Empagliflozin drives ferroptosis in anoikis-resistant cells by activating miR-128-3p dependent pathway and inhibiting CD98hc in breast cancer.

A tumour suppressor miRNA, miR-128-3p, is widely involved in various biological processes and has been found to get downregulated in breast cancer patients. We previously published that ectopically expressed miR-128-3p suppressed migration, invasion, cell cycle arrest, and breast cancer stem cells. In the present study, we explored the role of Empagliflozin (EMPA) as a miR-128-3p functionality-mimicking drug in inducing ferroptosis by inhibiting CD98hc. Given that CD98hc is one of the proteins critical in triggering ferroptosis, we confirmed that miR-128-3p and EMPA inhibited SP1, leading to inhibition of CD98hc expression. Further, transfection with siCD98hc, miR-128-3p mimics, and inhibitors was performed to assess their involvement in the ferroptosis of anoikis-resistant cells. We proved that anoikis-resistant cells possess high ROS and iron levels. Further, miR-128-3p and EMPA treatments induced ferroptosis by inhibiting GSH and enzymatic activity of GPX4 and also induced lipid peroxidation. Moreover, EMPA suppressed bioluminescence of 4T1-Red-FLuc induced thoracic cavity, peritoneal tumour burden and lung nodules in an in-vivo metastatic model of breast cancer. Collectively, we revealed that EMPA sensitized the ECM detached cells to ferroptosis by synergically activating miR-128-3p and lowering the levels of SP1 and CD98hc, making it a potential adjunct drug for breast cancer chemotherapy.

Association of COVID-19 with Comorbidities: An Update.

Coronavirus disease (COVID-19) is caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) which was identified in Wuhan, China in December 2019 and jeopardized human lives. It spreads at an unprecedented rate worldwide, with serious and still-unfolding health conditions and economic ramifications. Based on the clinical investigations, the severity of COVID-19 appears to be highly variable, ranging from mild to severe infections including the death of an infected individual. To add to this, patients with comorbid conditions such as age or concomitant illnesses are significant predictors of the disease's severity and progression. SARS-CoV-2 enters inside the host cells through ACE2 (angiotensin converting enzyme2) receptor expression; therefore, comorbidities associated with higher ACE2 expression may enhance the virus entry and the severity of COVID-19 infection. It has already been recognized that age-related comorbidities such as Parkinson's disease, cancer, diabetes, and cardiovascular diseases may lead to life-threatening illnesses in COVID-19-infected patients. COVID-19 infection results in the excessive release of cytokines, called "cytokine storm", which causes the worsening of comorbid disease conditions. Different mechanisms of COVID-19 infections leading to intensive care unit (ICU) admissions or deaths have been hypothesized. This review provides insights into the relationship between various comorbidities and COVID-19 infection. We further discuss the potential pathophysiological correlation between COVID-19 disease and comorbidities with the medical interventions for comorbid patients. Toward the end, different therapeutic options have been discussed for COVID-19-infected comorbid patients.

Assessment of metabolic stability and pharmacokinetics by LC-MS/MS and establishment of the safe dose of IMID-2, a novel anticancer molecule under drug discovery.

Pyruvate kinase (PK) M2 activators ramp up glycolysis in cancer cells, leading to a reversal of the Warburg effect in cancer cells. A promising PKM2 activator molecule, IMID-2, developed by the National Institute of Pharmaceutical Education and Research-Ahmedabad showed promising anticancer activity against MCF-7 and COLO-205 cell lines, which represent breast and colon cancer. Its physicochemical properties, like solubility, ionization constant, partition coefficient and distribution constant, have already been established. Its metabolic pathway is also well established through in vitro and in vivo metabolite profiling and reported previously. In this study, we have evaluated the metabolic stability of IMID-2 using LC-MS/MS and investigated the safety aspect of the molecule through an acute oral toxicity study. In vivo studies in rats confirmed that the molecule is safe even at a dose level of 175 mg/kg. Furthermore, a pharmacokinetic study of IMID-2 was also carried out using LC-MS/MS to understand its absorption, distribution, metabolism, and excretion profile. The molecule was found to have promising bioavailability through the oral route. This research work is thus another step in the drug testing of this promising anticancer molecule. The molecule can be considered to be a potential anticancer lead based on the earlier report substantiated by current findings.

Empagliflozin mediated miR-128-3p upregulation promotes differentiation of hypoxic cancer stem-like cells in breast cancer.

AIMS: The hsa-miR-128-3p expression is downregulated in advanced breast cancer patients. Empagliflozin (EMPA) is an anti-diabetic drug with anticancer potential. The present study investigated the effect of EMPA on cancer cell differentiation by acting as a miR-128-3p mimicking drug in breast cancer. MAIN METHODS: Our results first demonstrate SP1 and PKM2 as the downstream effectors of hsa-miR-128-3p. Further, transfection with siPKM2, miR-128-3p mimics, and inhibitors was performed to assess their involvement in cancer stemness using flow cytometry. Further, EMPA as miR-128-3p mimicking drug was screened and explored on cancer cell differentiation. Then, we treated the 4T1-Red-FLuc allograft breast tumor with EMPA to assess its inhibitory potential toward tumor growth using IVIS® Spectrum. Immunohistochemistry was performed to evaluate cancer cell differentiation and cell proliferation. KEY FINDINGS: We found that hsa-miR-128-3p is the upstream regulator of SP1 and PKM2 in hypoxic breast cancer cells. Overexpression of miR-128-3p with mimics downregulate SP1 and PKM2, whereas miR-128-3p inhibitor shows an opposite effect. The enhanced expression of miR-128-3p and PKM2 knockdown diminishes hypoxia-induced CD44 expression and enhance CD44+/CD24+ differentiated cells. We also identified EMPA as the miR-128-3p mimicking drug that can enhance the differentiated cell population. Further, EMPA suppressed in vivo tumor growth, lung metastasis, tumor bioluminescence, and cell proliferation. Therefore, EMPA abrogates breast cancer stemness by inactivating SP1 and PKM2 via enhanced miR-128-3p expression. SIGNIFICANCE: EMPA could be a promising drug in combination with other chemotherapeutic drugs in advanced breast cancer.

Neuroprotective Effect of Swertiamarin in a Rotenone Model of Parkinson's Disease: Role of Neuroinflammation and Alpha-Synuclein Accumulation.

Parkinson's disease (PD) is a progressive neurodegenerative disease with no permanent cure affecting around 1% of the population over 65. There is an urgency to search for a disease-modifying agent with fewer untoward effects. PD pathology involves the accumulation of toxic alpha-synuclein (α-syn) and neuronal inflammation leading to the degeneration of dopaminergic (DAergic) neurons. Swertiamarin (SWE), a well-studied natural product, possesses a strong anti-inflammatory effect. It is a secoiridoid glycoside isolated from Enicostemma littorale Blume. SWE showed a reversal effect on the α-syn accumulation in the 6-hydroxydopamine (6-OHDA)-induced Caenorhabditis elegans model of PD. However, there are no reports in the literature citing the effect of SWE as a neuroprotective agent in rodents. The present study aimed to evaluate the anti-inflammatory activity of SWE against lipopolysaccharide (LPS)-induced C6 glial cell activation and its neuroprotective effect in the intrastriatal rotenone mouse PD model. SWE treatment showed a significant reduction in interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interleukin-1ß (IL-1ß) levels in LPS-induced C6 glial cell activation. Further, our studies demonstrated the suppression of microglial and astroglial activation in substantia nigra (SN) after administration of SWE (100 mg/kg, intraperitoneally) in a rotenone mouse model. Moreover, SWE alleviated the rotenone-induced α-syn overexpression in the striatum and SN. SWE ameliorated the motor impairment against rotenone-induced neurotoxicity and mitigated the loss of DAergic neurons in the nigrostriatal pathway. Therefore, SWE has the potential to develop as an adjunct therapy for PD, but it warrants further mechanistic studies.

Chlorogenic Acid: a Polyphenol from Coffee Rendered Neuroprotection Against Rotenone-Induced Parkinson's Disease by GLP-1 Secretion.

Parkinson's disease (PD) is a chronic motor disorder, characterized by progressive loss of dopaminergic neurons. Numerous studies suggest that glucagon-like peptide-1 (GLP-1) secretagogue has a neuroprotective role in PD models. The present study evaluated potential of coffee bioactive compounds in terms of their ability to bind GPR-40/43 and tested the neuroprotective effect of best candidate on rotenone-induced PD mice acting via GLP-1 release. In silico molecular docking followed by binding free energy calculation revealed that chlorogenic acid (CGA) has a strong binding affinity for GPR-40/43 in comparison to other bioactive polyphenols. Molecular dynamics simulation studies revealed stable nature of GPR40-CGA and GPR43-CGA interaction and also provided information about the amino acid residues involved in binding. Subsequently, in vitro studies demonstrated that CGA-induced secretion of GLP-1 via enhancing cAMP levels in GLUTag cells. Furthermore, in vivo experiments utilizing rotenone-induced mouse model of PD revealed a significant rise in plasma GLP-1 after CGA administration (50 mg/kg, orally for 13 weeks) with concomitant increase in colonic GPR-40 and GPR-43 mRNA expression. CGA treatment also prevented rotenone-induced motor and cognitive impairments and significantly restored the rotenone-induced oxidative stress. Meanwhile, western blot results confirmed that CGA treatment downregulated rotenone-induced phosphorylated alpha-synuclein levels by upregulating PI3K/AKT signaling and inactivating GSK-3ß through the release of GLP-1. CGA treatment ameliorated rotenone-induced dopaminergic nerve degeneration and alpha-synuclein accumulation in substantia nigra and augmented mean density of dopaminergic nerve fibers in striatum. These findings demonstrated novel biological function of CGA as a GLP-1 secretagogue. An increase in endogenous GLP-1 may render neuroprotection against a rotenone mouse model of PD and has the potential to be used as a neuroprotective agent in management of PD.

AMPK-dependent autophagy activation and alpha-Synuclein clearance: a putative mechanism behind alpha-mangostin's neuroprotection in a rotenone-induced mouse model of Parkinson's disease.

Alpha-Synuclein (α-Syn) accumulation is central to the pathogenesis of Parkinson's disease (PD), hence the quest for finding potential therapeutics that may promote the α-Syn clearance is the need of the hour. To this, activation of the evolutionarily conserved protein and key regulator of the autophagy, 5'AMP-activated protein kinase (AMPK) is well-known to induce autophagy and subsequently the clearance of α-Syn aggregates. Alpha-mangostin (AM) a polyphenolic xanthone obtained from Garcinia Mangostana L. was previously reported to activate AMPK-dependent autophagy in various pre-clinical cancer models. However, no studies evidenced the effect of AM on AMPK-dependent autophagy activation in the PD. Therefore, the present study aimed to investigate the neuroprotective activity of AM in the chronic rotenone mouse model of PD against rotenone-induced α-Syn accumulation and to dissect molecular mechanisms underlying the observed neuroprotection. The findings showed that AM exerts neuroprotection against rotenone-induced α-Syn accumulation in the striatum and cortex by activating AMPK, upregulating autophagy (LC3II/I, Beclin-1), and lysosomal (TFEB) markers. Of note, an in-vitro study utilizing rat pheochromocytoma cells verified that AM conferred the neuroprotection only through AMPK activation, as the presence of inhibitors of AMPK (dorsomorphin) and autophagy (3-methyl adenine) failed to mitigate rotenone-induced α-Syn accumulation. Moreover, AM also counteracted rotenone-induced behavioral deficits, oxidative stress, and degeneration of nigro-striatal dopaminergic neurons. In conclusion, AM provided neuroprotection by ameliorating the rotenone-induced α-Syn accumulation through AMPK-dependent autophagy activation and it can be considered as a therapeutic agent which might be having a higher translational value in the treatment of PD.

Targeting specificity protein 1 with miR-128-3p overcomes TGF-ß1 mediated epithelial-mesenchymal transition in breast cancer: An in vitro study.

BACKGROUND: Specificity protein 1 (SP1) was found to play a critical role in the regulation of TGF-ß1 driven epithelial-mesenchymal transition (EMT). Recent clinical findings demonstrated a significant drop in the expression of miR-128-3p with the cancer progression in breast cancer patients. However, the impact of miR-128-3p on the SP1 expression in breast cancer remains unknown. Herein, we evaluated the role of miR-128-3p mimics in suppressing EMT of breast cancer cell lines by regulating the TGF-ß1/SP1 axis. METHODS: miR-128-3p interaction with SP1 was detected by in silico tools and dual-luciferase reporter assay. qPCR, western blot, and immunocytochemistry experiments were conducted for determining the expression levels of miR-128-3p and EMT markers with and without the treatment of miR-128-3p mimics. Further, to understand the effect of miR-128-3p mimics on cancer progression, experiments such as wound healing assay, transwell assay, adhesion assay, and cell cycle analysis were performed. RESULTS: A significant inverse relation between SP1 and miR-128-3p levels was found in MCF-7 and MDA-MB-231 cell lines. miR-128-3p overexpression impeded the SP1 mediated EMT markers in TGF-ß1 stimulated cells by inhibiting the SP1 nuclear function. Further, treatment with miR-128-3p mimics significantly reduced the migration, invasion and spreading capability of TGF-ß1 stimulated cells. Flow cytometry results showed the impeding role of miR-128-3p on the cell cycle progression. CONCLUSIONS: Upregulated miR-128-3p inhibited SP1, thereby limiting the TGF-ß1 induced EMT in MCF-7 and MDA-MB-231 cell lines for the first time. This study may pave the path to explore novel miRNA therapeutics for eradicating advanced breast cancer cases.

Mesenchymal Stem Cell-Derived Exosomes Loaded with miR-155 Inhibitor Ameliorate Diabetic Wound Healing.

Diabetic wounds are one of the debilitating complications that affect up to 20% of diabetic patients. Despite the advent of extensive therapies, the recovery rate is unsatisfactory, and approximately, 25% of patients undergo amputation, thereby demanding alternative therapeutic strategies. On the basis of the individual therapeutic roles of the miR-155 inhibitor and mesenchymal stem cells (MSC)-derived exosomes, we conjectured that the combination of the miR-155 inhibitor and MSC-derived exosomes would have synergy in diabetic wound healing. Herein, miR-155-inhibitor-loaded MSC-derived exosomes showed synergistic effects in keratinocyte migration, restoration of FGF-7 levels, and anti-inflammatory action, leading to accelerated wound healing mediated by negative regulation of miR-155, using an in vitro co-culture model and in vivo mouse model of the diabetic wound. Furthermore, treatment with miR-155-inhibitor-loaded MSC-derived exosomes led to enhanced collagen deposition, angiogenesis, and re-epithelialization in diabetic wounds. This study revealed the therapeutic potential of miR-155-inhibitor-loaded MSC-derived exosomes in diabetic wound healing and opened the doors for encapsulating miRNAs along with antibiotics within the MSC-derived exosomes toward improved management of chronic, nonhealing diabetic wounds.

Boronic acid derivative activates pyruvate kinase M2 indispensable for redox metabolism in oral cancer cells.

PKM2is considered a desirable target as its enzymatic activation is expected to cause a diminution in tumorigenesis and prevent limitless replication in cancerous cells. However, considering the functional consequences of kinase inhibitors, the design of PKM2 activators has been an attractive strategy that has yielded potent anticancer molecules like DASA-58. Therefore, a new class of boronic acid derivate was developed to elucidate the possible mechanistic link between PKM2 activation and TPI1 activity, which has a significant role in the redox balance in cancer. The present in vitro study revealed that treatment with boronic acid-based compound 1 and DASA-58 was found to activate PKM2 with an AC50 of 25 nM and 52 nM, respectively. Furthermore, at the AC50 concentration of compound 1, we found a significant increase in TPI1 activity and a decrease in GSH and NADP+/NADPH ratio. We also found increased ROS levels and decreased lactate secretion with treatment. Together with these findings, we can presume that compound 1 affects the redox balance by activating PKM2 and TPI1 activity. Implementation of this treatment strategy may improve the effect of chemotherapy in the conditions of ROS induced cancer drug resistance. This study for the first time supports the link between PKM2 and the TPI1 redox balance pathway in oral cancer. Collectively, the study findings provide a novel molecule for PKM2 activation for the therapeutic intervention in oral cancer.

Role of miRNAs in Cancer Diagnostics and Therapy: A Recent Update.

The discovery of microRNAs (miRNAs) has been one of the revolutionary developments and has led to the advent of new diagnostic and therapeutic opportunities for the management of cancer. In this regard, miRNA dysregulation has been shown to play a critical role in various stages of tumorigenesis, including tumor invasion, metastasis as well as angiogenesis. Therefore, miRNA profiling can provide accurate fingerprints for the development of diagnostic and therapeutic platforms. This review discusses the recent discoveries of miRNA- based tools for early detection of cancer as well as disease monitoring in cancers that are common, like breast, lung, hepatic, colorectal, oral and brain cancer. Based on the involvement of miRNA in different cancers as oncogenic miRNA or tumor suppressor miRNA, the treatment with miRNA inhibitors or mimics is recommended. However, the stability and targeted delivery of miRNA remain the major limitations of miRNA delivery. In relation to this, several nanoparticle-based delivery systems have been reported which have effectively delivered the miRNA mimics or inhibitors and showed the potential for transforming these advanced delivery systems from bench to bedside in the treatment of cancer metastasis and chemoresistance. Based on this, we attempted to uncover recently reported advanced nanotherapeutic approaches to deliver the miRNAs in the management of different cancers.

MiR-155 Inhibitor-Laden Exosomes Reverse Resistance to Cisplatin in a 3D Tumor Spheroid and Xenograft Model of Oral Cancer.

Cisplatin resistance is one of the major concerns in the treatment of oral squamous cell carcinoma (OSCC). Accumulating evidence suggests microRNA (miRNA) dysregulation as one of the mediators of chemoresistance. Toward this, our previous study revealed the role of exosomal microRNA-155 (miR-155) in cisplatin resistance via downregulation of FOXO3a, a direct target of miR-155, and induction of epithelial-to-mesenchymal transition in OSCC. In the present study, we demonstrate the therapeutic potential of miR-155 inhibitor-laden exosomes in the sensitization of a cisplatin-resistant (cisRes) OSCC 3D tumor spheroid and xenograft mouse model. The cisRes OSSC 3D tumor spheroid model recapitulated the hallmarks of solid tumors such as enhanced hypoxia, reactive oxygen species, and secretory vascular endothelial growth factor. Further treatment with miR-155 inhibitor-loaded exosomes showed the upregulation of FOXO3a and induction of the mesenchymal-to-epithelial transition with improved sensitization to cisplatin in cisRes tumor spheroids and xenograft mouse model. Moreover, the exosomal miR-155 inhibitor suppressed the stem-cell-like property as well as drug efflux transporter protein expression in cisplatin-resistant tumors. Taken together, our findings, for the first time, established that the miR-155 inhibitor-loaded exosomes reverse chemoresistance in oral cancer, thereby providing an alternative therapeutic strategy for the management of refractory oral cancer patients.

Pyruvate kinase M2 in chronic inflammations: a potpourri of crucial protein-protein interactions.

Chronic inflammation (CI) is a primary contributing factor involved in multiple diseases like cancer, stroke, diabetes, Alzheimer's disease, allergy, asthma, autoimmune diseases, coeliac disease, glomerulonephritis, sepsis, hepatitis, inflammatory bowel disease, reperfusion injury, and transplant rejections. Despite several expansions in our understanding of inflammatory disorders and their mediators, it seems clear that numerous proteins participate in the onset of CI. One crucial protein pyruvate kinase M2 (PKM2) much studied in cancer is also found to be inextricably woven in the onset of several CI's. It has been found that PKM2 plays a significant role in several disorders using a network of proteins that interact in multiple ways. For instance, PKM2 forms a close association with epidermal growth factor receptors (EGFRs) for uncontrolled growth and proliferation of tumor cells. In neurodegeneration, PKM2 interacts with apurinic/apyrimidinic endodeoxyribonuclease 1 (APE1) to onset Alzheimer's disease pathogenesis. The cross-talk of protein tyrosine phosphatase 1B (PTP1B) and PKM2 acts as stepping stones for the commencement of diabetes. Perhaps PKM2 stores the potential to unlock the pathophysiology of several diseases. Here we provide an overview of the notoriously convoluted biology of CI's and PKM2. The cross-talk of PKM2 with several proteins involved in stroke, Alzheimer's, cancer, and other diseases has also been discussed. We believe that considering the importance of PKM2 in inflammation-related diseases, new options for treating various disorders with the development of more selective agents targeting PKM2 may appear.

Protective effect of alpha mangostin on rotenone induced toxicity in rat model of Parkinson's disease.

Parkinson's disease (PD) is a progressive, late-onset, and degenerative disorder that affects the central nervous system with an unknown etiology. Due to its incredible complexity in disease nature, many of the existing treatment approaches show a vain recovery in Parkinson's patients. Therefore, an in search of disease-modifying therapeutics for an effective recovery is essential. Alpha mangostin is an important polyphenolic xanthone reported for its neuroprotective effect against rotenone-induced α-synuclein aggregation and loss of tyrosine hydroxylase positive (TH+)-neurons in SH-SY5Y cells. Hence, the current study aims to test its protective effect in managing the in-vivo rat model of PD. To justify this aim, adult male Sprague Dawley rats (250 ± 20 g) were subjected to chronic treatment of rotenone (2 mg/kg/day, s.c.) for 21 days. In parallel alpha mangostin treatment (10 mg/kg, i.p) was administered along with rotenone for 21 days. Chronic rotenone treatment for 21 days increased lipid peroxidation, nitrite concentration, and decreased glutathione levels. Further, depletion of TH+-dopaminergic neuron expression in substantia nigra pars compacta (SNc), and the development of motor and behavioral deficits in rotenone treated animals like cognitive impairment, muscle incoordination, and neuromuscular weakness were observed. Moreover, western blot studies ascertained the reduced normal alpha-synuclein levels and increased phosphorylated α-synuclein levels in comparison to the vehicle-treated group. Treatment with alpha mangostin significantly restored the locomotor activity, memory deficits, and improved the levels of antioxidant enzymes. It also significantly reduced the levels of phosphorylated α-synuclein which in turn gave protection against TH+-dopaminergic neuronal loss in SNc, suggesting it's anti-oxidant and anti-aggregatory potential against α-synuclein. In conclusion through our current results, we could suggest that alpha mangostin has a potential neuroprotective effect against rotenone-induced PD and might be used as a neuroprotective agent. Further mechanistic studies on preclinical and clinical levels are required to be conducted with alpha mangostin to avail and foresee it as a potential agent in the treatment and management of PD.

Edaravone-caffeine combination for the effective management of rotenone induced Parkinson's disease in rats: An evidence based affirmative from a comparative analysis of behavior and biomarker expression.

Restoration of cellular microenvironment is important in the treatment of neurodegenerative diseases for optimal functioning and survival of neurons. Oxidative stress has been proposed as one of the major pathogenic drivers in Parkinson's disease. Parkinson's model was developed by chronic administration of a pesticide rotenone that inhibits mitochondrial complex I resulting in generation of reactive oxygen species. In this study, our aim was to evaluate neuroprotective effect rendered by edaravone, a potent free radical scavenger in combination with caffeine, an effective inhibitor of adenosine A2A receptor as well as a proven antioxidant. Here we demonstrate that a three-week treatment with edaravone-caffeine combination was able to significantly diminish rotenone induced oxidative damage at the cellular level as well as muscle weakness and cognitive impairment generally associated with Parkinson's disease. This effect is attributable to edaravone's capability of scavenging the perxoynitrite free radical. Herein, we have assessed the levels of protein nitroxidation marker 3-nitrotyrosine in the striatum and lipid peroxidation marker malondialdehyde in striatum, cerebrospinal fluid, plasma and urine of rats. On the 21st day, statistical difference was observed in the striatal biomarker levels (p = 0.001) between the controls, treated and untreated groups. We discovered that when edaravone was co-administered with caffeine, the effect was more significant compared to the group solely treated with edaravone demonstrating a synergistic effect. Simultaneous therapeutic intervention with drug combination showed a pronounced decrease in oxidative damage markers as well as better muscle strength and cognition compared to the untreated groups.

Pyruvate Kinase M2: a Metabolic Bug in Re-Wiring the Tumor Microenvironment.

Metabolic reprogramming is a newly emerged hallmark of cancer attaining a recent consideration as an essential factor for the progression and endurance of cancer cells. A prime event of this altered metabolism is increased glucose uptake and discharge of lactate into the cells surrounding constructing a favorable tumor niche. Several oncogenic factors help in promoting this consequence including, pyruvate kinase M2 (PKM2) a rate-limiting enzyme of glycolysis in tumor metabolism via exhibiting its low pyruvate kinase activity and nuclear moon-lightening functions to increase the synthesis of lactate and macromolecules for tumor proliferation. Not only its role in cancer cells but also its role in the tumor microenvironment cells has to be understood for developing the small molecules against it which is lacking with the literature till date. Therefore, in this present review, the role of PKM2 with respect to various tumor niche cells will be clarified. Further, it highlights the updated list of therapeutics targeting PKM2 pre-clinically and clinically with their added limitations. This upgraded understanding of PKM2 may provide a pace for the reader in developing chemotherapeutic strategies for better clinical survival with limited resistance.

Self-renewal signaling pathways in breast cancer stem cells.

Breast cancer, a death-dealing disease mainly affects the women populace in the world. Outmoded remedial treatments like chemo and radiotherapy against breast cancer have manifold limitations like systemic and local toxicity resulting in the failure of treatment and cancer relapse. Recurrence and treatment failure is due to the presence of the minor number of cells in the tumor called cancer stem cells (CSCs) stocked with the properties like epithelial-mesenchymal transition, drug resistibility, auto self-renewability, and stemness. But, the stemness in these cells is different from the normal stem cells with regards to their self-renewal signaling pathways which gets dysregulated due to genomic and epigenome changes. In the earlier period's headway in the cancer research led to the advancement of new targets by understanding the pathophysiological mechanism behind cancer progression but still, the mortality rate i. the breast cancer is at its peak due to their unclear understanding of the stemness signaling regulations. The present review highlights the current clinical limitations in treating cancer stem cells and discusses the recent writings of their stemness signaling regulations required in maintenance of self-renewal capability and metastasis. More importantly, it further describes the present clinical and preclinical updates targeting cancer stem cells pathways. A strong consideration of these signalings and developing the treatment strategies with the existed chemotherapy may possibly offer a promising approach to eradicate cancer stem cells for improving the cancer survival rate to persuade a long-term clinical response.

Influence of caffeine on 3,4-methylenedioxymethamphetamine-induced dopaminergic neuron degeneration and neuroinflammation is age-dependent.

Previous studies have demonstrated that caffeine administration to adult mice potentiates glial activation induced by 3,4-methylenedioxymethamphetamine (MDMA). As neuroinflammatory response seems to correlate with neurodegeneration, and the young brain is particularly vulnerable to neurotoxicity, we evaluated dopamine neuron degeneration and glial activation in the caudate-putamen (CPu) and substantia nigra pars compacta (SNc) of adolescent and adult mice. Mice were treated with MDMA (4 × 20 mg/kg), alone or with caffeine (10 mg/kg). Interleukin (IL)-1ß, tumor necrosis factor (TNF)-α, neuronal nitric oxide synthase (nNOS) were evaluated in CPu, whereas tyrosine hydroxylase (TH), glial fibrillary acidic protein, and CD11b were evaluated in CPu and SNc by immunohistochemistry. MDMA decreased TH in SNc of both adolescent and adult mice, whereas TH-positive fibers in CPu were only decreased in adults. In CPu of adolescent mice, caffeine potentiated MDMA-induced glial fibrillary acidic protein without altering CD11b, whereas in SNc caffeine did not influence MDMA-induced glial activation. nNOS, IL-1ß, and TNF-α were increased by MDMA in CPu of adults, whereas in adolescents, levels were only elevated after combined MDMA plus caffeine. Caffeine alone modified only nNOS. Results suggest that the use of MDMA in association with caffeine during adolescence may exacerbate the neurotoxicity and neuroinflammation elicited by MDMA. Previous studies have demonstrated that caffeine potentiated glial activation induced by 3,4-methylenedioxymethamphetamine (MDMA) in adult mice. In this study, caffeine was shown to potentiate MDMA-induced dopamine neuron degeneration in substantia nigra pars compacta, astrogliosis, and TNF-α levels in caudate-putamen of adolescent mice. Results suggest that combined use of MDMA plus caffeine during adolescence may worsen the neurotoxicity and neuroinflammation elicited by MDMA.

Neuroprotective and anti-inflammatory effects of the adenosine A(2A) receptor antagonist ST1535 in a MPTP mouse model of Parkinson's disease.

Adenosine A(2A) receptor antagonists are one of the most attractive classes of drug for the treatment of Parkinson's disease (PD) as they are effective in counteracting motor dysfunctions and display neuroprotective and anti-inflammatory effects in animal models of PD. In this study, we evaluated the neuroprotective and anti-inflammatory properties of the adenosine A(2A) receptor antagonist ST1535 in a subchronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. C57BL/6J mice were repeatedly administered with vehicle, MPTP (20 mg/kg), or MPTP + ST1535 (2 mg/kg). Mice were sacrificed three days after the last administration of MPTP. Immunohistochemistry for tyrosine hydroxylase (TH) and cresyl violet staining were employed to evaluate dopaminergic neuron degeneration in the substantia nigra pars compacta (SNc) and caudate-putamen (CPu). CD11b and glial fibrillary acidic protein (GFAP) immunoreactivity were, respectively, evaluated as markers of microglial and astroglial response in the SNc and CPu. Stereological analysis for TH revealed a 32% loss of dopaminergic neurons in the SNc after repeated MPTP administration, which was completely prevented by ST1535 coadministration. Similarly, CPu decrease in TH (25%) was prevented by ST1535. MPTP treatment induced an intense gliosis in both the SNc and CPu. ST1535 totally prevented CD11b immunoreactivity in both analyzed areas, but only partially blocked GFAP increase in the SNc and CPu. A(2A) receptor antagonism is a new opportunity for improving symptomatic PD treatment. With its neuroprotective effect on dopaminergic neuron toxicity induced by MPTP and its antagonism on glial activation, ST1535 represents a new prospect for a disease-modifying drug.