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Novel lung adenocarcinoma and nuclear factor-kappa B (NF-κB) inhibitors: synthesis and evaluation of lantadene congeners

Suthar SK, Boon HL, Sharma M

Eur J Med Chem, 2014 Mar 3;74:135-44.
PMID: 24457265 DOI: 10.1016/j.ejmech.2013.12.052

The C-3, C-17 and C-22 congeners of pentacyclic triterpenoids reduced lantadene A (3), B (4) and 22β-hydroxyoleanolic acid (5) were synthesized and were tested in vitro for their NF-κB and IKKβ inhibitory potencies and cytotoxicity against A549 lung cancer cells. The lead congeners 12 and 13 showed IC50 of 0.56 and 0.42 μmol, respectively against TNF-α induced activation of NF-κB. The congeners 12 and 13 exhibited inhibition of IKKβ in a single-digit micromolar dose and at the same time, 12 and 13 showed marked cytotoxicity against A549 lung cancer cells with IC50 of 0.12 and 0.08 μmol, respectively. The lead ester congeners were stable in the acidic pH, while hydrolyzed readily in the human blood plasma to release the active parent moieties.
Application of an optimal class of antisymmetric wavelet filter banks for obstructive sleep apnea diagnosis using ECG signals

Sharma M, Agarwal S, Acharya UR

Comput Biol Med, 2018 09 01;100:100-113.
PMID: 29990643 DOI: 10.1016/j.compbiomed.2018.06.011

Obstructive sleep apnea (OSA) is a sleep disorder caused due to interruption of breathing resulting in insufficient oxygen to the human body and brain. If the OSA is detected and treated at an early stage the possibility of severe health impairment can be mitigated. Therefore, an accurate automated OSA detection system is indispensable. Generally, OSA based computer-aided diagnosis (CAD) system employs multi-channel, multi-signal physiological signals. However, there is a great need for single-channel bio-signal based low-power, a portable OSA-CAD system which can be used at home. In this study, we propose single-channel electrocardiogram (ECG) based OSA-CAD system using a new class of optimal biorthogonal antisymmetric wavelet filter bank (BAWFB). In this class of filter bank, all filters are of even length. The filter bank design problem is transformed into a constrained optimization problem wherein the objective is to minimize either frequency-spread for the given time-spread or time-spread for the given frequency-spread. The optimization problem is formulated as a semi-definite programming (SDP) problem. In the SDP problem, the objective function (time-spread or frequency-spread), constraints of perfect reconstruction (PR) and zero moment (ZM) are incorporated in their time domain matrix formulations. The global solution for SDP is obtained using interior point algorithm. The newly designed BAWFB is used for the classification of OSA using ECG signals taken from the physionet's Apnea-ECG database. The ECG segments of 1 min duration are decomposed into six wavelet subbands (WSBs) by employing the proposed BAWFB. Then, the fuzzy entropy (FE) and log-energy (LE) features are computed from all six WSBs. The FE and LE features are classified into normal and OSA groups using least squares support vector machine (LS-SVM) with 35-fold cross-validation strategy. The proposed OSA detection model achieved the average classification accuracy, sensitivity, specificity and F-score of 90.11%, 90.87% 88.88% and 0.92, respectively. The performance of the model is found to be better than the existing works in detecting OSA using the same database. Thus, the proposed automated OSA detection system is accurate, cost-effective and ready to be tested with a huge database.
A novel automated diagnostic system for classification of myocardial infarction ECG signals using an optimal biorthogonal filter bank

Sharma M, Tan RS, Acharya UR

Comput Biol Med, 2018 11 01;102:341-356.
PMID: 30049414 DOI: 10.1016/j.compbiomed.2018.07.005

Myocardial infarction (MI), also referred to as heart attack, occurs when there is an interruption of blood flow to parts of the heart, due to the acute rupture of atherosclerotic plaque, which leads to damage of heart muscle. The heart muscle damage produces changes in the recorded surface electrocardiogram (ECG). The identification of MI by visual inspection of the ECG requires expert interpretation, and is difficult as the ECG signal changes associated with MI can be short in duration and low in magnitude. Hence, errors in diagnosis can lead to delay the initiation of appropriate medical treatment. To lessen the burden on doctors, an automated ECG based system can be installed in hospitals to help identify MI changes on ECG. In the proposed study, we develop a single-channel single lead ECG based MI diagnostic system validated using noisy and clean datasets. The raw ECG signals are taken from the Physikalisch-Technische Bundesanstalt database. We design a novel two-band optimal biorthogonal filter bank (FB) for analysis of the ECG signals. We present a method to design a novel class of two-band optimal biorthogonal FB in which not only the product filter but the analysis lowpass filter is also a halfband filter. The filter design problem has been composed as a constrained convex optimization problem in which the objective function is a convex combination of multiple quadratic functions and the regularity and perfect reconstruction conditions are imposed in the form linear equalities. ECG signals are decomposed into six subbands (SBs) using the newly designed wavelet FB. Following to this, discriminating features namely, fuzzy entropy (FE), signal-fractal-dimensions (SFD), and renyi entropy (RE) are computed from all the six SBs. The features are fed to the k-nearest neighbor (KNN). The proposed system yields an accuracy of 99.62% for the noisy dataset and an accuracy of 99.74% for the clean dataset, using 10-fold cross validation (CV) technique. Our MI identification system is robust and highly accurate. It can thus be installed in clinics for detecting MI.
Novel Pathways and Mechanism of Nicotine-Induced Oral Carcinogenesis

Sharma M, Shetty SS, Radhakrishnan R

Recent Pat Anticancer Drug Discov, 2021 08 06.
PMID: 34365933 DOI: 10.2174/1574892816666210806161312

BACKGROUND: Smokeless Tobacco (SLT) contains 9 times more nicotine than Smoked Tobacco (SMT). The carcinogenic effect of nicotine is intensified by converting nicotine-to-nicotine-derived Nitrosamines (NDNs).
METHODS: A review of the literature was conducted with a tailored search strategy to unravel the novel pathways and mechanisms of nicotine-induced oral carcinogenesis.
RESULTS: Nicotine and NDNs act on nicotinic Acetylcholine Receptors (nAChRs) as agonists. Nicotine facilitates cravings through α4β2nAChR and α7nAChR, via enhanced brain dopamine release. Nicotine binding to nAChR promotes proliferation, migration, invasion, chemoresistance, radioresistance, and metastasis of oral cancer cells. Nicotine binding to α7nAChR on keratinocytes triggers Ras/Raf-1/MEK1/ERK cascade promoting anti-apoptosis and pro-proliferative effects. Furthermore, the nicotine-enhanced metastasis is subdued on nAChR blockade through reduced nuclear localization of p-EGFR.
CONCLUSION: Protracted exposure to nicotine/NDN augments cancer-stimulatory α7nAChR and desensitizes cancer inhibitory α4β2nAChR. Since nAChRs dictate both addictive and carcinogenic effects of nicotine, it seems counterintuitive to designate nicotine just as an addictive agent devoid of any carcinogenicity.
Evaluation of real-world preferences and performance of hearing aids fitted according to the NAL-NL1 and DSL v5 procedures in children with moderately severe to profound hearing loss

Quar TK, Ching TY, Newall P, Sharma M

Int J Audiol, 2013 May;52(5):322-32.
PMID: 23570290 DOI: 10.3109/14992027.2012.755740

The study aims to compare the performance of hearing aids fitted according to the NAL-NL1 and DSL v5 prescriptive procedure for children.
Adductor accessorius - an unusual supernumerary adductor muscle of thigh

Goel S, Arora J, Mehta V, Sharma M, Suri RK, Rath G, et al.

Clin Ter, 2015;166(3):114-7.
PMID: 26152618 DOI: 10.7417/CT.2015.1840

The knowledge of variant anatomy of medial compartment of thigh is extremely important in surgical procedures requiring obturator nerve block. The nerve block is also recommended for providing additional analgesia following major knee surgeries and for relieving painful adductor muscle spasm. The interfascial injection technique is commonly followed in ultrasound guided obturator nerve block. For this procedure it is imperative to identify the adductor muscles on sonography to inject the anesthetic solution in the intermuscular fascial planes. The presence of an additional muscle can prove useful in myocutaneous flap surgeries for reconstruction especially of perineum. We hereby report a case of such an anomalous supernumerary adductor muscle present between adductor brevis and proximal part of adductor magnus, in an adult Indian male cadaver, recorded during routine dissection in Department of Anatomy, Vardhman Mahavir Medical College and Safdarjung Hospital. The muscle was innervated by the posterior division of obturator nerve. The morphology, embryological basis and clinical aspects are also discussed.
Unusual branching pattern of brachial artery - Embryological basis and clinicoanatomical insight

Hansdak R, Arora J, Sharma M, Mehta V, Suri RK, Das S

Clin Ter, 2015;166(2):65-7.
PMID: 25945432 DOI: 10.7417/CT.2015.1817

Variations in the arterial pattern of upper limb are of colossal importance to the surgeons as they are liable to iatrogenic injuries. During routine dissection for undergraduate medical students, an anomaly of brachial artery was discovered. The brachial artery terminated at higher level into ulnar and radial artery. The common interosseus artery took origin arising from radial artery. The ulnar artery did not give any branches in the forearm. Both radial and ulnar artery displayed a superficial course in the forearm. The anatomical knowledge of these variations may be of great help for the clinicians in planning and conducting flap harvesting during reconstructive surgeries and in arteriography.
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.
An accurate sleep stages classification system using a new class of optimally time-frequency localized three-band wavelet filter bank

Sharma M, Goyal D, Achuth PV, Acharya UR

Comput Biol Med, 2018 07 01;98:58-75.
PMID: 29775912 DOI: 10.1016/j.compbiomed.2018.04.025

Sleep related disorder causes diminished quality of lives in human beings. Sleep scoring or sleep staging is the process of classifying various sleep stages which helps to detect the quality of sleep. The identification of sleep-stages using electroencephalogram (EEG) signals is an arduous task. Just by looking at an EEG signal, one cannot determine the sleep stages precisely. Sleep specialists may make errors in identifying sleep stages by visual inspection. To mitigate the erroneous identification and to reduce the burden on doctors, a computer-aided EEG based system can be deployed in the hospitals, which can help identify the sleep stages, correctly. Several automated systems based on the analysis of polysomnographic (PSG) signals have been proposed. A few sleep stage scoring systems using EEG signals have also been proposed. But, still there is a need for a robust and accurate portable system developed using huge dataset. In this study, we have developed a new single-channel EEG based sleep-stages identification system using a novel set of wavelet-based features extracted from a large EEG dataset. We employed a novel three-band time-frequency localized (TBTFL) wavelet filter bank (FB). The EEG signals are decomposed using three-level wavelet decomposition, yielding seven sub-bands (SBs). This is followed by the computation of discriminating features namely, log-energy (LE), signal-fractal-dimensions (SFD), and signal-sample-entropy (SSE) from all seven SBs. The extracted features are ranked and fed to the support vector machine (SVM) and other supervised learning classifiers. In this study, we have considered five different classification problems (CPs), (two-class (CP-1), three-class (CP-2), four-class (CP-3), five-class (CP-4) and six-class (CP-5)). The proposed system yielded accuracies of 98.3%, 93.9%, 92.1%, 91.7%, and 91.5% for CP-1 to CP-5, respectively, using 10-fold cross validation (CV) technique.
p40 in metastatic pulmonary trophoblastic tumour: potential diagnostic pitfall on histopathology

Vallonthaiel AG, Walia R, Pramanik R, Sharma MC, Jain D

Malays J Pathol, 2017 Aug;39(2):175-179.
PMID: 28866701

p40, one of the two isomers of p63, is nowadays widely used for diagnosis of squamous cell carcinoma, especially in subtyping non-small cell carcinoma on lung biopsies. We describe a case in which lung tumour was misdiagnosed as squamous cell carcinoma due to p40 immunopositivity. A 36-year-old lady presented with cough and left sided chest pain of 2 months duration. Chest imaging revealed a lesion in left lower lobe of the lung and biopsy was suggestive of squamous cell carcinoma. However, past history revealed amputation of great toe for non-healing discharging ulcer which on histopathology was diagnosed as choriocarcinoma. She also had a history of hysterectomy five years ago, details of which were not available. Post-amputation β-hCG levels were high and she had been treated with multimodality chemotherapy for choriocarcinoma. She had good response to chemotherapy initially, however became resistant later on. Review of the lung biopsy in the light of the past history along with extensive literature review led to the final diagnosis of metastatic trophoblastic tumour to lung. Hence, awareness that p40 immunopositivity can be seen in trophoblastic tumours is essential to avoid misdiagnosis, especially in sites like the lung where squamous cell carcinoma is common.
Synthesis and Antitumor Evaluation of Glutathione Responsive Self-Immolative Disulphide Linked Camptothecin-Biotin Conjugate

Kaur A, Dhiman S, Lee HB, Sharma M

Anticancer Agents Med Chem, 2022;22(18):3182-3192.
PMID: 35469577 DOI: 10.2174/1871520622666220425114553

BACKGROUND: Camptothecin is a naturally occurring alkaloid obtained from the stem wood of the Chinese tree, Camptotheca acuminata. It exerts pharmacological effects due to its ability to selectively inhibit the type-I topoisomerase DNA nuclear enzyme. Several semisynthetic analogs of camptothecin have been synthesized to date possessing antitumor activity.
OBJECTIVE: Camptothecin (CPT) is one of the most promising anticancer drugs but it produces various side effects because of its non-selectivity towards cancer cells. To overcome these adverse effects, we synthesized biotin conjugate of camptothecin, which was linked via a self-immolative disulfide linker (CPT-SS-Biotin).
METHODS: Biotin conjugated camptothecin linked through a disulfide bond was synthesized following schemes, and the structural characterization was carried out. The stability and drug release studies were performed in the presence of glutathione (GSH) while in vitro studies were performed on 4T1 tumor cell lines. In vivo pharmacological investigation was done using an antitumor Wistar rat model.
RESULTS: The stability and drug release studies were performed in the presence of glutathione (GSH), and CPT-SSBiotin was found to be physiologically stable moiety and can only be cleaved in the presence of GSH to release free CPT. The CPT-SS-Biotin showed higher toxicity in the biotin-overexpressing 4T1 tumor cell line with a lower IC50 value (8.44 μM) compared to camptothecin alone (IC50 > 30 μM). CPT-SS-Biotin also showed 10.6% higher cellular uptake by cells in comparison to free camptothecin. The CPT-SS-Biotin was delivered to cells by binding to the biotin receptors on the cell surface, followed by energy-dependent endocytosis and internalization to cause cellular toxicity.
CONCLUSION: In-vivo tumor suppression studies and in vitro cell line studies along with serological parameters and histopathological studies showed that conjugate produced a high therapeutic effect and remarkably reduced toxic effects in comparison to free CPT. The results suggested that biotinylation of camptothecin via disulfide linker can be a safe and efficacious method in cancer therapeutics.
Ovalbumin production without poultry

Diwan D, Sharma M, Tabatabaei M, Gupta VK

Nat Food, 2021 Dec;2(12):924-925.
PMID: 37118249 DOI: 10.1038/s43016-021-00438-y
Fulltext Iron deficiency anemia in children with cyanotic congenital heart disease and effect on cyanotic spells

Mukherjee S, Sharma M, Devgan A, Jatana SK

Med J Armed Forces India, 2018 Jul;74(3):235-240.
PMID: 30093766 DOI: 10.1016/j.mjafi.2017.07.003

BACKGROUND: Iron deficiency anemia (IDA) in cyanotic congenital heart disease (CCHD) and its association with cyanotic spells has been documented in literature. However, Indian data especially in the pediatric age group is scarce. This study was conducted to find out the prevalence of IDA in this population.
METHODS: An observational study was conducted in a tertiary care hospital. Children with CCHD in the age group of birth-12 years were included in the study. Hematological parameters of these patients were determined and compared. An assessment of the incidence of cyanotic spells in the iron-deficient and iron non-deficient children was also done. Data analysis was done using Fischer's exact test.
RESULTS: The prevalence of IDA was 47.06% in the study population. The study also showed that hemoglobin and hematocrit levels were paradoxically higher in the iron-deficient group as compared to the non-deficient, though the iron studies revealed the iron deficiency. The incidence of cyanotic spells was higher in the iron-deficient group. The mean corpuscular volume (MCV), red cell distribution width (RDW), serum ferritin, serum iron, total iron binding capacity (TIBC), and transferrin saturation (TS) values were the parameters, which were found to be statistically significant to differentiate the study groups.
CONCLUSION: The prevalence of IDA in children with CCHD was found to be high. Iron-deficient group had an increased frequency of cyanotic spells as compared to the non-deficient group, which was statistically significant.
Term Live Secondary Abdominal Pregnancy: A Case Report

Pannu D, Bharti R, Anand HP, Sharma M

Malays J Med Sci, 2016 Sep;23(5):96-99.
PMID: 27904431

Term, live abdominal pregnancy secondary to rupture of a uterine rudimentary horn is a rare condition. Pregnancies conceived in the rudimentary horn of the uterus usually rupture during early gestation and present as a catastrophic event. However, rarely, after rupture of the uterine horn the foetus may continue to grow in the abdominal cavity and reach term gestation. A primigravida with a term pregnancy was referred to our centre for caesarean section with ultrasonography findings of transverse lie and placenta previa. During surgery, a live baby was extracted from the abdominal cavity, revealing a bicornuate uterus with rupture of the rudimentary horn. The early peroperative diagnosis and prompt control of the bleeding with excision of the rudimentary horn and transfusion of multiple blood products saved the patient's life. The case is presented for its rarity and to highlight the importance of a high index of suspicion in cases presenting with abnormal foetal presentation.
Comparing NAL-NL1 and DSL v5 in Hearing Aids Fit to Children with Severe or Profound Hearing Loss: Goodness of Fit-to-Targets, Impacts on Predicted Loudness and Speech Intelligibility

Ching TY, Quar TK, Johnson EE, Newall P, Sharma M

J Am Acad Audiol, 2015 Mar;26(3):260-74.
PMID: 25751694 DOI: 10.3766/jaaa.26.3.6

BACKGROUND: An important goal of providing amplification to children with hearing loss is to ensure that hearing aids are adjusted to match targets of prescriptive procedures as closely as possible. The Desired Sensation Level (DSL) v5 and the National Acoustic Laboratories' prescription for nonlinear hearing aids, version 1 (NAL-NL1) procedures are widely used in fitting hearing aids to children. Little is known about hearing aid fitting outcomes for children with severe or profound hearing loss.
PURPOSE: The purpose of this study was to investigate the prescribed and measured gain of hearing aids fit according to the NAL-NL1 and the DSL v5 procedure for children with moderately severe to profound hearing loss; and to examine the impact of choice of prescription on predicted speech intelligibility and loudness.
RESEARCH DESIGN: Participants were fit with Phonak Naida V SP hearing aids according to the NAL-NL1 and DSL v5 procedures. The Speech Intelligibility Index (SII) and estimated loudness were calculated using published models.
STUDY SAMPLE: The sample consisted of 16 children (30 ears) aged between 7 and 17 yr old.
DATA COLLECTION AND ANALYSIS: The measured hearing aid gains were compared with the prescribed gains at 50 (low), 65 (medium), and 80 dB SPL (high) input levels. The goodness of fit-to-targets was quantified by calculating the average root-mean-square (RMS) error of the measured gain compared with prescriptive gain targets for 0.5, 1, 2, and 4 kHz. The significance of difference between prescriptions for hearing aid gains, SII, and loudness was examined by performing analyses of variance. Correlation analyses were used to examine the relationship between measures.
RESULTS: The DSL v5 prescribed significantly higher overall gain than the NAL-NL1 procedure for the same audiograms. For low and medium input levels, the hearing aids of all children fit with NAL-NL1 were within 5 dB RMS of prescribed targets, but 33% (10 ears) deviated from the DSL v5 targets by more than 5 dB RMS on average. For high input level, the hearing aid fittings of 60% and 43% of ears deviated by more than 5 dB RMS from targets of NAL-NL1 and DSL v5, respectively. Greater deviations from targets were associated with more severe hearing loss. On average, the SII was higher for DSL v5 than for NAL-NL1 at low input level. No significant difference in SII was found between prescriptions at medium or high input level, despite greater loudness for DSL v5 than for NAL-NL1.
CONCLUSIONS: Although targets between 0.25 and 2 kHz were well matched for both prescriptions in commercial hearing aids, gain targets at 4 kHz were matched for NAL-NL1 only. Although the two prescriptions differ markedly in estimated loudness, they resulted in comparable predicted speech intelligibility for medium and high input levels.
Development of solid dispersion systems of dapivirine to enhance its solubility

Gorajana A, Ying CC, Shuang Y, Fong P, Tan Z, Gupta J, et al.

Curr Drug Deliv, 2013 Jun;10(3):309-16.
PMID: 23360246

Dapivirine, formerly known as TMC 120, is a poorly-water soluble anti-HIV drug, currently being developed as a vaginal microbicide. The clinical use of this drug has been limited due to its poor solubility. The aim of this study was to design solid dispersion systems of Dapivirine to improve its solubility. Solid dispersions were prepared by solvent and fusion methods. Dapivirine release from the solid dispersion system was determined by conducting in-vitro dissolution studies. The physicochemical characteristics of the drug and its formulation were studied using Differential Scanning Calorimetry (DSC), powder X-ray Diffraction (XRD), Fourier-transform Infrared Spectroscopy (FTIR) and Scanning Electron Microscopy (SEM). A significant improvement in drug dissolution rate was observed with the solid dispersion systems. XRD, SEM and DSC results indicated the transformation of pure Dapivirine which exists in crystalline form into an amorphous form in selected solid dispersion formulations. FTIR and HPLC analysis confirmed the absence of drug-excipient interactions. Solid dispersion systems can be used to improve the dissolution rate of Dapivirine. This improvement could be attributed to the reduction or absence of drug crystallinity, existence of drug particles in an amorphous form and improved wettability of the drug.
Fulltext Vesicular drug delivery systems as theranostics in COVID-19

Satija S, Mehta M, Sharma M, Prasher P, Gupta G, Chellappan DK, et al.

Future Med Chem, 2020 09;12(18):1607-1609.
PMID: 32589055 DOI: 10.4155/fmc-2020-0149
Fulltext Signaling pathways promoting epithelial mesenchymal transition in oral submucous fibrosis and oral squamous cell carcinoma

Shetty SS, Sharma M, Fonseca FP, Jayaram P, Tanwar AS, Kabekkodu SP, et al.

Jpn Dent Sci Rev, 2020 Nov;56(1):97-108.
PMID: 32874377 DOI: 10.1016/j.jdsr.2020.07.002

Epithelial-mesenchymal transition (EMT) is a critical process that occurs during the embryonic development, wound healing, organ fibrosis and the onset of malignancy. Emerging evidence suggests that the EMT is involved in the invasion and metastasis of cancers. The inflammatory reaction antecedent to fibrosis in the onset of oral submucous fibrosis (OSF) and the role of EMT in its malignant transformation indicates a hitherto unexplored involvement of EMT. This review focuses on the role of EMT markers which are regulators of the EMT mediated complex network of molecular mechanisms involved in the pathogenesis of OSF and OSCC. Further the gene enrichment analysis and pathway analysis supports the association of the upregulated and downregulated genes in various EMT regulating pathways.
Role of Yes-associated protein and transcriptional coactivator with PDZ-binding motif in the malignant transformation of oral submucous fibrosis

Sharma M, Hunter KD, Fonseca FP, Shetty SS, Radhakrishnan R

Arch Oral Biol, 2021 Aug;128:105164.
PMID: 34044344 DOI: 10.1016/j.archoralbio.2021.105164

OBJECTIVE(S): The objective of the present manuscript is to elucidate the role of matrix stiffness in the malignant transformation of oral submucous fibrosis.
DESIGN: The role of matrix stiffness in several cancers including oral cancer was reviewed with a tailored search strategy using relevant keywords as per the Medline format. The role of molecular mediators, Yes-associated protein 1 (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) was weighed in the context of OSF along two distinct pathways.
RESULTS: Increased matrix stiffness activates the transcriptional coactivators, YAP and TAZ shuttling between the nucleus and cytoplasm. YAP and TAZ, serve as mechanical transducers in promoting cell migration, invasion and epithelial-mesenchymal transition (EMT). The hypoxic microenvironment in the advanced stage of OSF promotes the migratory phenotype through mechanical memory.
CONCLUSIONS: Reprogramming of a stiff matrix has the potential to restore the Hippo-YAP/TAZ tumor suppressor pathway and reverse fibrosis-associated tumor development.
Fulltext Understanding the molecular mechanism associated with reversal of oral submucous fibrosis targeting hydroxylysine aldehyde-derived collagen cross-links

Shetty SS, Sharma M, Kabekkodu SP, Kumar NA, Satyamoorthy K, Radhakrishnan R

J Carcinog, 2021;20:9.
PMID: 34526855 DOI: 10.4103/jcar.JCar_24_20

Fibrosis is a pathological state characterized by excessive deposition of the extracellular matrix components leading to impaired tissue function in the affected organ. It results in scarring of the affected tissue akin to an over-healing wound as a consequence of chronic inflammation and repair in response to injury. Persistent trauma of susceptible oral mucosa due to habitual chewing of betel quid resulting in zealous healing of the mucosal tissue is one plausible explanation for the onset of oral submucous fibrosis (OSF). The irreversibility and resistance of collagen to degradation and its high potential to undergo malignant change are a major reason for morbidity in OSF. Hence, early diagnosis and timely treatment are crucial to prevent the progression of OSF to malignancy. This review focuses on the mechanistic insight into the role of collagen cross-links in advancing fibrosis and possible therapeutic targets that bring about a reversal of fibrosis. These options may be beneficial if attempted as a specific therapeutic modality in OSF as is in organ fibrosis. The upregulation of lysyl oxidase and lysyl hydroxylase has been shown to exhibit the higher levels of the hydroxylysine aldehyde-derived cross-links in fibrosis and tumor stroma promoting the tumor cell survival, resistance, and invasion. The in silico analysis highlights the potential drugs that may target the genes regulating collagen crosslinking.

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