Syed Zahid Ali Shah | China Agricultural University (original) (raw)

Papers by Syed Zahid Ali Shah

Prion infections of the central nervous system (CNS) are characterized by initial reactive gliosi... more Prion infections of the central nervous system
(CNS) are characterized by initial reactive gliosis followed by
overt neuronal death. Gliosis is likely to be caused initially by
the deposition of misfolded, proteinase K-resistant, isoforms
(termed PrPSc) of the normal cellular prion protein (PrPc) in
the brain. Proinflammatory cytokines and chemokines released
by PrPSc-activated glia and stressed neurons may also contribute
directly or indirectly to the disease development by enhancing
gliosis and inducing neurotoxicity. Recent studies have
illustrated that early neuroinflammation activates nuclear factor
of activated Tcells (NFAT) in the calcineurin signaling cascade,
resulting in nuclear translocation of nuclear factor kappa B
(NF-κB) to promote apoptosis. Hence, useful therapeutic approaches
to slow down the course of prion disease development
should control early inflammatory responses to suppress NFAT
signaling. Here we used a hamster model of prion diseases to
test, for the first time, the neuroprotective and NFATsuppressive
effect of a second-generation semisynthetic tetracycline
derivative, minocycline, versus a calcineurin inhibitor,
FK506, with known NFAT suppressive activity. Our results
indicate that prolonged treatment with minocycline, starting
from the presymptomatic stage of prion disease was more effective
than FK506 given either during the presymptomatic or
symptomatic stage of prion disease. Specifically, minocycline
treatment reduced the expression of the astrocyte activation
marker glial fibrillary acidic protein and of the microglial activation
marker ionized calcium-binding adapter molecule-1,
subsequently reducing the level of proinflammatory cytokines
interleukin 1β and tumor necrosis factor-α. We further found
that minocycline and FK506 treatment inhibited mitogenactivated
protein kinase p38 phosphorylation and NF-κB nuclear
translocation in a caspase-dependent manner, and enhanced
phosphorylated cyclic adenosine monophosphate response
element-binding protein and phosphorylated Bcl2-
associated death promoter levels to reduce cognitive impairment
and apoptosis. Taken together, our results indicate that
minocycline is a better choice for prolonged use in prion diseases
and encourage its further clinical development as a possible
treatment for this disease.

Molecular neurobiology, Jan 25, 2016

Sporadic Creutzfeldt-Jakob disease (sCJD) is the most frequent fatal human prion disease with a r... more Sporadic Creutzfeldt-Jakob disease (sCJD) is the most frequent fatal human prion disease with a rapid progression and unknown mechanism. The synaptic vesicle (SV) cycle pathway has been a hot research field associated with many neurodegenerative diseases that affect synaptic function and thus may affect pathogenesis of the disorder. Here, we used the iTRAQ-based proteomic method and a KEGG pathway enrichment analysis to meticulously analyze all pathways involved in sCJD disease. In total, 1670 proteins were validated in pooled cerebrospinal fluid (CSF) from 20 patients with sCJD compared with that from 13 patients without CJD. The demographic analysis demonstrated that 557 proteins were upregulated and 595 proteins were downregulated with a 1.5-fold change, and 690 proteins involved in 39 pathways changed significantly (p ≤ 0.05) according to the enrichment analysis. The SV cycle pathway and proteins involved were further evaluated, and 14 proteins were confirmed to participate in t...

The study was conducted to explore the effect of two herbal drugs, Caesalpinia crista and Nigella... more The study was conducted to explore the effect of two herbal drugs, Caesalpinia crista and Nigella sativa in comparison with Oxfendazole in broilers experimentally induced with Ascaridia galli infection. A total of 130 day old broiler chicks were divided into five groups i.e. A, B, C, D and E each group having 26 birds. Group E was kept as negative control, while all other groups were induced with experimental Ascardia galli infection on 15 th day. Group A was kept as positive control and groups B and C were treated with Caesalpinia crista and Nigella sativa as methanolic extract orally once @50mg/kg body weight and group D was medicated with Oxfendazole @10mg/kg body weight orally once on 25 th day post infection. On 25th day post infection before treatment 4 birds from each group were slaughtered, and worm count was done. The efficacy was confirmed by counting the worm, slaughtering all the bird on 30 th day post infection. The mean worm count was significantly different (p<0.05) between the treated and non-treated groups. The efficacy of the plant extracts were less as compare to Oxfendazole. The efficacy of Caesalpinia crista and Nigella sativa was 70.83% and 57.5% respectively while the efficacy of Oxfendazole was 90.83%. The efficacy of drugs was calculated on the basis of reduction in total worm count after treatment.

Mycobacterium bovis is the causative agent of tuberculosis in a wide range of mammals, including ... more Mycobacterium bovis is the causative agent of tuberculosis in a wide range of mammals, including humans. Macrophages are the first line of host defense. They secrete proinflam-matory cytokines, such as interleukin-1 beta (IL-1β), in response to mycobacterial infection, but the underlying mechanisms by which human macrophages are activated and release IL-1β following M. bovis infection are poorly understood. Here we show that the 'nucleotide binding and oligomerization of domain-like receptor (NLR) family pyrin domain containing 7 protein' (NLRP7) inflammasome is involved in IL-1β secretion and caspase-1 activation induced by M. bovis infection in THP-1 macrophages. NLRP7 inflammasome activation promotes the induction of pyroptosis as well as the expression of tumor necrosis factor alpha (TNF-α), Chemokine (CC motif) ligand 3 (CCL3) and IL-1β mRNAs. Thus, the NLRP7 inflammasome contributes to IL-1β secretion and induction of pyroptosis in response to M. bovis infection in THP-1 macrophages.

The aggregation of disease-specific misfolded proteins resulting in endoplasmic reticulum stress ... more The aggregation of disease-specific misfolded proteins resulting in endoplasmic reticulum stress is associated with early pathological events in many neurodegenerative diseases , and apoptotic signaling is initiated when the stress goes beyond the maximum threshold level of endoplasmic reticu-lum stress sensors. All eukaryotic cells respond to the accumulation of unfolded proteins in the endoplasmic reticulum (ER) by signaling an adaptive pathway termed as unfolded protein response (UPR). Recently, the focus of research shifted from work on specific proteins as pathogenesis in these neurodegenerative diseases towards a more specific generic pathway known as UPR. ER is a major organelle for protein quality control, and cellular stress disrupts normal functioning of ER. The UPR acts as a protective mechanism during endo-plasmic reticulum stress, but persistent long-term stress triggers UPR-mediated apoptotic pathways ultimately leading to cell death. Here in this review, we will briefly summarize the molecular events of endoplasmic reticulum stress-associated UPR signaling pathways and their potential therapeutic role in neurodegenerative diseases.

The retromer complex is a protein complex that plays a central role in endosomal trafficking. Ret... more The retromer complex is a protein complex that plays a central role in endosomal trafficking. Retromer dysfunction has been linked to a growing number of neurological disorders. The process of intracellular trafficking and recycling is crucial for maintaining normal intracellular homeostasis, which is partly achieved through the activity of the retromer complex. The retromer complex plays a primary role in sorting endosomal cargo back to the cell surface for reuse, to the trans-Golgi network (TGN), or alternatively to specialized endomembrane compartments, in which the cargo is not subjected to lysosomal-mediated degradation. In most cases, the retromer acts as a core that interacts with associated proteins, including sorting nexin family member 27 (SNX27), members of the vacuolar protein sorting 10 (VPS10) receptor family, the major endosomal actin polymerization-promoting complex known as Wiskott-Aldrich syndrome protein and scar homolog (WASH), and other proteins. Some of the molecules carried by the retromer complex are risk factors for neurodegenerative diseases. Defects such as haplo-insufficiency or mutations in one or several units of the retromer complex lead to various pathologies. Here, we summarize the molecular architecture of the retromer complex and the roles of this system in intracellular trafficking related the pathogenesis of neurodegenerative diseases.

Dysregulated calcium signaling and accumulation of aberrant proteins causing endoplasmic reticulu... more Dysregulated calcium signaling and accumulation of aberrant proteins causing endoplasmic reticulum stress are the early sign of intra-axonal pathological events in many neurodegenerative diseases, and apoptotic signaling is initiated when the stress goes beyond the maximum threshold level of endoplasmic reticulum. The fate of the cell to undergo apoptosis is controlled by Ca2 + signaling and dynamics at the level of the endoplasmic reticulum. Endoplasmic reticu-lum resident inositol 1,4,5-trisphosphate receptors (IP3R) play a pivotal role in cell death signaling by mediating Ca2 + flux from the endoplasmic reticulum into the cytosol and mito-chondria. Hence, many prosurvival and prodeath signaling pathways and proteins affect Ca2 + signaling by directly targeting IP3R channels, which can happen in an IP3R-isoform-dependent manner. Here, in this review, we summarize the regulatory mechanisms of inositol triphosphate receptors in calcium regulation and initiation of apoptosis during unfolded protein response.

Transmissible spongiform encephalopathies (TSEs) are caused by the accumulation of the abnormal p... more Transmissible spongiform encephalopathies (TSEs) are caused by the accumulation of the abnormal prion protein scrapie (

In order to determine the production patterns of sheep and goats the study was carried out during... more In order to determine the production patterns of sheep and goats the study was carried out during 2005 in five areas of District Qila Abdullah (Balochistan) i.e. Chaman, Qilla Abdullah, PirAlizai, Gulistan and Maizaiadda, where mostly the flocks comprised of Bibrik, Balochi and Dumbi sheep breeds and Kamori, Jatan, Lehri and Khurasani goat breeds. The results showed that the capital cost on animal averaged Rs. 450, while feeding cost was Rs. 3079, medication and vaccination charges Rs. 26, labor charges Rs.135, marketing charges Rs.16 and miscellaneous charges Rs. 9 to accumulate overall per animal recurring cost Rs. 3264.65 per animal/year. Producers received gross revenue of Rs. 5252 from the sale of animals, manure and wool/hair against an expenditure Rs. 3824, hence the net returns came to Rs. 1428 per animal. The farmer earned Rs. 1.38 (1:1.38) on one rupee investment. Breakdown of consumer's rupee revealed that producer shared 68 paisa from consumer's rupee and pocketed Rs.0.38 against the cost of one rupee. The cost benefit ratio (average 0.43) in Chaman, Qila Abdullah, PirAlizai, Gulistan and Maizaiadda was 1:0.52, 1:0.39, 1:0.41, 1:0.36 and 1:0.44, respectively. The findings of the study showed that sheep and goat farming is a profitable business in the Balochistan province, especially Qila Abdulla district.

To link to this article: http://dx.

Mycobacterium bovis is the

Infectious bursal disease (IBD), caused by IBD virus (IBDV), is an acute, highly contagious immun... more Infectious bursal disease (IBD), caused by IBD virus (IBDV), is an acute, highly contagious immunosuppressive avian disease. Although agedependent changes in susceptibility of chickens to IBDV have been established, the relationship between agedependent structural changes in bursa of Fabricius and susceptibility of chickens to IBDV is still unclear. In the present study, we examined the bursa anatomical structure and pathological changes in specific-pathogenfree (SPF) white leghorn chickens 0 to 8 weeks post hatch (w.p.h.) and IBDV BC6/85-infected SPF chickens 2 to 6 w.p.h. respectively, by histology, histopathology, immunohistochemistry, and transmission electron microscopy. Almost all IBDV-exposed chickens (2 to 6 w.p.h.) were infected, with the severest bursal inflammation and complication in chickens at 3 w.p.h. Furthermore, the bursae of healthy chickens at 3 to 6 w.p.h. had decreased laminin immunoreactivities, lots of splits, and irregular shapes in basement membrane (BM) of cortico-medullary epithelium (CME), irregu-larly arranged CME, and large numbers of immunoglobulin M-bearing (IgM+) B lymphocytes in the medulla. The decreased barrier function of corticomedullary border and large amount of IgM+ B lymphocytes provide a chance for IBDV to easily contact and infect target cells at 3 to 6 w.p.h. By contrast, regular BM, neatly arranged CME, and few IgM+ B lymphocytes in healthy chickens younger than 2 w.p.h., as well as reduced IgM+ B lymphocytes and high immunoglobulin A (IgA) content in healthy chickens older than 8 w.p.h., were observed, suggesting that the integrity of corticomedullary border barrier, a small amount of target cells and high IgA content of the bursa could be the reasons for these chickens being less susceptible to IBDV. Although studies have shown how IBDV affects bursa, we focus first on the age-dependent changes of CME, BM of CME and IgA content, and our findings are the first to elucidate the structural development of bursa in relation to IBDV susceptibility from a morphological perspective.

The aim of this study was to examine the effect of mating ratio (male: female) and vitamin E-Sele... more The aim of this study was to examine the effect of mating ratio (male: female) and vitamin E-Selenium supplementation on egg production and egg weight of quail breeders. Total 720 Japanese quails of ten weeks of age with an average of 50% egg production were divided into four groups A, B, C and D having male: female mating ratio of 1:1, 1:2, 1:3 and 1:4 respectively. All the four groups were further subdivided into vitamin E-Selenium supplemented (at the rate of 1ml/6 liters of drinking water) and control subgroups. Each subgroup was further replicated three times with 30quails/replicate. Egg production was significantly (P<0.05) affected by mating ratio and vitamin E-Selenium supplementation. The egg production was highest (72 %) in ratio 1:4 while the least (52 %) in 1:1 ratio. The egg production with the supplementation of vitamin E-Selenium was highest (77 %) in ratio 1:4 while the least (52 %) in 1:1 ratio. Egg weight was significantly (P<0.05) affected by mating ratio but vitamin E-Selenium supplementation had no significant (P<0.05) effect on egg weight. The highest egg weight was (12.2g) for 1:3 mating group while least was (10.25gm) for 1:1 mating group.

Axonal degeneration is a hallmark of many neuro-degenerative disorders including transmissible sp... more Axonal degeneration is a hallmark of many neuro-degenerative disorders including transmissible spongiform encephalopathies (TSE). However, the full complement of axonal degeneration triggers is not fully understood. In an in vitro prion model, we observed that treatment of rat spinal neurons with the prion peptide, PrP106-126, activated death receptor 6 (DR6, also known as TNFRSF21), caspase-6, cas-pase-3, and induced axonal degeneration. Knockdown of DR6 by siRNA blocked caspase-6 and caspase-3 activation and axonal degeneration. We also found that cleaved caspase-3 is only enriched in cell bodies, but cleaved caspase-6 is expressed in both cell bodies and axons. Axonal degeneration was prevented by preincubation of neurons with a caspase-6 inhibitor or siRNA of caspase-6. Our findings suggest that both DR6 and caspase-6 play important roles in axonal degen-eration and caspase-6 acts downstream of DR6. We also observed that nicotinamide nucleotide adenylyltransferase 1 protein (Nmnat1), which had been reported to protect neurons from degeneration, alleviated axonal degeneration without blocking caspase-6 activation, suggesting that Nmnat acts downstream or parallel to caspase-6 activation. Our results indicate that PrP106-126 triggered axonal degeneration of the spinal cord neurons, DR6 is a key regulator of axonal degeneration, and the signaling pathway of DR6/caspase-6 mediates axonal degeneration induced by the prion fragment. Our findings raise the hope of targeting the DR6 as a potential therapeutic strategy in prion-related neurodegenerative diseases.

Accumulation of misfolded/unfolded aggregated proteins in the brain is a hallmark of many neurode... more Accumulation of misfolded/unfolded aggregated proteins in the brain is a hallmark of many neurodegener-ative diseases affecting humans and animals. Dysregulation of calcium (Ca 2?) and disruption of fast axonal transport (FAT) are early pathological events that lead to loss of synaptic integrity and axonal degeneration in early stages of neurodegenerative diseases. Dysregulated Ca 2? in the brain is triggered by accumulation of misfolded/unfolded aggregated proteins in the endoplasmic reticulum (ER), a major Ca 2? storing organelle, ultimately leading to neu-ronal dysfunction and apoptosis. Calcineurin (CaN), a Ca 2? /calmodulin-dependent serine/threonine phosphatase, has been implicated in T cells activation through the induction of nuclear factor of activated T cells (NFAT). In addition to the involvement of several other signaling cascades, CaN has been shown to play a role in early synaptic dysfunction and neuronal death. Therefore, inhibiting hyperactivated CaN in early stages of disease might be a promising therapeutic strategy for treating patients with protein misfolding diseases. In this review, we briefly summarize the structure of CaN, inhibition mechanisms by which immunosuppressants inhibit CaN, role of CaN in maintaining neuronal and synaptic integrity and homeostasis and the role played by CaN in protein unfolding/misfolding neurodegenerative diseases.

Molecular neurobiology, Jan 25, 2016

To link to this article: http://dx.

Mycobacterium bovis is the