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Is tetherin a true antiviral: The influenza a virus controversy

Sharma A, Lal SK

Rev Med Virol, 2019 05;29(3):e2036.
PMID: 30706579 DOI: 10.1002/rmv.2036

Tetherin, an interferon-inducible gene was first discovered to be an antiviral factor in 2008. A vast range of viruses, such as influenza A virus (IAV), dengue virus, Ebola virus, HIV, and RSV, have been reported to be susceptible to the antiviral activity of tetherin. Multiple reports have been published encompassing the role of tetherin in the IAV life cycle. To date, nine reports have been published regarding the role of tetherin in the IAV life cycle, with four reports supporting tetherin as an antiviral factor while five other reports suggesting no effect. To this end, this review summarizes the list of viruses currently known to be inhibited by tetherin and describes mechanisms used by viruses to overcome the antiviral potential of tetherin. Further, using IAV as disease model, we provide existing evidence in favor and against tetherin being considered as an antiviral candidate. Subsequent analysis of the experimental procedures across IAV-tetherin published reports revealed that the experimental setup (ie, cell lines, transfection reagents, and multiplicity of infection), strain-specific activity of NS1, and differing roles of NS1 in different cell lines may add up to the contributing factors leading to the discrepancies observed.
Fulltext Zika Virus: Transmission, Detection, Control, and Prevention

Sharma A, Lal SK

Front Microbiol, 2017;8:110.
PMID: 28217114 DOI: 10.3389/fmicb.2017.00110

Zika virus (ZIKV) is a mosquito-borne Flavivirus discovered in Uganda in the 1940s. To date, three major ZIKV outbreaks have been reported. ZIKV infections have known to be primarily asymptomatic while causing mild illness in a few cases. However, the recent emergence and spread of ZIKV in the Americas has resulted in the declaration of "Public Health Emergency of International Concern" due to the potential association between the infection and prenatal microcephaly or other brain anomalies. In Brazil, a 20-fold increase in prenatal microcephaly cases and 19% increase in Guillain-Barré Syndrome (GBS) cases were reported in 2015, as compared to the preceding year. The probable deleterious effects of ZIKV infection prompt the urgent development of diagnostics and therapeutics. To this end, the existing evidences supporting the increasingly common prenatal microcephaly and GBS association and the current known ZIKV transmission dynamics, modes of detection (molecular and serology-based), and current control strategies are summarized in this review. This review also emphasizes the importance of understanding ZIKV transmission in order to design a sensitive yet cost and time-efficient detection technique. Development of an efficient detection technique would subsequently allow for better surveillance and control of ZIKV infection. Currently, limited literature is available on the pathogenesis of ZIKV, hence, focusing on the modes of ZIKV transmission could potentially contribute to the understanding of the disease spectrum and formulation of targeted treatment and control.
Fulltext Compartment syndrome of the foot in a child

Sharma AK, Sharaf I, Ajay S

Med J Malaysia, 2001 Jun;56 Suppl C:70-2.
PMID: 11814254

We report a case of a 12-year-old boy with acute compartment syndrome of the foot following a road-traffic accident. Due to the rarity of the injury, there was a delay in diagnosing the injury. An emergency fasciotomy was performed 19 hours after the injury. The foot healed with a mild extension contracture of the second toe.
AML1 protein interacts with influenza A virus neuraminidase and upregulates IFN-β response in infected mammalian cells

Gaur P, Kumar P, Sharma A, Lal SK

Lett Appl Microbiol, 2020 Apr;70(4):252-258.
PMID: 31990997 DOI: 10.1111/lam.13279

Neuraminidase (NA) is an integral membrane protein of influenza A virus (IAV) and primarily aids in the release of progeny virions, following the intracellular viral replication cycle. In an attempt to discover new functions of NA, we conducted a classical yeast two-hybrid screen and found acute myeloid leukaemia marker 1 (AML1) as a novel interacting partner of IAV-NA. The interaction was further validated by co-immunoprecipitation in IAV-infected cells and in an in vitro coupled transcription/translation system. Interestingly, we found an increase in the expression of AML1 upon IAV infection in a dose-dependent manner. As expected, we also observed an increase in the IFN-β levels, the first line of defence against viral infections. Subsequently, when AML1 was downregulated using siRNA, the IFN-β levels were found to be remarkably reduced. Our study also shows that AML1 is induced upon IAV infection and results in the induction of IFN-β. Thus, AML1 is proposed to be an important player in IFN induction and has a role in an antiviral response against IAV infection. SIGNIFICANCE AND IMPACT OF THE STUDY: Influenza epidemics and pandemics are constant threats to human health. Development of antiviral therapeutics has focused on important and major IAV proteins as targets. However, the rate at which this virus mutates makes the task challenging. Thus, next-generation approaches aim at host cellular proteins that aid the virus in its replication. This study reports a new host-virus interaction, of acute myeloid leukaemia marker 1 (AML1) with influenza A neuraminidase (IAV-NA). We have found that this interaction has a direct effect on the upregulation of host IFN-β response. Further studies may lead to a greater understanding of this new innate defence pathway in infected cells.
Fulltext Can the Pirani Score Predict the Number of Casts and the Need for Tenotomy in the Management of Clubfoot by the Ponseti Method?

Sharma A, Shukla S, Kiran B, Michail S, Agashe M

Malays Orthop J, 2018 Mar;12(1):26-30.
PMID: 29725509 DOI: 10.5704/MOJ.1803.005

Introduction: We assessed the role of the Pirani score in determining the number of casts and its ability to suggest requirement for tenotomy in the management of clubfoot by the Ponseti method. Materials and Methods: Prospective analysis of 66 (110 feet) cases of idiopathic clubfoot up to one year of age was done. Exclusion criteria included children more than one year of age at the start of treatment, non-idiopathic cases and previously treated or operated cases. Results: The initial Pirani score was (5.5±0.7) for the tenotomy group and the initial Pirani score was (3.3±1.6) for the non-tenotomy group. There was a significant difference between the initial Pirani score for the tenotomy and the non-tenotomy group with t= -7.9, df= 64 p<0.0001. The tenotomy group had a significantly higher number of casts (four to seven) compared to non-tenotomy group (two to five) t=-10.4, df=64, p<0.0001. Spearman's rank correlation coefficient was significant and confirmed positive correlation between the initial Pirani score and the number of casts required to correct the deformity (r = 0.931, p<0.0001). Conclusion: Initial high Pirani score suggests the need for greater number of casts to achieve correction and probable need for tenotomy. The number of casts required in achieving complete correction increases with increase in the initial Pirani score. The initial high hindfoot score (2.5-3) signifies the probable need of a minor surgical intervention of percutaneous tendoachilles tenotomy. Based on the initial Pirani score, parents can be informed about the probable duration of treatment and the need for tenotomy.
Haematological parameters and screening tests of haemostasis in children with sepsis: results from a tertiary care centre in India

Sharma A, Sikka M, Bhankar H, Gomber S, Sharma S

Malays J Pathol, 2017 Aug;39(2):155-159.
PMID: 28866697

Sepsis is a common cause of death in infants and children. Haemostatic abnormalities have been reported in such patients. There is scant information on the nature and frequency of these abnormalities in children especially from India. Our aim was to evaluate the nature and frequency of haematological and haemostatic abnormalities in children with sepsis. Fifty children between 1-10 years of age admitted with sepsis and 50 age-matched, healthy controls were included in the study. Complete blood counts, examination of stained peripheral blood film, prothrombin time (PT), activated partial thromboplastin time (APTT), plasma fibrinogen, C-reactive protein, liver function tests and serum creatinine were done in all patients and controls. Prolonged PT and APTT were seen in 9 (18%) and 24 (48%) patients respectively. Plasma fibrinogen was decreased in 6% and increased in 8% patients. One or more haemostatic parameter was abnormal in 35 (70%) patients and in all patients who died.
Acinic cell carcinoma of the parotid gland: A diagnostic dilemma on cytology

Sharma A, Ahuja S, Diwaker P, Wadhwa N, Arora VK

Malays J Pathol, 2019 Aug;41(2):191-194.
PMID: 31427555

INTRODUCTION: Acinic cell carcinoma (ACC) represents 1-6% of parotid gland neoplasms.
CASE REPORT: We report cytomorphological features of two uncommon variants of acinic cell carcinoma. The first case was an eleven-year-old female with a nodular mass in parotid and the FNA smears demonstrated a lymphoepithelial lesion composed of epithelial tumour cells with features of acinar cells in a lymphoid background. The second case was a 62-year-old male with a large parotid mass. The FNA smears revealed presence of extracellular, acellular amyloid-like material with tumour cells arranged in follicles.
DISCUSSION: Awareness of cytomorphological features of these unusual variants of acinic cell carcinoma may help to avoid diagnostic pitfall.
Fulltext Bilateral Asymmetrical Fracture Dislocation of Shoulder with Rare Combination of Injuries after Epileptic Seizure: A Case Report

Sharma A, Jindal S, Narula MS, Garg S, Sethi A

Malays Orthop J, 2017 Mar;11(1):74-76.
PMID: 28435581 DOI: 10.5704/MOJ.1703.011

The incidence of bilateral gleno-humeral joint dislocation is rare, is almost always posterior and is usually caused by sports injuries, epileptic seizures, electrical shock, or electroconvulsive therapy. Bilateral fracture-dislocation is even rarer, with a few cases reported in the literature. We report an unusual case with dislocation of the both glenohumeral joints in opposite direction after a seizure episode, with fracture of greater tuberosity on one side and of the lesser tuberosity on the contralateral side. Although there have been a few reports of bilateral asymmetric fracture dislocations of the shoulder in the past, an injury pattern resembling our case has, to the best of our knowledge, not been described in the literature so far. This report includes a detailed discussion regarding the mechanism of injury in a case of asymmetrical dislocation following a seizure episode. At final follow-up, the patient had healed fractures, painless near normal range of motion with no redislocations.
Fulltext First and Second Metatarsophalangeal Joint Open Dislocations: A Case Report

Sharma A, Dosajh R, Bedi GS, Gupta K, Jain A

Malays Orthop J, 2017 Mar;11(1):71-73.
PMID: 28435580 DOI: 10.5704/MOJ.1703.010

Dislocation of multiple metatarsophalangeal joint is an uncommon injury. The mechanism of injury is a high energy force distal to proximal with foot in hyperextension at the metatarsophalangeal (MTP) joint. The acute hyperextension of the toe at the moment of injury causes avulsion of the plantar part of the capsule from the junction of head and neck of the metatarsal. If the collateral ligaments remain intact, they maintain the locked fibrocartilaginous plate over the dorsum of the head of the metatarsal, making closed reduction impossible. We report a case of simultaneous 1st and 2nd MTP joint open dislocation. In the present case, we chose the plantar approach utilizing the already present plantar wound. At 18 months post-operative follow-up, there was no instance of redislocations or signs of avascular necrosis of head of metatarsal.
Fulltext COVID-19: A Review on the Novel Coronavirus Disease Evolution, Transmission, Detection, Control and Prevention

Sharma A, Ahmad Farouk I, Lal SK

Viruses, 2021 Jan 29;13(2).
PMID: 33572857 DOI: 10.3390/v13020202

Three major outbreaks of the coronavirus, a zoonotic virus known to cause respiratory disease, have been reported since 2002, including SARS-CoV, MERS-CoV and the most recent 2019-nCoV, or more recently known as SARS-CoV-2. Bats are known to be the primary animal reservoir for coronaviruses. However, in the past few decades, the virus has been able to mutate and adapt to infect humans, resulting in an animal-to-human species barrier jump. The emergence of a novel coronavirus poses a serious global public health threat and possibly carries the potential of causing a major pandemic outbreak in the naïve human population. The recent outbreak of COVID-19, the disease caused by SARS-CoV-2, in Wuhan, Hubei Province, China has infected over 36.5 million individuals and claimed over one million lives worldwide, as of 8 October 2020. The novel virus is rapidly spreading across China and has been transmitted to 213 other countries/territories across the globe. Researchers have reported that the virus is constantly evolving and spreading through asymptomatic carriers, further suggesting a high global health threat. To this end, current up-to-date information on the coronavirus evolution and SARS-CoV-2 modes of transmission, detection techniques and current control and prevention strategies are summarized in this review.
Fulltext The threat of increased transmission of non-knowlesi zoonotic malaria in humans: a systematic review

Chaturvedi R, Biswas S, Bisht K, Sharma A

Parasitology, 2023 Nov;150(13):1167-1177.
PMID: 37929579 DOI: 10.1017/S003118202300077X

Of the 5 human malarial parasites, Plasmodium falciparum and Plasmodium vivax are the most prevalent species globally, while Plasmodium malariae, Plasmodium ovale curtisi and Plasmodium ovale wallikeri are less prevalent and typically occur as mixed-infections. Plasmodium knowlesi, previously considered a non-human primate (NHP) infecting species, is now a cause of human malaria in Malaysia. The other NHP Plasmodium species, Plasmodium cynomolgi, Plasmodium brasilianum, Plasmodium inui, Plasmodium simium, Plasmodium coatneyi and Plasmodium fieldi cause malaria in primates, which are mainly reported in southeast Asia and South America. The non-knowlesi NHP Plasmodium species also emerged and were found to cross-transmit from their natural hosts (NHP) – to human hosts in natural settings. Here we have reviewed and collated data from the literature on the NHPs-to-human-transmitting non-knowlesi Plasmodium species. It was observed that the natural transmission of these NHP parasites to humans had been reported from 2010 onwards. This study shows that: (1) the majority of the non-knowlesi NHP Plasmodium mixed species infecting human cases were from Yala province of Thailand; (2) mono/mixed P. cynomolgi infections with other human-infecting Plasmodium species were prevalent in Malaysia and Thailand and (3) P. brasilianum and P. simium were found in Central and South America.
Antibiogram Profile of Salmonella enterica Serovar Typhi in India - A Two Year Study

Kumar Y, Sharma A, Mani KR

Trop Life Sci Res, 2013 Aug;24(1):45-54.
PMID: 24575241

Typhoid fever continues to remain a major health problem in the developing world, and the emergence of multidrug-resistant (MDR) strains has further reduced therapeutic options for treatment of the disease. The National Salmonella and Escherichia Centre in Kasauli, India received 128 Salmonella Typhi isolates during 2008-2009. These were evaluated for antimicrobial resistance, prevalent resistotypes and the proportion of MDR strains, using standard methods for 11 antimicrobials. An abrupt decrease in the proportion of MDR strains was observed. Only 4.7% of the isolates were found to be MDR with resistotypes chloramphenicol-ampicillin-streptomycin-nalidixic acid-trimethoprim (C-AS-Na-Tr) and chloramphenicol-ampicillin-nalidixic acid-trimethoprim (C-A-Na-Tr), which is very low compared to other studies from India. Nalidixic acid resistance was found to be present in 93.8% of the isolates. Moreover, the difference in the mean minimum inhibitory concentration (MIC) of ciprofloxacin for nalidixic acid-resistant and nalidixic acid-sensitive strains was found to be statistically significant (p<0.001), which calls into question the further use of ciprofloxacin for the treatment of typhoid fever because of potential treatment failures. The low proportion of MDR strains increases the possibility of first-line drugs for the treatment of typhoid fever.
Fulltext Early results of a rotation flap to treat chronic anal fissures

Singh M, Sharma A, Duthie G, Balasingh D, Kandasamy P

Asian J Surg, 2005 Jul;28(3):189-91.
PMID: 16024313

Treatment of anal fissures has changed dramatically in the past decade. This is primarily due to a better understanding of its pathophysiology and the implications of the various available options. Only a few anal fissures fail to respond to medical therapy. Sphincterotomy and anal dilatation have fallen out of favour due to the risk of incontinence. Island flaps have been proposed to address this, but 60-70% of the flap donor sites break down with complications. We propose using a rotation flap to overcome this problem.
Comparative evaluation of the efficacy of different herbal irrigants on the removal of smear layer of primary teeth: A scanning electron microscopy study

Mali S, Singla S, Tyagi P, Sharma A, Talreja N, Gautam A

J Indian Soc Pedod Prev Dent, 2021 1 7;38(4):374-380.
PMID: 33402620 DOI: 10.4103/JISPPD.JISPPD_315_20

Aim and Objectives: The aim and objectives of this study are to evaluate and compare the effectiveness of Myristica fragrans - Nutmeg, Terminalia chebula - Myrobolan, Ocimum sanctum-tulsi, and 2.5% sodium hypochlorite (NaOCl) on the removal of the smear layer by the scanning electron microscope (SEM).
Settings and Design: Endodontic treatment aims at disinfection and then obturation of root canal system in to prevent re-infection. Root canal irrigants play a pivotal role in the disinfection process. One of the important properties of an irrigant is the removal of complete smear layer and debris. Smear layer has the potential to protect bacteria within the dentinal tubules; therefore removal may be prudent. Smear layer removal increases the bond strength of resin sealers which results in better apical seal.
Materials and Methods: Forty extracted single-rooted, primary teeth were allocated randomly into four groups of ten each: Group 1 - NaOCl, Group 2 - Nutmeg, Group 3 - Myrobolan, and Group 4 - Tulsi. Samples were stored in sterile saline (0.9% NaCl) and then decoronated at the level of the cementoenamel junction. Working length was determined followed by appropriate irrigation. The roots were split into two halves with a chisel and were stored in 2.5% glutaraldehyde solution for 24 h. After fixation, the samples were dehydrated in ethanol series (70, 90, and 95 and twice at 100%). Each specimen was mounted on Al stub and sputter coated with a 20 nm layer of gold. Samples were then examined using a SEM quantum 60 at magnification of ×2000.
Results: Tulsi demonstrated the most statistically significant results followed by myrobolan and nutmeg extract. All herbal extracts were found to be significantly effective than 2.5% NaOCl.
Conclusion: Tulsi, nutmeg and myrobolan can be effectively used as an irrigant in primary teeth.
Synthesis of lantadene analogs with marked in vitro inhibition of lung adenocarcinoma and TNF-α induced nuclear factor-kappa B (NF-κB) activation

Monika, Sharma A, Suthar SK, Aggarwal V, Lee HB, Sharma M

Bioorg Med Chem Lett, 2014 Aug 15;24(16):3814-8.
PMID: 25027934 DOI: 10.1016/j.bmcl.2014.06.068

The new series of pentacyclic triterpenoids reduced lantadene A (3), B (4), and 22β-hydroxy-3-oxo-olean-12-en-28-oic acid (5) analogs were synthesized and tested in vitro for their NF-κB and IKKβ inhibitory potencies and cytotoxicity against A549 lung cancer cells. The lead analog (11) showed sub-micromolar activity against TNF-α induced activation of NF-κB and exhibited inhibition of IKKβ in a single-digit micromolar dose. At the same time, 11 showed promising cytotoxicity against A549 lung cancer cells with IC50 of 0.98 μM. The Western blot analysis further showed that the suppression of NF-κB activity by the lead analog 11 was due to the inhibition of IκBα degradation, a natural inhibitor of NF-κB. The physicochemical evaluation demonstrated that the lead analog 11 was stable in the simulated gastric fluid of pH 2, while hydrolyzed at a relatively higher rate in the human blood plasma to release the active parent moieties. Molecular docking analysis showed that 11 was hydrogen bonded with the Arg-31 and Gln-110 residues of the IKKβ.
Fulltext SARS coronavirus outbreaks past and present-a comparative analysis of SARS-CoV-2 and its predecessors

Low ZY, Yip AJW, Sharma A, Lal SK

Virus Genes, 2021 Aug;57(4):307-317.
PMID: 34061288 DOI: 10.1007/s11262-021-01846-9

The Coronavirus Disease 2019 (COVID-19), a pneumonic disease caused by the SARS Coronavirus 2 (SARS-CoV-2), is the 7th Coronavirus to have successfully infected and caused an outbreak in humans. Genome comparisons have shown that previous isolates, the SARS-related coronavirus (SARSr-CoV), including the SARS-CoV are closely related, yet different in disease manifestation. Several explanations were suggested for the undetermined origin of SARS-CoV-2, in particular, bats, avian and Malayan pangolins as reservoir hosts, owing to the high genetic similarity. The general morphology and structure of all these viral isolates overlap with analogous disease symptoms such as fever, dry cough, fatigue, dyspnoea and headache, very similar to the current SARS-CoV-2. Chest CT scans for SARS-CoV-2, SARS-CoV and MERS-CoV reveal pulmonary lesions, bilateral ground-glass opacities, and segmental consolidation in the lungs, a common pathological trait. With greatly overlapping similarities among the previous coronavirus, the SARS-CoV, it becomes interesting to observe marked differences in disease severity of the SARS-CoV-2 thereby imparting it the ability to rapidly transmit, exhibit greater stability, bypass innate host defences, and increasingly adapt to their new host thereby resulting in the current pandemic. The most recent B.1.1.7, B.1.351 and P.1 variants of SARS-CoV-2, highlight the fact that changes in amino acids in the Spike protein can contribute to enhanced infection and transmission efficiency. This review covers a comparative analysis of previous coronavirus outbreaks and highlights the differences and similarities among different coronaviruses, including the most recent isolates that have evolved to become easily transmissible with higher replication efficiency in humans.
Recent Applications of Artificial Intelligence in detection of Gastrointestinal, Hepatic and Pancreatic Diseases

Kumar R, Khan FU, Sharma A, Aziz IB, Poddar NK

Curr Med Chem, 2021 Apr 04.
PMID: 33820515 DOI: 10.2174/0929867328666210405114938

There is substantial progress in artificial intelligence (AI) algorithms and their medical sciences applications in the last two decades. AI-assisted programs have already been established for remotely health monitoring using sensors and smartphones. A variety of AI-based prediction models available for the gastrointestinal inflammatory, non-malignant diseases, and bowel bleeding using wireless capsule endoscopy, electronic medical records for hepatitis-associated fibrosis, pancreatic carcinoma using endoscopic ultrasounds. AI-based models may be of immense help for healthcare professionals in the identification, analysis, and decision support using endoscopic images to establish prognosis and risk assessment of patient's treatment using multiple factors. Although enough randomized clinical trials are warranted to establish the efficacy of AI-algorithms assisted and non-AI based treatments before approval of such techniques from medical regulatory authorities. In this article, available AI approaches and AI-based prediction models for detecting gastrointestinal, hepatic, and pancreatic diseases are reviewed. The limitation of AI techniques in such disease prognosis, risk assessment, and decision support are discussed.
Fulltext Pythium Damping-Off and Root Rot of Capsicum annuum L.: Impacts, Diagnosis, and Management

Arora H, Sharma A, Sharma S, Haron FF, Gafur A, Sayyed RZ, et al.

Microorganisms, 2021 Apr 13;9(4).
PMID: 33924471 DOI: 10.3390/microorganisms9040823

Capsicum annuum L. is a significant horticulture crop known for its pungent varieties and used as a spice. The pungent character in the plant, known as capsaicinoid, has been discovered to have various health benefits. However, its production has been affected due to various exogenous stresses, including diseases caused by a soil-borne pathogen, Pythium spp. predominantly affecting the Capsicum plant in younger stages and causing damping-off, this pathogen can incite root rot in later plant growth stages. Due to the involvement of multiple Pythium spp. and their capability to disperse through various routes, their detection and diagnosis have become crucial. However, the quest for a point-of-care technology is still far from over. The use of an integrated approach with cultural and biological techniques for the management of Pythium spp. can be the best and most sustainable alternative to the traditionally used and hazardous chemical approach. The lack of race-specific resistance genes against Pythium spp. can be compensated with the candidate quantitative trait loci (QTL) genes in C. annuum L. This review will focus on the epidemiological factors playing a major role in disease spread, the currently available diagnostics in species identification, and the management strategies with a special emphasis on Pythium spp. causing damping-off and root rot in different cultivars of C. annuum L.
Skin Diseases and their Treatment Strategies in Sub-Saharan African Regions

Anwar ET, Gupta N, Porwal O, Sharma A, Malviya R, Singh A, et al.

Infect Disord Drug Targets, 2021 Sep 27.
PMID: 34579638 DOI: 10.2174/1871526521666210927120334

BACKGROUND: In the rural areas of sub-Saharan African regions, skin diseases are so common. Due to which the population of the sub-Saharan region suffers from different types of skin disorders. In these regions, many treatment options are not available for the treatment of skin disease.
AIM: The current study aims to discuss various skin diseases and their treatment strategies specifically in sub-Saharan African regions.
METHOD: Extensive literature survey was carried out by using scopus, science direct, elsevier, google scholar and bentham science databases.
RESULT AND DISCUSSION: It was demonstrated from the literature surveys that different effective techniques are used in the management of skin disease. In the result, it was shown that the condition of the disease is at a dangerous level which must be controlled.
CONCLUSION: It is concluded from the manuscript that the skin disorder in the sub-Saharan region is at a very dangerous level. The research must be done to develop a better understanding of the disease and its treatment.
Fulltext Circadian Rhythm Disruption and Alzheimer's Disease: The Dynamics of a Vicious Cycle

Sharma A, Sethi G, Tambuwala MM, Aljabali AAA, Chellappan DK, Dua K, et al.

Curr Neuropharmacol, 2021;19(2):248-264.
PMID: 32348224 DOI: 10.2174/1570159X18666200429013041

All mammalian cells exhibit circadian rhythm in cellular metabolism and energetics. Autonomous cellular clocks are modulated by various pathways that are essential for robust time keeping. In addition to the canonical transcriptional translational feedback loop, several new pathways of circadian timekeeping - non-transcriptional oscillations, post-translational modifications, epigenetics and cellular signaling in the circadian clock - have been identified. The physiology of circadian rhythm is expansive, and its link to the neurodegeneration is multifactorial. Circadian rhythm disruption is prevelant in contamporary society where light-noise, shift-work, and transmeridian travel are commonplace, and is also reported from the early stages of Alzheimer's disease (AD). Circadian alignment by bright light therapy in conjunction with chronobiotics is beneficial for treating sundowning syndrome and other cognitive symptoms in advanced AD patients. We performed a comprehensive analysis of the clinical and translational reports to review the physiology of the circadian clock, delineate its dysfunction in AD, and unravel the dynamics of the vicious cycle between two pathologies. The review delineates the role of putative targets like clock proteins PER, CLOCK, BMAL1, ROR, and clock-controlled proteins like AVP, SIRT1, FOXO, and PK2 towards future approaches for management of AD. Furthermore, the role of circadian rhythm disruption in aging is delineated.

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