Publications by authors named "Syed A Ali"

97 Publications

Transcriptional Repression of MFG-E8 Causes Disturbance in the Homeostasis of Cell Cycle Through DOCK/ZP4/STAT Signaling in Buffalo Mammary Epithelial Cells.

Front Cell Dev Biol 2021 1;9:568660. Epub 2021 Apr 1.

Proteomics and Cell Biology Lab, Animal Biotechnology Center, ICAR-National Dairy Research Institute, Karnal, India.

The mammary gland is a unique apocrine gland made up of a branching network of ducts that end in alveoli. It is an ideal system to study the molecular mechanisms associated with cell proliferation, differentiation, and oncogenesis. MFG-E8, also known as Lactadherin, is a vital glycoprotein related to the milk fat globule membrane and initially identified to get secreted in bovine milk. Our previous report suggests that a high level of MFG-E8 is indicative of high milk yield in dairy animals. Here, we showed that MFG-E8 controls the cell growth and morphology of epithelial cells through a network of regulatory transcription factors. To understand the comprehensive action, we downregulated its expression in MECs by MFG-E8 specific shRNA. We generated a knockdown proteome profile of differentially expressed proteins through a quantitative iTRAQ experiment on a high-resolution mass spectrometer (Q-TOF). The downregulation of MFG-E8 resulted in reduced phagocytosis and cell migration ability, whereas it also leads to more lifespan to knockdown vis-a-vis healthy cells, which is confirmed through BrdU, MTT, and Caspase 3/7. The bioinformatics analysis revealed that MFG-E8 knockdown perturbs a large number of intracellular signaling, eventually leading to cessation in cell growth. Based on the directed network analysis, we found that MFG-E8 is activated by CX3CL1, TP63, and CSF2 and leads to the activation of SOCS3 and CCL2 for the regulation of cell proliferation. We further proved that the depletion of MFG-E8 resulted in activated cytoskeletal remodeling by MFG-E8 knockdown, which results in the activation of three independent pathways ZP4/JAK-STAT5, DOCK1/STAT3, and PIP3/AKT/mTOR. Overall, this study suggests that MFG-E8 expression in mammary epithelial cells is an indication of intracellular deterioration in cell health. To date, to the best of our knowledge, this is the first study that explores the downstream targets of MFG-E8 involved in the regulation of mammary epithelial cell health.
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http://dx.doi.org/10.3389/fcell.2021.568660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047144PMC
April 2021

Extensive Variation in the Activities of and Viper Venoms Suggests Divergent Envenoming Strategies Are Used for Prey Capture.

Toxins (Basel) 2021 02 2;13(2). Epub 2021 Feb 2.

Venom Evolution Lab, School of Biological Sciences, University of Queensland, St Lucia, QLD 4072, Australia.

Snakes of the genera and (Viperidae: Viperinae) are known as the desert vipers due to their association with the arid environments of the Middle East. These species have received limited research attention and little is known about their venom or ecology. In this study, a comprehensive analysis of desert viper venoms was conducted by visualising the venom proteomes via gel electrophoresis and assessing the crude venoms for their cytotoxic, haemotoxic, and neurotoxic properties. Plasmas sourced from human, toad, and chicken were used as models to assess possible prey-linked venom activity. The venoms demonstrated substantial divergence in composition and bioactivity across all experiments. venom activated human coagulation factors X and prothrombin and demonstrated potent procoagulant activity in human, toad, and chicken plasmas, in stark contrast to the potent neurotoxic venom of . The venom of also induced coagulation, though this did not appear to be via the activation of factor X or prothrombin. The coagulant properties of and venoms varied among plasmas, demonstrating strong anticoagulant activity in the amphibian and human plasmas but no significant effect in that of bird. This is conjectured to reflect prey-specific toxin activity, though further ecological studies are required to confirm any dietary associations. This study reinforces the notion that phylogenetic relatedness of snakes cannot readily predict venom protein composition or function. The significant venom variation between these species raises serious concerns regarding antivenom paraspecificity. Future assessment of antivenom is crucial.
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http://dx.doi.org/10.3390/toxins13020112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7913145PMC
February 2021

Current landscape in motoneuron regeneration and reconstruction for motor cranial nerve injuries.

Neural Regen Res 2020 Sep;15(9):1639-1649

Department of Otolaryngology-Head and Neck Surgery, University of Michigan Medical School, Ann Arbor, MI, USA.

The intricate anatomy and physiology of cranial nerves have inspired clinicians and scientists to study their roles in the nervous system. Damage to motor cranial nerves may result from a variety of organic or iatrogenic insults and causes devastating functional impairment and disfigurement. Surgical innovations directed towards restoring function to injured motor cranial nerves and their associated organs have evolved to include nerve repair, grafting, substitution, and muscle transposition. In parallel with this progress, research on tissue-engineered constructs, development of bioelectrical interfaces, and modulation of the regenerative milieu through cellular, immunomodulatory, or neurotrophic mechanisms has proliferated to enhance the available repertoire of clinically applicable reconstructive options. Despite these advances, patients continue to suffer from functional limitations relating to inadequate cranial nerve regeneration, aberrant reinnervation, or incomplete recovery of neuromuscular function. These shortfalls have profound quality of life ramifications and provide an impetus to further elucidate mechanisms underlying cranial nerve denervation and to improve repair. In this review, we summarize the literature on reconstruction and regeneration of motor cranial nerves following various injury patterns. We focus on seven cranial nerves with predominantly efferent functions and highlight shared patterns of injuries and clinical manifestations. We also present an overview of the existing reconstructive approaches, from facial reanimation, laryngeal reinnervation, to variations of interposition nerve grafts for reconstruction. We discuss ongoing endeavors to promote nerve regeneration and to suppress aberrant reinnervation and the development of synkinesis. Insights from these studies will shed light on recent progress and new horizons in understanding the biomechanics of peripheral nerve neurobiology, with emphasis on promising strategies for optimizing neural regeneration and identifying future directions in the field of motor cranial neuron research.
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http://dx.doi.org/10.4103/1673-5374.276325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7437597PMC
September 2020

Functional venomics of the Big-4 snakes of Pakistan.

Toxicon 2020 May 12;179:60-71. Epub 2020 Mar 12.

H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences (ICCBS), University of Karachi, Karachi, 75270, Pakistan. Electronic address:

In South Asia, the "Big-4" venomous snakes Naja naja, Bungarus caeruleus, Daboia russelii, and Echis carinatus are so-called because they are the most medically important snakes in the region. Antivenom is the only effective treatment option for snakebite envenoming but antivenom is not produced domestically in Pakistan making the country reliant on polyvalent products imported from India and Saudi Arabia. The present study investigated the toxin composition and activity of the venoms of Pakistani specimens by means of proteomic and physio/pharmacological experiments. To evaluate the composition of venoms, 1D/2D-PAGE of crude venoms and RP-HPLC followed by SDS-PAGE were performed. Enzymatic, hemolytic, coagulant and platelet aggregating activities of crude venoms were assayed and were concordant with expectations based on the abundance of protein species in each. Neutralization assays were performed using Bharat polyvalent antivenom (BPAV), a product raised against venoms from Big-4 specimens from southern India. BPAV exhibited cross-reactivity against the Pakistani venoms, however, neutralization of clinically relevant activities was variable and rarely complete. Cumulatively, the presented data not only highlight geographical variations present in the venoms of the Big-4 snakes of South Asia, but also demonstrate the neutralization potential of Indian polyvalent against the venom of Pakistani specimens. Given the partial neutralization observed, it is clear that whilst BPAV is a life-saving product in Pakistan, in future it is hoped that a region-specific product might be manufactured domestically, using venoms of local snakes in the immunising mixture.
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http://dx.doi.org/10.1016/j.toxicon.2020.03.001DOI Listing
May 2020

A novel histological index for evaluation of environmental enteric dysfunction identifies geographic-specific features of enteropathy among children with suboptimal growth.

PLoS Negl Trop Dis 2020 01 13;14(1):e0007975. Epub 2020 Jan 13.

Department of Pathology, University of Virginia, Charlottesville, VA, United States of America.

Background: A major limitation to understanding the etiopathogenesis of environmental enteric dysfunction (EED) is the lack of a comprehensive, reproducible histologic framework for characterizing the small bowel lesions. We hypothesized that the development of such a system will identify unique histology features for EED, and that some features might correlate with clinical severity.

Methods: Duodenal endoscopic biopsies from two cohorts where EED is prevalent (Pakistan, Zambia) and North American children with and without gluten sensitive enteropathy (GSE) were processed for routine hematoxylin & eosin (H&E) staining, and scanned to produce whole slide images (WSIs) which we shared among study pathologists via a secure web browser-based platform. A semi-quantitative scoring index composed of 11 parameters encompassing tissue injury and response patterns commonly observed in routine clinical practice was constructed by three gastrointestinal pathologists, with input from EED experts. The pathologists then read the WSIs using the EED histology index, and inter-observer reliability was assessed. The histology index was further used to identify within- and between-child variations as well as features common across and unique to each cohort, and those that correlated with host phenotype.

Results: Eight of the 11 histologic scoring parameters showed useful degrees of variation. The overall concordance across all parameters was 96% weighted agreement, kappa 0.70, and Gwet's AC 0.93. Zambian and Pakistani tissues shared some histologic features with GSE, but most features were distinct, particularly abundance of intraepithelial lymphocytes in the Pakistani cohort, and marked villous destruction and loss of secretory cell lineages in the Zambian cohort.

Conclusions: We propose the first EED histology index for interpreting duodenal biopsies. This index should be useful in future clinical and translational studies of this widespread, poorly understood, and highly consequential disorder, which might be caused by multiple contributing processes, in different regions of the world.
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http://dx.doi.org/10.1371/journal.pntd.0007975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6980693PMC
January 2020

Contextual Fear Conditioning Alter Microglia Number and Morphology in the Rat Dorsal Hippocampus.

Front Cell Neurosci 2019 14;13:214. Epub 2019 May 14.

School of Clinical Sciences, Queensland University of Technology, Brisbane, QLD, Australia.

Contextual fear conditioning is a Pavlovian conditioning paradigm capable of rapidly creating fear memories to contexts, such as rooms or chambers. Contextual fear conditioning protocols have long been utilized to evaluate how fear memories are consolidated, maintained, expressed, recalled, and extinguished within the brain. These studies have identified the lateral portion of the amygdala and the dorsal portion of the hippocampus as essential for contextual fear memory consolidation. The current study was designed to evaluate how two different contextual fear memories alter amygdala and hippocampus microglia, brain derived neurotrophic factor (BDNF), and phosphorylated cyclic-AMP response element binding (pCREB). We find rats provided with standard contextual fear conditioning to have more microglia and more cells expressing BDNF in the dentate gyrus as compared to a context only control group. Additionally, standard contextual fear conditioning altered microglia morphology to become amoeboid in shape - a common response to central nervous system insult, such as traumatic brain injury, infection, ischemia, and more. The unpaired fear conditioning procedure (whereby non-reinforced and non-overlapping auditory tones were provided at random intervals during conditioning), despite producing equivalent levels of fear as the standard procedure, did not alter microglia, BDNF or pCREB number in any dorsal hippocampus or lateral amygdala brain regions. Despite this, the unpaired fear conditioning protocol produced some alterations in microglia morphology, but less compared to rats provided with standard contextual fear conditioning. Results from this study demonstrate that contextual fear conditioning is capable of producing large alterations to dentate gyrus plasticity and microglia, whereas unpaired fear conditioning only produces minor changes to microglia morphology. These data show, for the first time, that Pavlovian fear conditioning protocols can induce similar responses as trauma, infection or other insults within the central nervous system.
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http://dx.doi.org/10.3389/fncel.2019.00214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6527886PMC
May 2019

Effect of Alcohol and Tea on Solubility of Soft-liner and Polymethyl Methacrylate Resin: An In Vitro Study.

J Contemp Dent Pract 2019 Jan 1;20(1):83-88. Epub 2019 Jan 1.

Department of Orthodontics, Peoples College of Dental Sciences, Bhopal, Madhya Pradesh, India.

Aim: To evaluate solubility of soft denture liner material and acrylic denture base resin when stored in 8% and 50% concentration of alcohol and tea(with milk and green tea) at an interval of 4,7,11 and 15 days.

Materials And Methods: An in vitro study wasdone on 75 standardized samples in disk form (15 mm × 2 mm), each for soft-liner and acrylic denture base resin. Samples were divided into 5 groups (15 per group/per material) and stored in distilled water (A), 8% alcohol (B), 50% alcohol (C), tea with milk (D) and green tea (E). Solubility was determined at each time interval by dividing difference of weight (taken after drying the sample in a desiccator) from day 1 divided by surface area of the specimen. For each day (i.e., 4, 7, 11 and 15),one-way analysis of variance (ANOVA) test was used to determine if the distribution of mean solubility was similar in five groups followed by post-hoc Tukey's test for pair-wise comparisons.

Results: Mean solubility of soft-liner was the highest tea with milk (D) followed by green tea (E), then 50% and 8 % alcohol (C and B) and was least in group A at each time of measurement. Mean solubility of an acrylic resin was highest for 8% alcohol (B) and all other groups it was similar.

Conclusion: This study shows increased solubility for soft-liners when immersed in tea with milk, green tea, and alcohol at 8% and 50% concentration. The solubility of acrylic resin also increases at 8% alcohol concentration.

Clinical Significance: Drinks/beverages used in our study are commonly consumed, the results of this study caution for restricting the frequency of intake. However, this needs to be confirmed by in-vivo studies designed to prove the association of denture life with the consumption pattern of these drinks/ beverages.
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January 2019

Lactate Dehydrogenase and β-Glucuronidase as Salivary Biochemical Markers of Periodontitis Among Smokers and Non-Smokers.

Sultan Qaboos Univ Med J 2018 Aug 19;18(3):e318-e323. Epub 2018 Dec 19.

Department of Periodontology, Aligarh Muslim University, Aligarh, Uttar Pradesh, India.

Objectives: This study aimed to establish lactate dehydrogenase (LDH) and β-glucuronidase as salivary biomarkers of periodontitis among smokers and non-smokers.

Methods: This cross-sectional case-control study was conducted at the Aligarh Muslim University, Aligarh, India, between January and June 2017. A total of 200 participants were divided into four groups based on their periodontal and smoking statuses. Unstimulated mixed saliva samples were collected to estimate LDH and β-glucuronidase levels. In addition, total protein was estimated using Lowry's method.

Results: There was a significant increase in enzyme activity in the periodontitis groups compared to the non-periodontitis groups ( <0.001). However, significantly lower enzyme activity was observed among smokers, irrespective of periodontal status ( <0.001). Nevertheless, a receiver operating characteristic curve analysis indicated the diagnostic potential of both enzymes to be fair-to-excellent.

Conclusion: Although smoking was found to significantly alter enzyme activity, LDH and β-glucuronidase were reliable salivary biomarkers of periodontitis among both smokers and non-smokers.
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http://dx.doi.org/10.18295/squmj.2018.18.03.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6307631PMC
August 2018

Protein kinase C: A versatile oncogene in the lung.

Mol Cell Oncol 2018 10;5(5):e1190886. Epub 2018 May 10.

Department of Cancer Biology, Mayo Clinic Florida Jacksonville, Florida.

We have recently demonstrated that protein kinase C (PKC) promotes a stem-like, tumor-initiating cell phenotype in -driven lung adenocarcinoma by activating a novel ELF3-NOTCH3 signaling axis. Combined PKC and NOTCH inhibition was identified as a novel strategy for the treatment of -driven lung adenocarcinoma.
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http://dx.doi.org/10.1080/23723556.2016.1190886DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6154840PMC
May 2018

The unravelled Enterococcus faecalis zoonotic superbugs: Emerging multiple resistant and virulent lineages isolated from poultry environment.

Zoonoses Public Health 2018 12 13;65(8):921-935. Epub 2018 Aug 13.

International Center for Chemical and Biological Sciences (ICCBS), H.E.J. Research Institute of Chemistry, University of Karachi, Karachi, Pakistan.

This study aimed to investigate the zoonotic potential by virtue of phylogenetic analysis, virulence and resistance gene profiles of Enterococcus faecalis originating from poultry environment. The ERIC, BOX and RAPD PCR analysis showed the clustering of E. faecalis strains (n = 74) into five groups (G1-G5) and fifteen sub-clusters (B1-B15), which share 50%-80% similarities with ATCC E. faecalis and clinical strains of human infection. E. faecalis strains harboured seven enterocins genes including ent1097 (85%), entB (84%), enterolysinA (51%), entSEK4 (51%), entL50 (31%), entA (25.7%) and ent1071 (14.9%). The highest prevalence of gelE-sprE (90%), lip-fl (90%) followed by cylL (62%), hyl (60%), katA (16%) and cylA (5.4%) was observed in poultry isolates. The fsr operon and gelE-sprE was co-associated in 66.2% strains. E. faecalis also harboured biofilm and endocarditis-associated genes, including efaAfs (97%), ebp-pilli (ebpABC and srtC 69.9%-80%), asa1 (71%), agg (55%), ace (54%) and esp-Tim (3%). Despite all found sensitive to vancomycin, 98.6% strains were multi-drug resistant to five to twelve tested antimicrobials. An increased-level of resistance (≥32 μg/ml) was observed to ampicillin (8.1%), meropenem (21.6%), chloramphenicol (73.4%), erythromycin (90.5%), tetracycline (100%) and high-level resistance to kanamycin (79.7%) and gentamicin (52.7%). The multi-drug resistant E. faecalis (MDRe.f) were carried pbp4 (90%), tetL (90%), tetM (70%), ermB (81%), cat (52.7%), acc6-aph2 (58.1%), aaph(3)-III (49.9%), gyrA (97%) and parC (98%) genes. Moreover, these MDRe.f were also harboured, hospital-associated marker IS16 (58%) and pheromone responsive genes, that is ccf (88%), cpd (74%), cob (62%) and eep (66%). Thus, regardless of the distinct phylogenetic background of E. faecalis of poultry origin, ATCC E. faecalis and clinical strains of human origin, we found major similarities in virulence, resistance gene profiles and mobile genetic elements (IS16 and pheromone responsive plasmids), supporting the zoonotic/reverse zoonotic risk associated with this organism.
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http://dx.doi.org/10.1111/zph.12512DOI Listing
December 2018

Isolation and characterization of a novel anti-salbutamol chicken scFv for human doping urinalysis.

Anal Biochem 2018 08 23;555:81-93. Epub 2018 Jun 23.

Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia (USM), 11800, Minden, Penang, Malaysia. Electronic address:

Anti-salbutamol antibodies remain as important tools for the detection of salbutamol abuse in athletic doping. This study evaluated the feasibility and efficiency of the chicken (Gallus gallus domesticus) as an immunization host to generate anti-salbutamol scFv antibodies by phage display. A phage display antibody library was constructed from a single chicken immunized against salbutamol-KLH conjugate. After a stringent biopanning strategy, a novel scFv clone which was inhibited by free salbutamol recorded the highest affinity. This scFv was expressed as soluble and functional protein in Escherichia coli T7 SHuffle Express B (DE3) strain. Cross-reactivity studies of the scFv towards other relevant β2-agonists revealed that the scFv cross-reacted significantly towards clenbuterol. The determined IC of the scFv towards the two β2-agonists were; IC salbutamol = ∼0.310 μg/ml, IC clenbuterol = ∼0.076 μg/ml. The generated scFv demonstrated poor stability based on accelerated stability studies. The scFv was used to develop an competitive indirect ELISA (LOD = 0.125 μg/ml) for detection of parent salbutamol in spiked human urine (n = 18) with ∼83.4% reliability at the cut-off of 1 μg/ml currently implemented by WADA and may be of potential use in human doping urinalysis.
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http://dx.doi.org/10.1016/j.ab.2018.05.009DOI Listing
August 2018

Correlation of TP53 Overexpression and Clinical Parameters with Five-Year Survival in Oral Squamous Cell Carcinoma Patients.

Cureus 2017 Jun 27;9(6):e1401. Epub 2017 Jun 27.

Surgery, The Aga Khan University.

Introduction TP53 mutation and overexpression have been correlated with poor survival in many cancers including oral squamous cell carcinoma (OSCC). We aim to understand the role of TP53 overexpression in OSCC in our population and correlate it with five-year survival to test its viability as a prognostic marker for OSCC patients. Materials and methods Patients with biopsy proven OSCC at Aga Khan University Hospital from January 2000 to January 2008 were recruited. Immunohistochemistry was used to establish TP53 status and the results were published. Following up on these patients, five-year data were collected and correlated with TP53 status and other clinicopathologic parameters. Results Overexpression of TP53 was not significantly associated with five-year survival (hazard ratio [HR]: 1.543; 95% CI: 0.911-2.612; p = 0.107). Conclusion Although we had proven statistical relevance when correlated with overall survival in our previous study, we were unable to extend the same relevance to TP53 overexpression when it comes to five-year survival.
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http://dx.doi.org/10.7759/cureus.1401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5573341PMC
June 2017

Differential procoagulant effects of saw-scaled viper (Serpentes: Viperidae: Echis) snake venoms on human plasma and the narrow taxonomic ranges of antivenom efficacies.

Toxicol Lett 2017 Oct 25;280:159-170. Epub 2017 Aug 25.

Venom Evolution Lab, School of Biological Sciences, University of Queensland, St Lucia QLD 4072 Australia. Electronic address:

Saw-scaled vipers (genus Echis) are one of the leading causes of snakebite morbidity and mortality in parts of Sub-Saharan Africa, the Middle East, and vast regions of Asia, constituting a public health burden exceeding that of almost any other snake genus globally. Venom-induced consumption coagulopathy, owing to the action of potent procoagulant toxins, is one of the most relevant clinical manifestations of envenomings by Echis spp. Clinical experience and prior studies examining a limited range of venoms and restricted antivenoms have demonstrated for some antivenoms an extreme lack of antivenom cross-reactivity between different species of this genus, sometimes resulting in catastrophic treatment failure. This study undertook the most comprehensive testing of Echis venom effects upon the coagulation of human plasma, and also the broadest examination of antivenom potency and cross-reactivity, to-date. 10 Echis species/populations and four antivenoms (two African, two Asian) were studied. The results indicate that the venoms are, in general, potently procoagulant but that the relative dependence on calcium or phospholipid cofactors is highly variable. Additionally, three out of the four antivenoms tested demonstrated only a very narrow taxonomic range of effectiveness in preventing coagulopathy, with only the SAIMR antivenom displaying significant levels of cross-reactivity. These results were in conflict with previous studies using prolonged preincubation of antivenom with venom to suggest effective cross-reactivity levels for the ICP Echi-Tab antivenom. These findings both inform upon potential clinical effects of envenomation in humans and highlight the extreme limitations of available treatment. It is hoped that this will spur efforts into the development of antivenoms with more comprehensive coverage for bites not only from wild snakes but also from specimens widely kept in zoological collections.
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http://dx.doi.org/10.1016/j.toxlet.2017.08.020DOI Listing
October 2017

Altered antibacterial activity of Curcumin in the presence of serum albumin, plasma and whole blood.

Pak J Pharm Sci 2017 Mar;30(2):449-457

Cluster of Oncological and Radiological Sciences, Advanced Medical and Dental Institute (AMDI), University Sains Malaysia (USM), Bertam, Kepala Batas, Pulau Pinang, Malaysia.

Antibacterial effect is one of the major therapeutic activities of plant-derived Curcumin. This work evaluated the effect of serum albumin, human plasma, and whole blood on the in vitro activity of Curcumin against eight clinical bacterial isolates by standard broth microdilution and plate-counting methods. Toxicological effects of Curcumin towards human red blood cells (RBCs) and peripheral blood mononuclear cells (PBMCs) were also investigated. Curcumin exhibited weak activity against gram-negative bacteria, except Escherichia coli and Shigella flexneri were susceptible and was most active against gram-positive bacteria: Staphylococcus aureus, Streptococcus pyogenes and Enterococcus faecalis. The antibacterial activity was impaired in the presence of bovine serum albumin (BSA), human plasma and whole blood. Curcumin was not toxic to PBMCs and RBCs at 200μg/mL. Furthermore, Curcumin showed synergistic activity in combination with antibiotics: Ciprofloxacin, Gentamicin, Vancomycin and Amikacin against Staphylococcus aureus. This study demonstrated that the interaction of Curcumin with plasma proteins diminishes its in vitro antibacterial activity. Curcumin derivatives with reduced affinity for plasma protein may improve the bioavailability and antibacterial activities.
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March 2017

The Evolution of Fangs, Venom, and Mimicry Systems in Blenny Fishes.

Curr Biol 2017 Apr 30;27(8):1184-1191. Epub 2017 Mar 30.

Venom Evolution Lab, School of Biological Sciences, The University of Queensland, St Lucia, QLD 4072, Australia. Electronic address:

Venom systems have evolved on multiple occasions across the animal kingdom, and they can act as key adaptations to protect animals from predators [1]. Consequently, venomous animals serve as models for a rich source of mimicry types, as non-venomous species benefit from reductions in predation risk by mimicking the coloration, body shape, and/or movement of toxic counterparts [2-5]. The frequent evolution of such deceitful imitations provides notable examples of phenotypic convergence and are often invoked as classic exemplars of evolution by natural selection. Here, we investigate the evolution of fangs, venom, and mimetic relationships in reef fishes from the tribe Nemophini (fangblennies). Comparative morphological analyses reveal that enlarged canine teeth (fangs) originated at the base of the Nemophini radiation and have enabled a micropredatory feeding strategy in non-venomous Plagiotremus spp. Subsequently, the evolution of deep anterior grooves and their coupling to venom secretory tissue provide Meiacanthus spp. with toxic venom that they effectively employ for defense. We find that fangblenny venom contains a number of toxic components that have been independently recruited into other animal venoms, some of which cause toxicity via interactions with opioid receptors, and result in a multifunctional biochemical phenotype that exerts potent hypotensive effects. The evolution of fangblenny venom has seemingly led to phenotypic convergence via the formation of a diverse array of mimetic relationships that provide protective (Batesian mimicry) and predatory (aggressive mimicry) benefits to other fishes [2, 6]. Our results further our understanding of how novel morphological and biochemical adaptations stimulate ecological interactions in the natural world.
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http://dx.doi.org/10.1016/j.cub.2017.02.067DOI Listing
April 2017

How the Cobra Got Its Flesh-Eating Venom: Cytotoxicity as a Defensive Innovation and Its Co-Evolution with Hooding, Aposematic Marking, and Spitting.

Toxins (Basel) 2017 03 13;9(3). Epub 2017 Mar 13.

Venom Evolution Lab, School of Biological Sciences, University of Queensland, St. Lucia, QLD 4072, Australia.

The cytotoxicity of the venom of 25 species of Old World elapid snake was tested and compared with the morphological and behavioural adaptations of hooding and spitting. We determined that, contrary to previous assumptions, the venoms of spitting species are not consistently more cytotoxic than those of closely related non-spitting species. While this correlation between spitting and non-spitting was found among African cobras, it was not present among Asian cobras. On the other hand, a consistent positive correlation was observed between cytotoxicity and utilisation of the defensive hooding display that cobras are famous for. Hooding and spitting are widely regarded as defensive adaptations, but it has hitherto been uncertain whether cytotoxicity serves a defensive purpose or is somehow useful in prey subjugation. The results of this study suggest that cytotoxicity evolved primarily as a defensive innovation and that it has co-evolved twice alongside hooding behavior: once in the and again independently in the king cobras (). There was a significant increase of cytotoxicity in the Asian linked to the evolution of bold aposematic hood markings, reinforcing the link between hooding and the evolution of defensive cytotoxic venoms. In parallel, lineages with increased cytotoxicity but lacking bold hood patterns evolved aposematic markers in the form of high contrast body banding. The results also indicate that, secondary to the evolution of venom rich in cytotoxins, spitting has evolved three times independently: once within the African , once within the Asian , and once in the genus. The evolution of cytotoxic venom thus appears to facilitate the evolution of defensive spitting behaviour. In contrast, a secondary loss of cytotoxicity and reduction of the hood occurred in the water cobra , which possesses streamlined neurotoxic venom similar to that of other aquatic elapid snakes (e.g., hydrophiine sea snakes). The results of this study make an important contribution to our growing understanding of the selection pressures shaping the evolution of snake venom and its constituent toxins. The data also aid in elucidating the relationship between these selection pressures and the medical impact of human snakebite in the developing world, as cytotoxic cobras cause considerable morbidity including loss-of-function injuries that result in economic and social burdens in the tropics of Asia and sub-Saharan Africa.
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http://dx.doi.org/10.3390/toxins9030103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5371858PMC
March 2017

The Cardiovascular and Neurotoxic Effects of the  Venoms of Six Bony and Cartilaginous Fish Species.

Toxins (Basel) 2017 02 16;9(2). Epub 2017 Feb 16.

Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia.

Fish venoms are often poorly studied, in part due to the difficulty in obtaining, extracting, and storing them. In this study, we characterize the cardiovascular and neurotoxic effects of the venoms from the following six species of fish: the cartilaginous stingrays Neotrygon kuhlii and Himantura toshi, and the bony fish Platycephalus fucus, Girella tricuspidata, Mugil cephalus, and Dentex tumifrons. All venoms (10-100 μg/kg, i.v.), except G. tricuspidata and P. fuscus, induced a biphasic response on mean arterial pressure (MAP) in the anesthetised rat. P. fucus venom exhibited a hypotensive response, while venom from G. tricuspidata displayed a single depressor response. All venoms induced cardiovascular collapse at 200 μg/kg, i.v. The in vitro neurotoxic effects of venom were examined using the chick biventer cervicis nerve-muscle (CBCNM) preparation. N. kuhlii, H. toshi, and P. fucus venoms caused concentration-dependent inhibition of indirect twitches in the CBCNM preparation. These three venoms also inhibited responses to exogenous acetylcholine (ACh) and carbachol (CCh), but not potassium chloride (KCl), indicating a post-synaptic mode of action. Venom from G. tricuspidata, M. cephalus, and D. tumifrons had no significant effect on indirect twitches or agonist responses in the CBCNM. Our results demonstrate that envenoming by these species of fish may result in moderate cardiovascular and/or neurotoxic effects. Future studies aimed at identifying the molecules responsible for these effects could uncover potentially novel lead compounds for future pharmaceuticals, in addition to generating new knowledge about the evolutionary relationships between venomous animals.
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http://dx.doi.org/10.3390/toxins9020067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5331446PMC
February 2017

Ect2-Dependent rRNA Synthesis Is Required for KRAS-TRP53-Driven Lung Adenocarcinoma.

Cancer Cell 2017 02 19;31(2):256-269. Epub 2017 Jan 19.

Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Griffin Cancer Research Building, Room 212, 4500 San Pablo Road, Jacksonville, FL 32224, USA. Electronic address:

The guanine nucleotide exchange factor (GEF) epithelial cell transforming sequence 2 (Ect2) has been implicated in cancer. However, it is not clear how Ect2 causes transformation and whether Ect2 is necessary for tumorigenesis in vivo. Here, we demonstrate that nuclear Ect2 GEF activity is required for Kras-Trp53 lung tumorigenesis in vivo and that Ect2-mediated transformation requires Ect2-dependent rDNA transcription. Ect2 activates rRNA synthesis by binding the nucleolar transcription factor upstream binding factor 1 (UBF1) on rDNA promoters and recruiting Rac1 and its downstream effector nucleophosmin (NPM) to rDNA. Protein kinase Cι (PKCι)-mediated Ect2 phosphorylation stimulates Ect2-dependent rDNA transcription. Thus, Ect2 regulates rRNA synthesis through a PKCι-Ect2-Rac1-NPM signaling axis that is required for lung tumorigenesis.
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http://dx.doi.org/10.1016/j.ccell.2016.12.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5310966PMC
February 2017

Antibacterial Action of Curcumin against : A Brief Review.

J Trop Med 2016 13;2016:2853045. Epub 2016 Nov 13.

Sunway Institute for Healthcare Development (SIHD), Sunway University, 47500 Bandar Sunway, Selangor Darul Ehsan, Malaysia; Anatomical Pathology Department, Sunway Medical Centre, 47500 Bandar Sunway, Selangor Darul Ehsan, Malaysia.

Curcumin, the major constituent of L. (Zingiberaceae family) or turmeric, commonly used for cooking in Asian cuisine, is known to possess a broad range of pharmacological properties at relatively nontoxic doses. Curcumin is found to be effective against (). As demonstrated by experiment, curcumin exerts even more potent effects when used in combination with various other antibacterial agents. Hence, curcumin which is a natural product derived from plant is believed to have profound medicinal benefits and could be potentially developed into a naturally derived antibiotic in the future. However, there are several noteworthy challenges in the development of curcumin as a medicine. infections, particularly those caused by the multidrug-resistant strains, have emerged as a global health issue and urgent action is needed. This review focuses on the antibacterial activities of curcumin against both methicillin-sensitive (MSSA) and methicillin-resistant (MRSA). We also attempt to highlight the potential challenges in the effort of developing curcumin into a therapeutic antibacterial agent.
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http://dx.doi.org/10.1155/2016/2853045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5124450PMC
November 2016

IQGAP1 Scaffold-MAP Kinase Interactions Enhance Multiple Myeloma Clonogenic Growth and Self-Renewal.

Mol Cancer Ther 2016 11 29;15(11):2733-2739. Epub 2016 Aug 29.

Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Despite improved outcomes in newly diagnosed multiple myeloma, virtually all patients relapse and ultimately develop drug-resistant disease. Aberrant RAS/MAPK signaling is activated in the majority of relapsed/refractory multiple myeloma patients, but its biological consequences are not fully understood. Self-renewal, as defined by the long-term maintenance of clonogenic growth, is essential for disease relapse, and we examined the role of RAS/MAPK activation on multiple myeloma self-renewal by targeting IQ motif-containing GTPase-activating protein 1 (IQGAP1), an intracellular scaffold protein required for mutant RAS signaling. We found that loss of IQGAP1 expression decreased MAPK signaling, cell-cycle progression, and tumor colony formation. Similarly, a peptide mimicking the WW domain of IQGAP1 that interacts with ERK inhibited the clonogenic growth and self-renewal of multiple myeloma cell lines and primary clinical specimens in vitro as well as tumor-initiating cell frequency in immunodeficient mice. During multiple myeloma progression, self-renewal may be enhanced by aberrant RAS/MAPK signaling and inhibited by targeting IQGAP1. Mol Cancer Ther; 15(11); 2733-9. ©2016 AACR.
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http://dx.doi.org/10.1158/1535-7163.MCT-16-0323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5097000PMC
November 2016

Rapid Radiations and the Race to Redundancy: An Investigation of the Evolution of Australian Elapid Snake Venoms.

Toxins (Basel) 2016 10 26;8(11). Epub 2016 Oct 26.

Venom Evolution Lab, School of Biological Sciences, University of Queensland, St Lucia, QLD 4072, Australia.

Australia is the stronghold of the front-fanged venomous snake family Elapidae. The Australasian elapid snake radiation, which includes approximately 100 terrestrial species in Australia, as well as Melanesian species and all the world's sea snakes, is less than 12 million years old. The incredible phenotypic and ecological diversity of the clade is matched by considerable diversity in venom composition. The clade's evolutionary youth and dynamic evolution should make it of particular interest to toxinologists, however, the majority of species, which are small, typically inoffensive, and seldom encountered by non-herpetologists, have been almost completely neglected by researchers. The present study investigates the venom composition of 28 species proteomically, revealing several interesting trends in venom composition, and reports, for the first time in elapid snakes, the existence of an ontogenetic shift in the venom composition and activity of brown snakes ( sp.). Trends in venom composition are compared to the snakes' feeding ecology and the paper concludes with an extended discussion of the selection pressures shaping the evolution of snake venom.
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http://dx.doi.org/10.3390/toxins8110309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5127106PMC
October 2016

Canopy Venom: Proteomic Comparison among New World Arboreal Pit-Viper Venoms.

Toxins (Basel) 2016 07 8;8(7). Epub 2016 Jul 8.

Venom Evolution Lab, School of Biological Sciences, University of Queensland, St Lucia, QLD 4072, Australia.

Central and South American pitvipers, belonging to the genera Bothrops and Bothriechis, have independently evolved arboreal tendencies. Little is known regarding the composition and activity of their venoms. In order to close this knowledge gap, venom proteomics and toxin activity of species of Bothriechis, and Bothrops (including Bothriopsis) were investigated through established analytical methods. A combination of proteomics and bioactivity techniques was used to demonstrate a similar diversification of venom composition between large and small species within Bothriechis and Bothriopsis. Increasing our understanding of the evolution of complex venom cocktails may facilitate future biodiscoveries.
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http://dx.doi.org/10.3390/toxins8070210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4963843PMC
July 2016

Oncogenic PKCι decides tumor-initiating cell fate.

Cell Cycle 2016 09 17;15(18):2383-4. Epub 2016 Jun 17.

a Department of Cancer Biology , Mayo Clinic , Jacksonville , FL , USA.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5026803PMC
http://dx.doi.org/10.1080/15384101.2016.1194624DOI Listing
September 2016

Targeting oncogenic protein kinase Cι for treatment of mutant KRAS LADC.

Small GTPases 2017 01 31;8(1):58-64. Epub 2016 May 31.

a Department of Cancer Biology , Mayo Clinic , Jacksonville , FL , USA.

Lung cancer is the leading cause of cancer death in the US with ∼124,000 new cases annually, and a 5 y survival rate of ∼16%. Mutant KRAS-driven lung adenocarcinoma (KRAS LADC) is a particularly prevalent and deadly form of lung cancer. Protein kinase Cι (PKCι) is an oncogenic effector of KRAS that activates multiple signaling pathways that stimulate transformed growth and invasion, and maintain a KRAS LADC tumor-initiating cell (TIC) phenotype. PKCι inhibitors used alone and in strategic combination show promise as new therapeutic approaches to treatment of KRAS LADC. These novel drug combinations may improve clinical management of KRAS LADC.
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http://dx.doi.org/10.1080/21541248.2016.1194953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5331898PMC
January 2017

Exosomes in Human Immunodeficiency Virus Type I Pathogenesis: Threat or Opportunity?

Adv Virol 2016 4;2016:9852494. Epub 2016 Jan 4.

Molecular Pathology Unit, Cancer Research Centre (CaRC), Institute for Medical Research (IMR), 50588 Kuala Lumpur, Malaysia.

Nanometre-sized vesicles, also known as exosomes, are derived from endosomes of diverse cell types and present in multiple biological fluids. Depending on their cellular origins, the membrane-bound exosomes packed a variety of functional proteins and RNA species. These microvesicles are secreted into the extracellular space to facilitate intercellular communication. Collective findings demonstrated that exosomes from HIV-infected subjects share many commonalities with Human Immunodeficiency Virus Type I (HIV-1) particles in terms of proteomics and lipid profiles. These observations postulated that HIV-resembled exosomes may contribute to HIV pathogenesis. Interestingly, recent reports illustrated that exosomes from body fluids could inhibit HIV infection, which then bring up a new paradigm for HIV/AIDS therapy. Accumulative findings suggested that the cellular origin of exosomes may define their effects towards HIV-1. This review summarizes the two distinctive roles of exosomes in regulating HIV pathogenesis. We also highlighted several additional factors that govern the exosomal functions. Deeper understanding on how exosomes promote or abate HIV infection can significantly contribute to the development of new and potent antiviral therapeutic strategy and vaccine designs.
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http://dx.doi.org/10.1155/2016/9852494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4766318PMC
March 2016

Protein Kinase Cι Drives a NOTCH3-dependent Stem-like Phenotype in Mutant KRAS Lung Adenocarcinoma.

Cancer Cell 2016 Mar;29(3):367-378

Department of Cancer Biology, Mayo Clinic Cancer Center, Jacksonville, FL 32224, USA. Electronic address:

We report that the protein kinase Cι (PKCι) oncogene controls expression of NOTCH3, a key driver of stemness, in KRAS-mediated lung adenocarcinoma (LADC). PKCι activates NOTCH3 expression by phosphorylating the ELF3 transcription factor and driving ELF3 occupancy on the NOTCH3 promoter. PKCι-ELF3-NOTCH3 signaling controls the tumor-initiating cell phenotype by regulating asymmetric cell division, a process necessary for tumor initiation and maintenance. Primary LADC tumors exhibit PKCι-ELF3-NOTCH3 signaling, and combined pharmacologic blockade of PKCι and NOTCH synergistically inhibits tumorigenic behavior in vitro and LADC growth in vivo demonstrating the therapeutic potential of PKCι-ELF3-NOTCH3 signal inhibition to more effectively treat KRAS LADC.
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http://dx.doi.org/10.1016/j.ccell.2016.02.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4795153PMC
March 2016