate various signal transduction pathways and inhibit translocation of transcription factors, thereby reverses P-gp mediated MDR in tumor cells. Therefore, phytochemicals may be considered an alternative to synthetic small molecule P-gp inhibitors for the reversal of MDR in cancer cells. This review discussed the role of natural phytochemicals that modulate ABCB1 expression through various signal transduction pathways in MDR cancer cells. Therefore, modulating the cell signaling pathways by phytochemicals might play crucial roles in modulating ABCB1 gene expression and the reversal of MDR.

SARS-CoV-2: Pathogenesis, Molecular Targets and Experimental Models.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a recent pandemic outbreak threatening human beings worldwide. This novel coronavirus disease-19 (COVID-19) infection causes severe morbidity and mortality and rapidly spreading across the countries. Therefore, there is an urgent need for basic fundamental research to understand the pathogenesis and druggable molecular targets of SARS-CoV-2. Recent sequencing data of the viral genome and X-ray crystallographic data of the viral proteins illustrate potential molecular targets that need to be investigated for structure-based drug design. Further, the SARS-CoV-2 viral pathogen isolated from clinical samples needs to be cultivated and titrated. All of these scenarios demand suitable laboratory experimental models. The experimental models should mimic the viral life cycle as it happens in the human lung epithelial cells. Recently, researchers employing primary human lung epithelial cells, intestinal epithelial cells, experimental cell lines like Vero cells, CaCo-2 cells, HEK-293, H1299, Calu-3 for understanding viral titer values. The human iPSC-derived lung organoids, small intestinal organoids, and blood vessel organoids increase interest among researchers to understand SARS-CoV-2 biology and treatment outcome. The SARS-CoV-2 enters the human lung epithelial cells using viral Spike (S1) protein and human angiotensin-converting enzyme 2 (ACE-2) receptor. The laboratory mouse show poor ACE-2 expression and thereby inefficient SARS-CoV-2 infection. Therefore, there was an urgent need to develop transgenic hACE-2 mouse models to understand antiviral agents' therapeutic outcomes. This review highlighted the viral pathogenesis, potential druggable molecular targets, and suitable experimental models for basic fundamental research.