Mir S Adil

All Publications

• Reduced FOXF1 links unrepaired DNA damage to pulmonary arterial hypertension. Nature communications Isobe, S., Nair, R. V., Kang, H. Y., Wang, L., Moonen, J. R., Shinohara, T., Cao, A., Taylor, S., Otsuki, S., Marciano, D. P., Harper, R. L., Adil, M. S., Zhang, C., Lago-Docampo, M., Körbelin, J., Engreitz, J. M., Snyder, M. P., Rabinovitch, M. 2023; 14 (1): 7578

  Abstract

  Pulmonary arterial hypertension (PAH) is a progressive disease in which pulmonary arterial (PA) endothelial cell (EC) dysfunction is associated with unrepaired DNA damage. BMPR2 is the most common genetic cause of PAH. We report that human PAEC with reduced BMPR2 have persistent DNA damage in room air after hypoxia (reoxygenation), as do mice with EC-specific deletion of Bmpr2 (EC-Bmpr2-/-) and persistent pulmonary hypertension. Similar findings are observed in PAEC with loss of the DNA damage sensor ATM, and in mice with Atm deleted in EC (EC-Atm-/-). Gene expression analysis of EC-Atm-/- and EC-Bmpr2-/- lung EC reveals reduced Foxf1, a transcription factor with selectivity for lung EC. Reducing FOXF1 in control PAEC induces DNA damage and impaired angiogenesis whereas transfection of FOXF1 in PAH PAEC repairs DNA damage and restores angiogenesis. Lung EC targeted delivery of Foxf1 to reoxygenated EC-Bmpr2-/- mice repairs DNA damage, induces angiogenesis and reverses pulmonary hypertension.

  View details for DOI 10.1038/s41467-023-43039-y

  View details for PubMedID 37989727

  View details for PubMedCentralID 4737700

• Elevated Intracranial Pressure in Cryptococcal Meningoencephalitis: Examining Old, New, and Promising Drug Therapies PATHOGENS Alanazi, A. H., Adil, M. S., Lin, X., Chastain, D. B., Henao-Martinez, A. F., Franco-Paredes, C., Somanath, P. R. 2022; 11 (7)

  Abstract

  Despite the availability of effective antifungal therapy, cryptococcal meningoencephalitis (CM) remains associated with elevated mortality. The spectrum of symptoms associated with the central nervous system (CNS) cryptococcosis is directly caused by the high fungal burden in the subarachnoid space and the peri-endothelial space of the CNS vasculature, which results in intracranial hypertension (ICH). Management of intracranial pressure (ICP) through aggressive drainage of cerebrospinal fluid by lumbar puncture is associated with increased survival. Unfortunately, these procedures are invasive and require specialized skills and supplies that are not readily available in resource-limited settings that carry the highest burden of CM. The institution of pharmacologic therapies to reduce the production or increase the resorption of cerebrospinal fluid would likely improve clinical outcomes associated with ICH in patients with CM. Here, we discuss the potential role of multiple pharmacologic drug classes such as diuretics, corticosteroids, and antiepileptic agents used to decrease ICP in various neurological conditions as potential future therapies for CM.

  View details for DOI 10.3390/pathogens11070783

  View details for Web of Science ID 000833835900001

  View details for PubMedID 35890028

  View details for PubMedCentralID PMC9321092

• Claudin-17 Deficiency in Mice Results in Kidney Injury Due to Electrolyte Imbalance and Oxidative Stress. Cells Adil, M. S., Parvathagiri, V., Verma, A., Liu, F., Rudraraju, M., Narayanan, S. P., Somanath, P. R. 2022; 11 (11)

  Abstract

  The multi-gene claudin (CLDN) family of tight junction proteins have isoform-specific roles in blood-tissue barrier regulation. CLDN17, a putative anion pore-forming CLDN based on its structural characterization, is assumed to regulate anion balance across the blood-tissue barriers. However, our knowledge about CLDN17 in physiology and pathology is limited. The current study investigated how Cldn17 deficiency in mice affects blood electrolytes and kidney structure. Cldn17-/- mice revealed no breeding abnormalities, but the newborn pups exhibited delayed growth. Adult Cldn17-/- mice displayed electrolyte imbalance, oxidative stress, and injury to the kidneys. Ingenuity pathway analysis followed by RNA-sequencing revealed hyperactivation of signaling pathways and downregulation of SOD1 expression in kidneys associated with inflammation and reactive oxygen species generation, demonstrating the importance of Cldn17 in the maintenance of electrolytes and reactive oxygen species across the blood-tissue barrier.

  View details for DOI 10.3390/cells11111782

  View details for PubMedID 35681477

• Regulation of Let-7a-5p and miR-199a-5p Expression by Akt1 Modulates Prostate Cancer Epithelial-to-Mesenchymal Transition via the Transforming Growth Factor-beta Pathway CANCERS Alwhaibi, A., Parvathagiri, V., Verma, A., Artham, S., Adil, M. S., Somanath, P. R. 2022; 14 (7)

  Abstract

  Akt1 suppression in advanced cancers has been indicated to promote metastasis. Our understanding of how Akt1 orchestrates this is incomplete. Using the NanoString®-based miRNA and mRNA profiling of PC3 and DU145 cells, and subsequent data analysis using the DIANA-mirPath, dbEMT, nCounter, and Ingenuity® databases, we identified the miRNAs and associated genes responsible for Akt1-mediated prostate cancer (PCa) epithelial-to-mesenchymal transition (EMT). Akt1 loss in PC3 and DU145 cells primarily induced changes in the miRNAs and mRNAs regulating EMT genes. These include increased miR-199a-5p and decreased let-7a-5p expression associated with increased TGFβ-R1 expression. Treatment with locked nucleic acid (LNA) miR-199a-5p inhibitor and/or let-7a-5p mimic induced expression changes in EMT genes correlating to their anticipated effects on PC3 and DU145 cell motility, invasion, and TGFβ-R1 expression. A correlation between increased miR-199a-5p and TGFβ-R1 expression with reduced let-7a-5p was also observed in high Gleason score PCa patients in the cBioportal database analysis. Collectively, our studies show the effect of Akt1 suppression in advanced PCa on EMT modulating miRNA and mRNA expression changes and highlight the potential benefits of miR-199a-5p and let-7a-5p in therapy and/or early screening of mPCa.

  View details for DOI 10.3390/cancers14071625

  View details for Web of Science ID 000781543100001

  View details for PubMedID 35406397

  View details for PubMedCentralID PMC8996869

• Bioinformatics analyses reveal cell-barrier junction modulations in lung epithelial cells on SARS-CoV-2 infection. Tissue barriers Adil, M. S., Khulood, D., Narayanan, S. P., Somanath, P. R. 2021: 2000300

  Abstract

  Cell junctions maintain the blood-tissue barriers to preserve vascular and tissue integrity. Viral infections reportedly modulate cell-cell junctions to facilitate their invasion. However, information on the effect of COVID-19 infection on the gene expression of cell junction and cytoskeletal proteins is limited. Using the Gene Expression Omnibus and Reactome databases, we analyzed the data on human lung A549, NHBE, and Calu-3 cells for the expression changes in cell junction and cytoskeletal proteins by SARS-CoV-2 (CoV-2) infection. The analysis revealed changes in 3,660 genes in A549, 100 genes in NHBE, and 592 genes in Calu-3 cells with CoV-2 infection. Interestingly, EGOT (9.8-, 3- and 8.3-fold; p < .05) and CSF3 (4.3-, 33- and 56.3-fold; p < .05) were the only two genes significantly elevated in all three cell lines (A549, NHBE and Calu-3, respectively). On the other hand, 39 genes related to cell junctions and cytoskeleton were modulated in lung cells, with DLL1 demonstrating alterations in all cells. Alterations were also seen in several miRNAs associated with the cell junction and cytoskeleton genes modulated in the analysis. Further, matrix metalloproteinases involved in disease pathologies, including MMP-3, -9, and -12 demonstrated elevated expression on CoV-2 infection (p < .05). The study findings emphasize the integral role of cell junction and cytoskeletal genes in COVID-19, suggesting their therapeutic potential. Our analysis also identified a distinct EGOT gene that has not been previously implicated in COVID-19. Further studies on these newly identified genes and miRNAs could lead to advances in the pathogenesis and therapeutics of COVID-19.

  View details for DOI 10.1080/21688370.2021.2000300

  View details for PubMedID 34740309

• Neuroprotective Effects of Fingolimod in a Cellular Model of Optic Neuritis CELLS Candadai, A. A., Liu, F., Verma, A., Adil, M. S., Alfarhan, M., Fagan, S. C., Somanath, P. R., Narayanan, S. 2021; 10 (11)

  Abstract

  Visual dysfunction resulting from optic neuritis (ON) is one of the most common clinical manifestations of multiple sclerosis (MS), characterized by loss of retinal ganglion cells, thinning of the nerve fiber layer, and inflammation to the optic nerve. Current treatments available for ON or MS are only partially effective, specifically target the inflammatory phase, and have limited effects on long-term disability. Fingolimod (FTY) is an FDA-approved immunomodulatory agent for MS therapy. The objective of the current study was to evaluate the neuroprotective properties of FTY in the cellular model of ON-associated neuronal damage. R28 retinal neuronal cell damage was induced through treatment with tumor necrosis factor-α (TNFα). In our cell viability analysis, FTY treatment showed significantly reduced TNFα-induced neuronal death. Treatment with FTY attenuated the TNFα-induced changes in cell survival and cell stress signaling molecules. Furthermore, immunofluorescence studies performed using various markers indicated that FTY treatment protects the R28 cells against the TNFα-induced neurodegenerative changes by suppressing reactive oxygen species generation and promoting the expression of neuronal markers. In conclusion, our study suggests neuroprotective effects of FTY in an in vitro model of optic neuritis.

  View details for DOI 10.3390/cells10112938

  View details for Web of Science ID 000723786000001

  View details for PubMedID 34831161

  View details for PubMedCentralID PMC8616192

• Akt-independent effects of triciribine on ACE2 expression in human lung epithelial cells: Potential benefits in restricting SARS-CoV2 infection. Journal of cellular physiology Adil, M. S., Verma, A., Rudraraju, M., Narayanan, S. P., Somanath, P. R. 2021; 236 (9): 6597-6606

  Abstract

  The severe acute respiratory syndrome coronavirus 2 that causes coronavirus disease 2019 (COVID-19) binds to the angiotensin-converting enzyme 2 (ACE2) to gain cellular entry. Akt inhibitor triciribine (TCBN) has demonstrated promising results in promoting recovery from advanced-stage acute lung injury in preclinical studies. In the current study, we tested the direct effect of TCBN on ACE2 expression in human bronchial (H441) and lung alveolar (A549) epithelial cells. Treatment with TCBN resulted in the downregulation of both messenger RNA and protein levels of ACE2 in A549 cells. Since HMGB1 plays a vital role in the inflammatory response in COVID-19, and because hyperglycemia has been linked to increased COVID-19 infections, we determined if HMGB1 and hyperglycemia have any effect on ACE2 expression in lung epithelial cells and whether TCBN has any effect on reversing HMGB1- and hyperglycemia-induced ACE2 expression. We observed increased ACE2 expression with both HMGB1 and hyperglycemia treatment in A549 as well as H441 cells, which were blunted by TCBN treatment. Our findings from this study, combined with our previous reports on the potential benefits of TCBN in the treatment of acute lung injury, generate reasonable optimism on the potential utility of TCBN in the therapeutic management of patients with COVID-19.

  View details for DOI 10.1002/jcp.30343

  View details for PubMedID 33624300

  View details for PubMedCentralID PMC8014085

• Vascular Permeability Assays In Vivo. Methods in molecular biology (Clifton, N.J.) Adil, M. S., Somanath, P. R. 2021; 2367: 165-175

  Abstract

  Whereas physiological vascular permeability (VP) mediates selective transport of plasma, electrolytes, proteins, and cells across an intact endothelial barrier, pathological VP results in the loss of endothelial barrier integrity. Whereas physiological VP is a feature of regular host defense and tissue repair, compromised barrier function may lead to aberrant vascular leakage, concurrent tissue edema, and inflammation eventually causing life-threatening conditions such as acute lung injury or acute respiratory distress syndrome, cancer, kidney injury, etc. Measurement of VP helps to identify, design, and optimize anti-leak therapies. Further, it can define the effect of a stimulus or a gene modulation in endothelial-barrier regulation. The degree of VP can be of importance to determine the stage of cancer and disease prognosis. This chapter discusses Miles assay, which is a well-established, relatively simple, and a reliable in vivo technique to assess VP as a surrogate measurement. Although a reliable technique, Miles assay is time-consuming, and the technique does not consider the compounding factors that may increase VP independently of endothelial-barrier regulation, such as blood pressure or blood flow. As an alternative, we describe fluorescein isothiocyanate-dextran lung permeability assay, a method that can also be adapted to measure VP and edema in other organs such as the brain and kidney.

  View details for DOI 10.1007/7651_2020_310

  View details for PubMedID 32803536

• Endothelial Permeability Assays In Vitro. Methods in molecular biology (Clifton, N.J.) Adil, M. S., Somanath, P. R. 2021; 2367: 177-191

  Abstract

  The endothelium is a thin layer of squamous cells that acts as a semipermeable barrier regulating vascular permeability to let molecules pass through it thereby maintaining tissue fluid homeostasis. Physiological increase in endothelial or vascular permeability is transient, transpired by post-tissue injury during the initial phases of healing, whereas pathological permeability is persistent commonly witnessed in conditions such as atherosclerosis, chronic inflammation, tumor growth, and diabetic retinopathy. The in vivo or in situ use of animal models in the assessment of permeability not only raises inevitable ethical concerns but also confers difficulty to apply to high-throughput screening. Therefore, there is an ever-increasing dependency on in vitro studies to assess drug permeability, and various research programs have suffered to develop appropriate in vitro assays for measurement and prediction. In vitro models that both mimic in vivo microvascular endothelium and can be utilized to record changes in endothelial permeability are vital in delineating the mechanisms involved in the prevention and treatment of disorders related to vascular permeability. The Transwell® and the electric cell-substrate impedance sensing (ECIS) assays are extensively used to assess the trans-endothelial permeability of solutes such as albumin, dextrans, and sucrose across endothelial monolayers and based on electrical resistance, etc. These models have several advantages such as the ease to perform and avoid the complexities of using a live animal.

  View details for DOI 10.1007/7651_2020_309

  View details for PubMedID 32691355

• Targeting Akt-associated microRNAs for cancer therapeutics. Biochemical pharmacology Adil, M. S., Khulood, D., Somanath, P. R. 2021; 189: 114384

  Abstract

  The uncontrolled growth and spread of abnormal cells because of activating protooncogenes and/or inactivating tumor suppressor genes are the hallmarks of cancer. The PI3K/Akt signaling is one of the most frequently activated pathways in cancer cells responsible for the regulation of cell survival and proliferation in stress and hypoxic conditions during oncogenesis. Non-coding RNAs are a large family of RNAs that are not involved in protein-coding, and microRNAs (miRNAs) are a sub-set of non-coding RNAs with a single strand of 18-25 nucleotides. miRNAs are extensively involved in the post-transcriptional regulation of gene expression and play an extensive role in the regulatory mechanisms including cell differentiation, proliferation, apoptosis, and tumorigenesis. The impact of cancer on mRNA stability and translation efficiency is extensive and therefore, cancerous tissues exhibit drastic alterations in the expression of miRNAs. miRNAs can be modulated by utilizing techniques such as miRNA mimics, miRNA antagonists, or CRISPR/Cas9. In addition to their capacity as potential targets in cancer therapy, they can be used as reliable biomarkers to diagnose the disease at the earliest stage. Recent evidence indicates that microRNA-mediated gene regulation intersects with the Akt pathway, forming an Akt-microRNA regulatory network. miRNAs and Akt in this network operate together to exert their cellular tasks. In the current review, we discuss the Akt-associated miRNAs in several cancers, their molecular regulation, and how this newly emerging knowledge may contribute greatly to revolutionize cancer therapy.

  View details for DOI 10.1016/j.bcp.2020.114384

  View details for PubMedID 33347867

  View details for PubMedCentralID PMC8187261

• Distinct effects of pharmacological inhibition of stromelysin1 on endothelial-to-mesenchymal transition and myofibroblast differentiation. Journal of cellular physiology Alharthi, A., Verma, A., Sabbineni, H., Adil, M. S., Somanath, P. R. 2021; 236 (7): 5147-5161

  Abstract

  Endothelial-to-mesenchymal transition (EndMT) and fibroblast-to-myofibroblast (FibroMF) differentiation are frequently reported in organ fibrosis. Stromelysin1, a matrix metalloprotease-3 (MMP3) has been indicated in vascular pathologies and organ injuries that often lead to fibrosis. In the current study, we investigated the role of stromelysin1 in EndMT and FibroMF differentiation, which is currently unknown. In our results, whereas TGFβ2 treatment of endothelial cells (ECs) induced EndMT associated with increased expression of stromelysin1 and mesenchymal markers such as α-smooth muscle actin (αSMA), N-cadherin, and activin linked kinase-5 (ALK5), inhibition of stromelysin1 blunted TGFβ2-induced EndMT. In contrast, treatment of NIH-3T3 fibroblasts with TGFβ1 promoted FibroMF differentiation accompanied by increased expression of αSMA, N-cadherin, and ALK5. Intriguingly, stromelysin1 inhibition in TGFβ1-stimulated myofibroblasts further exacerbated fibroproliferation with increased FibroMF marker expression. Gene Expression Omnibus (GEO) data analysis indicated increased stromelysin1 expression associated with EndMT and decreased stromelysin1 expression in human pulmonary fibrosis fibroblasts. In conclusion, our study has identified that EndMT and FibroMF differentiation are reciprocally regulated by stromelysin1.

  View details for DOI 10.1002/jcp.30221

  View details for PubMedID 33319933

  View details for PubMedCentralID PMC8026649

• Cisatracurium attenuates LPS-induced modulation of MMP3 and junctional protein expression in human microvascular endothelial cells. Bioscience trends Kadry, R. W., Adil, M. S., Newsome, A. S., Somanath, P. R. 2021; 15 (1): 50-54

  Abstract

  Acute respiratory distress syndrome (ARDS) is a life-threatening form of acute lung injury (ALI) associated with hypoxemic lung damage and inflammation. Matrix metalloproteinase protein-3 (MMP3 or Stromelysin-1) is known to promote vascular injury in ALI/ARDS. Cisatracurium, a nicotinic neuromuscular blocker, is used in ARDS patients to decrease mechanical ventilator dyssynchrony, increase oxygenation, and improve mortality. However, the magnitude and the underlying mechanisms of these potential benefits of cisatracurium remains unclear. We investigated the effect of cisatracurium on lipopolysaccharide-induced MMP3 expression in human microvascular endothelial cells. In our results, cisatracurium treatment significantly decreased LPS-induced MMP3 expression and increased expression of cell junction proteins such as vascular endothelial cadherin (VE-cadherin) and claudin-5.

  View details for DOI 10.5582/bst.2020.03399

  View details for PubMedID 33627570

  View details for PubMedCentralID PMC8106770

• Cell-cell junctions: structure and regulation in physiology and pathology. Tissue barriers Adil, M. S., Narayanan, S. P., Somanath, P. R. 2021; 9 (1): 1848212

  Abstract

  Epithelial and endothelial cell-cell contacts are established and maintained by several intercellular junctional complexes. These structurally and biochemically differentiated regions on the plasma membrane primarily include tight junctions (TJs), and anchoring junctions. While the adherens junctions (AJs) provide essential adhesive and mechanical properties, TJs hold the cells together and form a near leak-proof intercellular seal by the fusion of adjacent cell membranes. AJs and TJs play essential roles in vascular permeability. Considering their involvement in several key cellular functions such as barrier formation, proliferation, migration, survival, and differentiation, further research is warranted on the composition and signaling pathways regulating cell-cell junctions to develop novel therapeutics for diseases such as organ injuries. The current review article presents our current state of knowledge on various cell-cell junctions, their molecular composition, and mechanisms regulating their expression and function in endothelial and epithelial cells.

  View details for DOI 10.1080/21688370.2020.1848212

  View details for PubMedID 33300427

  View details for PubMedCentralID PMC7849786

• Differential regulation of TGFβ type-I receptor expressions in TGFβ1-induced myofibroblast differentiation. Canadian journal of physiology and pharmacology Gah, A., Adil, M. S., Sabbineni, H., Verma, A., Somanath, P. R. 2020; 98 (12): 841-848

  Abstract

  Fibroblast-to-myofibroblast (FibroMF) differentiation is crucial for embryogenesis and organ fibrosis. Although transforming growth factor-β (TGFβ) is the primary mediator of FibroMF differentiation, the type-I receptor (TGFβRI) responsible for this has not yet been confirmed. In the current study, we investigated the ALK1 and ALK5 expressions in TGFβ1-stimulated NIH 3T3 fibroblasts to compare with the data from the Gene Expression Omnibus (GEO) repository. In our results, whereas TGFβ1 treatment promoted FibroMF differentiation accompanied by increased ALK5 expression and reduced ALK1 expression, TGFβ1-induced FibroMF differentiation and increased α-smooth muscle actin (αSMA) and ALK5 expression were inhibited by co-treatment with ALK5 inhibitor SB431542. GEO database analysis indicated increased ALK5 expression and reduced ALK1 expression in fibrotic compared to normal mouse or human tissues correlating with organ fibrosis progression. Finally, the inhibitors of Akt, mTOR, and β-catenin suppressed TGFβ1-induced ALK5 expression, indicating that the Akt pathway promotes FibroMF differentiation via ALK5 expression and fibrosis.

  View details for DOI 10.1139/cjpp-2020-0123

  View details for PubMedID 32702244

• Is amiloride a promising cardiovascular medication to persist in the COVID-19 crisis? Drug discoveries & therapeutics Adil, M. S., Narayanan, S. P., Somanath, P. R. 2020; 14 (5): 256-258

  Abstract

  In the ongoing coronavirus diseases-2019 (COVID-19) crisis that caused immense suffering and deaths, the choice of therapy for the prevention and life-saving conditions must be based on sound scientific evidence. Uncertainty and apprehension are exacerbated in people using angiotensin-converting enzyme (ACE) inhibitors to control their comorbidities such as hypertension and diabetes. These drugs are reported to result in unfavorable outcome as they tend to increase the levels of ACE2 which mediates the entry of SARS-CoV-2. Amiloride, a prototypic inhibitor of epithelial sodium channels (ENaC) can be an ideal candidate for COVID-19 patients, given its ACE reducing and cytosolic pH increasing effects. Moreover, its potassium-sparing and anti-epileptic activities make it a promising alternative or a combinatorial agent.

  View details for DOI 10.5582/ddt.2020.03070

  View details for PubMedID 33116037

• Convalescent plasma appears efficacious and safe in COVID-19. Therapeutic advances in infectious disease Khulood, D., Adil, M. S., Sultana, R. 2020; 7: 2049936120957931

  Abstract

  A cluster of pneumonia cases of unknown etiology associated with pyrexia and acute respiratory distress was identified in Southern China. Links between the previous severe acute respiratory syndrome (SARS) cases and the region's seafood market were noted with the possibility of a new zoonosis and SARS-CoV-2 was identified as the responsible agent. Currently, there are no effective prophylactic or therapeutic options to deal with coronavirus disease-19 (COVID-19) or any other human coronavirus (HCoV) infections. Convalescent plasma (CP) therapy is a classic adaptive immunotherapy which has been in use for more a century to prevent and treat infections including SARS, Middle East respiratory syndrome (MERS), and H1N1 pandemic. Moreover, the World Health Organization regarded CP transfusion as the most promising therapy to treat MERS-CoV. This review was undertaken to demonstrate the potential of CP in the treatment of the pandemic COVID-19 disease. A total of eight studies conducted on CP therapy in patients with COVID-19 were reviewed wherein 25,028 patients above 18 years of age were involved. The vast majority of patients reported favorable outcomes when treated with CP with <1% serious adverse events. Despite its promising beneficial effects in patients severely ill with COVID-19, CP therapy requires further evaluation in randomized clinical trials (RCTs) as a lack of satisfactory efficacy data from this area certainly enhances the hesitancy with regard to employing this treatment. In the present circumstances of unsatisfactory pharmacological therapy and the urgent need for a successful curative remedy, considering the use of CP therapy is reasonable provided RCTs confirm its safety, efficacy, and tolerability.

  View details for DOI 10.1177/2049936120957931

  View details for PubMedID 33062267

  View details for PubMedCentralID PMC7534072

• PAK1 inhibitor IPA-3 mitigates metastatic prostate cancer-induced bone remodeling. Biochemical pharmacology Verma, A., Artham, S., Alwhaibi, A., Adil, M. S., Cummings, B. S., Somanath, P. R. 2020; 177: 113943

  Abstract

  Metastatic prostate cancer (PCa) has high mortality and a poor 5-year survival rate primarily due to the lack of effective treatments. Bone is the primary site of PCa metastasis in humans and the development of reliable therapeutic options for bone metastatic PCa will make a huge impact in reducing the mortality among these patients. Although P21 activated kinases (PAKs) have been studied in the past for their role in cancer, the efficacy of targeting PAKs to treat lung and bone metastatic PCa has not been tested yet. In the current study, we report that targeting PAK1 using IPA-3, an allosteric inhibitor of PAK1 kinase activity, significantly inhibits the murine metastatic PCa (RM1) cell proliferation and motility in vitro, and metastasis to the lungs in vivo. More importantly, we demonstrate for the first time that treatment with IPA-3 can blunt metastatic PCa-induced bone remodeling in vivo as analyzed by the 3-dimensional microcomputer tomography analysis. Our study has identified IPA-3 as a potential drug to treat bone metastatic PCa.

  View details for DOI 10.1016/j.bcp.2020.113943

  View details for PubMedID 32240651

  View details for PubMedCentralID PMC7414983

• Delayed Akt suppression in the lipopolysaccharide-induced acute lung injury promotes resolution that is associated with enhanced effector regulatory T cells. American journal of physiology. Lung cellular and molecular physiology Artham, S., Verma, A., Alwhaibi, A., Adil, M. S., Manicassamy, S., Munn, D. H., Somanath, P. R. 2020; 318 (4): L750-L761

  Abstract

  The adaptive immune response could play a major role in the resolution of lung injury. Although regulatory T cells (Tregs) have been implicated in promoting the resolution of lung injury, therapeutic strategies to enhance Treg quantity and activity at the site of injury need further exploration. In the current study, Akt inhibition using triciribine (TCBN), given 48 h after lipopolysaccharide (LPS) administration, increased Tregs-promoted resolution of acute lung injury (ALI). TCBN treatment enhanced the resolution of LPS-induced ALI on day 7 by reducing pulmonary edema and neutrophil activity associated with an increased number of CD4+/FoxP3+/CD103+ and CTLA4+ effector Tregs, specifically in the injured lungs and not in the spleen. Treatment of EL-4 T-lymphocytes with two Akt inhibitors (TCBN and MK-2206) for 72 h resulted in increased FoxP3 expression in vitro. On the other end, Treg-specific PTEN knockout (PTENTreg KO) mice that have a higher Akt activity in its Tregs exhibited a significant impairment in ALI resolution, increased edema, and neutrophil activity associated with a reduced number of CD4+/FoxP3+/CD103+ and CTLA4+ effector Tregs as compared with the control group. In conclusion, our study identifies a potential target for the treatment of late-stage ALI by promoting resolution through effector Treg-mediated suppression of inflammation.

  View details for DOI 10.1152/ajplung.00251.2019

  View details for PubMedID 32073894

  View details for PubMedCentralID PMC7191478

• PRIME study: Prescription review to impede medication errors. The International journal of risk & safety in medicine Adil, M. S., Sultana, R., Khulood, D. 2020; 31 (2): 67-79

  Abstract

  Medication errors may account up to one-third of all medical errors in hospitals, thereby leading to adverse outcomes such as higher mortality rate and longer hospital stay.The primary objective of the study was to determine whether patient safety can be improved by clinical pharmacy services. The study also aimed to reveal whether medication errors can be prevented by any means.A prospective, observational study was conducted in a multispecialty hospital in India. Prescription audit was performed for patients followed by necessary intervention by the concerned physician. Chi-squared test, paired t-test and ANOVA were performed to test statistical significance.A total of 699 errors were encountered by 501 of 1149 patients enrolled. Prescription errors accounted for the majority (87.1%) of errors followed by administration (7.4%), transcription (4.3%) and dispensing (1.2%) errors. Average error per patient showed a significant gradual decline from baseline (2.08) to the final follow-up (1.06). ICU patients encountered a higher rate (52.8%) of errors than general ward group (42.8%), while geriatric population witnessed a low error rate (18.8%) compared to adults (72%).The study was not only successful in highlighting the impact of medication error assessment on patient safety, but it also demonstrated that medication errors can be lowered with the help of clinical pharmacy services. Findings from the study conclude that medication errors can be prevented if healthcare professionals are educated appropriately to avoid recurrence of past mistakes.

  View details for DOI 10.3233/JRS-191025

  View details for PubMedID 32039861

• Nodal pathway activation due to Akt1 suppression is a molecular switch for prostate cancer cell epithelial-to-mesenchymal transition and metastasis. Biochemical pharmacology Alwhaibi, A., Verma, A., Artham, S., Adil, M. S., Somanath, P. R. 2019; 168: 1-13

  Abstract

  Several studies have unraveled the negative role of Akt1 in advanced cancers, including metastatic prostate cancer (mPCa). Hence, understanding the consequences of targeting Akt1 in the mPCa and identifying its downstream novel targets is essential. We studied how Akt1 deletion in PC3 and DU145 cells activates the Nodal pathway and promotes PCa epithelial-to-mesenchymal transition (EMT) and metastasis. Here we show that Akt1 loss increases Nodal expression in PCa cells accompanied by activation of FoxO1/3a, and EMT markers Snail and N-cadherin as well as loss of epithelial marker E-cadherin. Treatment with FoxO inhibitor AS1842856 abrogated the Nodal expression in Akt1 deleted PCa cells. Akt1 deficient PCa cells exhibited enhanced cell migration and invasion in vitro and lung metastasis in vivo, which were attenuated by treatment with Nodal pathway inhibitor SB505124. Interestingly, Nodal mRNA analysis from two genomic studies in cBioportal showed a positive correlation between Nodal expression and Gleason score indicating the positive role of Nodal in human mPCa. Collectively, our data demonstrate Akt1-FoxO3a-Nodal pathway as an important mediator of PCa metastasis and present Nodal as a potential target to treat mPCa patients.

  View details for DOI 10.1016/j.bcp.2019.06.010

  View details for PubMedID 31202735

  View details for PubMedCentralID PMC6733630

• The unconventional role of Akt1 in the advanced cancers and in diabetes-promoted carcinogenesis. Pharmacological research Alwhaibi, A., Verma, A., Adil, M. S., Somanath, P. R. 2019; 145: 104270

  Abstract

  Decades of research have elucidated the critical role of Akt isoforms in cancer as pro-tumorigenic and metastatic regulators through their specific effects on the cancer cells, tumor endothelial cells and the stromal cells. The pro-cancerous role of Akt isoforms through enhanced cell proliferation and suppression of apoptosis in cancer cells and the cells in the tumor microenvironment is considered a dogma. Intriguingly, studies also indicate that the Akt pathway is essential to protect the endothelial-barrier and prevent aberrant vascular permeability, which is also integral to tumor perfusion and metastasis. To complicate this further, a flurry of recent reports strongly indicates the metastasis suppressive role of Akt, Akt1 in particular in various cancer types. These reports emanated from different laboratories have elegantly demonstrated the paradoxical effect of Akt1 on cancer cell epithelial-to-mesenchymal transition, invasion, tumor endothelial-barrier disruption, and cancer metastasis. Here, we emphasize on the specific role of Akt1 in mediating tumor cell-vasculature reciprocity during the advanced stages of cancers and discuss how Akt1 differentially regulates cancer metastasis through mechanisms distinct from its pro-tumorigenic effects. Since Akt is integral for insulin signaling, endothelial function, and metabolic regulation, we also attempt to shed some light on the specific effects of diabetes in modulating Akt pathway in the promotion of tumor growth and metastasis.

  View details for DOI 10.1016/j.phrs.2019.104270

  View details for PubMedID 31078742

  View details for PubMedCentralID PMC6659399

• EMPADE Study: Evaluation of Medical Prescriptions and Adverse Drug Events in COPD Patients Admitted to Intensive Care Unit. Journal of clinical and diagnostic research : JCDR Adil, M. S., Khan, M. A., Khan, M. N., Sultan, I., Khan, M. A., Ali, S. A., Farooqui, A. 2015; 9 (11): FC05-8

  Abstract

  Inappropriate drug usage may preclude ideal benefit due to increased medical cost, antimicrobial resistance, adverse effects and mortality. Therefore drug utilization studies have become a plausible means in evaluating the healthcare systems. COPD management usually involves more than one drug which may escalate the risk of ADEs (adverse drug events).The present study was aimed at assessing the current drug practice and ADEs in COPD management in ICU.A total of 1,044 patients admitted for the treatment of COPD were included in the study. Their prescriptions were recorded for evaluation of drug utilization and patients were counseled for assessing ADEs. Results were evaluated by Chi-square test and percentages.All-embracing 15,360 drugs were prescribed at an average of 14.71 drugs per patient, wherein β2-agonists were extensively prescribed agents followed by inhaled-corticosteroids and anti-cholinergics. 372 ADEs were reported in 252 patients, wherein restlessness was the most frequent ADE and theophylline was found to be associated with highest cases of ADEs.Practitioners should prescribe least number of drugs to mitigate the likelihood of adverse outcomes in patients due to numerous drugs usage, which may be achieved by following GOLD guidelines. The present work may help in improving the current management of COPD by rectifying the flaws delineated in this article.

  View details for DOI 10.7860/JCDR/2015/14563.6721

  View details for PubMedID 26675667

  View details for PubMedCentralID PMC4668426

• Causality assessment of adverse drug reaction in Pulmonology Department of a Tertiary Care Hospital. Journal of basic and clinical pharmacy Khan, A., Adil, M. S., Nematullah, K., Ihtisham, S., Aamer, K., Aamir, S. 2015; 6 (3): 84-8

  Abstract

  Adverse drug reaction (ADR) is considered to be the sixth leading cause of death. The incidence rate estimates approximately 2% of hospital admissions are due to ADRs.To monitor ADRs in Pulmonology department of a tertiary care hospital patient with pulmonary diseases in an inpatient department of pulmonology.A prospective, single centered, observational and open labeled study was carried out in Princess Esra Hospital. The patient population was broadly divided into four categories based on diagnosis - chronic obstructive pulmonary disease, Infections, Asthma and Others. Suspected ADRs were reported, analyzed, and causality assessment was carried out using Naranjo's algorithm scale.A total of 302 patients were observed, of which 98 patients experienced ADRs, which accounted for 32.23% of the incidence and totally 160 ADEs were observed. Adult Patients were found to have higher incidence (32.09%) while the incidence rate was slightly greater in geriatric patients (32.39%). The highest incidence of ADEs were found in others group (78.57%). Majority of ADRs were suspected to be due to theophylline (19.39%). Gastrointestinal system (38.75%) was the most common organ system affected due to ADRs. Drug was withdrawn in 12 patients, and specific treatment was administered to 32 patients in view of clinical status. Specific treatment for the management of suspected reaction was administered in 32.65% of ADR reports.A relatively high incidence of adverse drug events (32.2%) have been recorded which shows that not only Geriatric patients, but also adults are more susceptible to adverse drug effects. A number of drugs in combination were used, and ADEs often get multiplied. Careful therapeutic monitoring and dose individualization is necessary.

  View details for DOI 10.4103/0976-0105.160744

  View details for PubMedID 26229344

  View details for PubMedCentralID PMC4513336

• ASSESSMENT OF PARENTAL UNDERSTANDING OF PAEDIATRIC MEDICAL PRESCRIPTIONS INTERNATIONAL JOURNAL OF MEDICAL RESEARCH & HEALTH SCIENCES Anjum, S., Mohiuddin, M., Reddy, N. U., Rao, N. J., Afreen, S., Adil, M. S., Javeedullah, M. 2014; 3 (3): 541-546

  View details for DOI 10.5958/2319-5886.2014.00393.2

  View details for Web of Science ID 000215297100007