Publications by authors named "Mahendra Pal Singh"

37 Publications

[email protected] metal-organic framework composite as an immunosensing platform for determination of hepatitis B virus surface antigen.

Mikrochim Acta 2021 10 6;188(11):365. Epub 2021 Oct 6.

TERI-Deakin Nanobiotechnology Centre, The Energy and Resources Institute, Gwal Pahari, Gurugram, Haryana, 122003, India.

An ultrasensitive electrochemical immunosensor has been prepared using an immunofunctionalized zirconium (Zr)-based metal-organic framework (MOF) with gold (Au) decoration [email protected](NH) composite-coated glassy carbon electrode (GCE) for the determination of infectious hepatitis B surface antigen (HBsAg). We fabricated GCE with specific composite via immune-functionalization using anti-HBsAg with Au nanoparticles embedded in UiO-66(NH). The electrochemical sensing performance of the immunofunctionalized [email protected](NH)/GCE with HBsAg was characterized by cyclic voltammetry and differential pulse voltammetry. Under optimized conditions, there was a linear dynamic relationship in the buffer system between the electrical signal and HBsAg levels over the range 1.13 fg mL-100 ng mL (R = 0.999) with a detection limit of 1.13 fg mL. The total analysis time was 15 min per sample. Further validations were performed with HBsAg-spiked human serum samples, and similar detection limits as in the buffer system were observed with reduced signal intensities at lower concentrations of HBsAg (1, 10, and 100 fg mL) and minimal interference. The HBsAg electrochemical immunosensing assay had good selectivity and excellent reproducibility, thereby indicating its significant potential in the super-fast diagnosis of hepatitis B.
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http://dx.doi.org/10.1007/s00604-021-05022-6DOI Listing
October 2021

TCF-1 controls T cell functions that regulate inflammation, CD8 T cell cytotoxicity and severity of colon cancer.

Nat Immunol 2021 09 12;22(9):1152-1162. Epub 2021 Aug 12.

Department of Immunology, Mayo Clinic, Rochester, MN, USA.

The transcription factor TCF-1 is essential for the development and function of regulatory T (T) cells; however, its function is poorly understood. Here, we show that TCF-1 primarily suppresses transcription of genes that are co-bound by Foxp3. Single-cell RNA-sequencing analysis identified effector memory T cells and central memory T cells with differential expression of Klf2 and memory and activation markers. TCF-1 deficiency did not change the core T cell transcriptional signature, but promoted alternative signaling pathways whereby T cells became activated and gained gut-homing properties and characteristics of the T17 subset of helper T cells. TCF-1-deficient T cells strongly suppressed T cell proliferation and cytotoxicity, but were compromised in controlling CD4 T cell polarization and inflammation. In mice with polyposis, T cell-specific TCF-1 deficiency promoted tumor growth. Consistently, tumor-infiltrating T cells of patients with colorectal cancer showed lower TCF-1 expression and increased T17 expression signatures compared to adjacent normal tissue and circulating T cells. Thus, T cell-specific TCF-1 expression differentially regulates T17-mediated inflammation and T cell cytotoxicity, and can determine colorectal cancer outcome.
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http://dx.doi.org/10.1038/s41590-021-00987-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8428683PMC
September 2021

Distribution and determinants of submandibular gland involvement in oral cavity squamous cell carcinoma.

Oral Oncol 2021 07 30;118:105316. Epub 2021 Apr 30.

Department of Surgical Oncology, All India Institute of Medical Sciences, Rishikesh, India. Electronic address:

Introduction: Though the submandibular gland (SMG) is routinely sacrificed for several reasons during neck dissection in patients undergoing curative surgery for oral cavity cancers, it might be an innocent bystander and should be considered for preservation. This study aimed to identify the incidence, different patterns of invasion, and risk factors of SMG involvement in oral cavity squamous cell carcinoma (SCC).

Methods: This was a retrospective study of the patients who underwent upfront curative surgery for a biopsy-proven oral cavity SCC. A consistent protocol-based treatment strategy was followed during the study period. Data about clinical profile including demographics, clinical and histology details, and treatment profile were extracted and analysed.

Results: A total of 303 patients underwent unilateral and bilateral neck dissections contributing 79.2% (n = 240) and 20.8% (n = 63) of patients respectively. The common primary sites were buccal mucosa (n = 129, 42.5%), tongue (n = 100, 33.0%) and alveolar gingiva (n = 52, 17.2%). A total of four SMGs showed tumor involvement resulting in a prevalence of 1.09% per neck dissection (n = 366) and 1.32% per patient (n = 303). Of these four cases of SMG involvement, one patient with alveolar cancer had direct tumor invasion while the other three (alveolar cancer - two, tongue cancer - one) patients had neck node metastasis.

Conclusion: The present study confirms a very low incidence of SMG involvement in patients with oral cavity cancer who undergo neck dissection. It is often observed in patients with high neck node burden (≥N2 disease and the presence of extracapsular spread) or direct invasion by the primary tumor.
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http://dx.doi.org/10.1016/j.oraloncology.2021.105316DOI Listing
July 2021

Social taboos: a formidable challenge in cancer care.

BMJ Case Rep 2021 Jan 11;14(1). Epub 2021 Jan 11.

Department of Surgical Oncology, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India

Taboo surrounding cancer has continued to be a stubborn and refractory public health issue especially in South Asian countries. Disparities in cancer care remain ubiquitous. Differences in the manner in which cancer is perceived, addressed, and treated might partly be a result of varying cultural influences. This case report highlights the clinical course of a female patient with neurofibromatosis who later developed a large facial malignant peripheral nerve sheath tumour. The case particularly addresses the catastrophic impact of the 'cancer-related social taboos' on various dimensions of cancer care ranging from primary and secondary prevention to definitive management. The financial issues in low-income to medium-income groups as potential deterrents to optimum treatment have also been highlighted. Approach to the common challenges faced by an oncologist practising in a society plagued by misconceptions about health and disease and potential remedial measures to debunk these myths have also been discussed.
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http://dx.doi.org/10.1136/bcr-2020-236095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7802719PMC
January 2021

Morin hydrate attenuates adenine-induced renal fibrosis via targeting cathepsin D signaling.

Int Immunopharmacol 2021 Jan 9;90:107234. Epub 2020 Dec 9.

Department of Biotechnology, Daegu University, Gyeongsan, Gyeongbuk 38453, Republic of Korea. Electronic address:

Lysosomal proteases such as cathepsins B, D, L, and K can regulate the process of fibrosis in most of the organs. However, the role of cathepsin D (CATD) in kidney fibrosis and corresponding chronic kidney disease (CKD) is still unknown. We investigated whether CATD immunomodulation using morin hydrate (MH) can attenuate kidney fibrosis in CKD. Here, CKD was developed by an oral dosage of adenine (AD) in the mice model. Histopathological detection using H & E and Oil-Red-O staining revealed tissue deposition. An escalation in serum creatinine, albumin, and blood urea nitrogen (BUN) revealed a failure in kidney function. An increase in fibrosis was determined using protein analysis and mRNA analysis of MMP-9 and MMP-2 respectively. Both immunoblot analysis and histological analysis indicated that MH immunomudulated CATD expression in AD treated kidneys. With docking analysis, we found MH can bind with the catalytic core of CATD with binding efficiency of -6.83 kcal/mol. Further, MH prevented AD mediated fibrosis by reducing collagen fragmentation as evidenced by the decrease in MMP-2 (P < 0.05) and MMP-9 (P < 0.001) protein levels. MH lowered the levels of inflammation by reducing the AD enhanced expression of MCP-1 and COX-2 nearly threefold. MH treatment increased body weight, enhance kidney function, and improved survival by nearly 150% compared to AD treated mice. CATD inactivation by MH after AD treatment resulted in decreased ECM degradation, fibrosis, and inflammation which resulted in improved renal function and survival.
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http://dx.doi.org/10.1016/j.intimp.2020.107234DOI Listing
January 2021

Morin Hydrate Sensitizes Hepatoma Cells and Xenograft Tumor towards Cisplatin by Downregulating PARP-1-HMGB1 Mediated Autophagy.

Int J Mol Sci 2020 Nov 4;21(21). Epub 2020 Nov 4.

Department of Biotechnology, Daegu University, Gyeongsan, Gyeongbuk 38453, Korea.

The cross-talk between apoptosis and autophagy influences anticancer drug sensitivity and cellular death in various cancer cell lines. However, the fundamental mechanisms behind this phenomenon are still unidentified. We demonstrated anti-cancerous role of cisplatin (CP) and morin hydrate (Mh) as an individual and/or in combination (CP-Mh) in hepatoma cells and tumor model. Exposure of CP resulted in the production of intracellular reactive oxygen species (ROS)-mediated cellular vacuolization, expansion of mitochondria membrane and activation of endoplasmic reticulum (ER)-stress. Consequently, Cyt translocation led to the increase of Bax/Bcl-2 ratio, which simultaneously triggered caspase-mediated cellular apoptosis. In addition, CP-induced PARP-1 activation led to ADP-ribosylation of HMGB1, which consequently developed autophagy as evident by the LC3I/II ratio. Chemically-induced inhibition of autophagy marked by increased cell death signified a protective role of autophagy against CP treatment. CP-Mh abrogates the PARP-1 expression and significantly reduced HMGB1-cytoplasmic translocation with subsequent inhibition of the HMGB1-Beclin1 complex formation. In the absence of PARP-1, a reduced HMGB1 mediated autophagy was observed followed by induced caspase-dependent apoptosis. To confirm the role of PARP-1-HMGB1 signaling in autophagy, we used the PARP-1 inhibitor, 4-amino-1,8-naphthalimide (ANI), HMGB1 inhibitor, ethyl pyruvate (EP), autophagy inhibitors, 3-methyl adenine (3-MA) and bafilomycin (baf) and small interfering RNAs (siRNA) to target Atg5 in combination of CP and Mh. Exposure to these inhibitors enhanced the sensitivity of HepG2 cells to CP. Collectively, our findings indicate that CP-Mh in combination served as a prominent regulator of autophagy and significant inducer of apoptosis that maintains a homeostatic balance towards HepG2 cells and the subcutaneous tumor model.
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http://dx.doi.org/10.3390/ijms21218253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885522PMC
November 2020

The diagnostic role of microRNA 21 in patients with nonsmall cell lung cancer: An exploratory study.

Lung India 2020 Nov-Dec;37(6):501-505

Department of Surgical Oncology, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India.

Background: Although histopathological examination of the biopsy specimen is the gold standard for the diagnosis of non small cell lung cancer (NSCLC), a blood-based noninvasive test (liquid biopsy) may prove to be helpful in patients with repeatedly negative biopsy or for response assessment following neoadjuvant therapy. The present study was conducted to explore the diagnostic value of circulating serum microRNA (miRNA) 21 in patients with NSCLC.

Methods: This case-control analytical study was carried out in a tertiary care teaching hospital in Northern India. The study consisted of 30 cases of biopsy-proven NSCLC and 30 controls. Serum miRNA-21 expression levels were estimated by extracting total RNA from the serum sample, reverse transcribing it to cDNA and quantified in relation to U6 reference miRNA.

Results: A total of 30 patients with NSCLC and 30 controls were included in the study. The subjects were comparable in two groups with reference to age, gender, and smoking. Pathological types were adenocarcinoma in 19 (63.3%) and squamous cell carcinoma in 11 (36.6%) patients. Majority of the patients had advanced disease-AJCC stage III in 15 patients and AJCC Stage IV in 13 patients; two patients had stage II disease. There was a significant upregulation of serum miRNA 21 gene expression in the patients with lung cancer compared to controls (median fold change, 3.39 vs. -2.81, P = 0.00). A fourfold change in serum miRNA 21 is significantly associated with the diagnosis of NSCLC with a high specificity of 97% and area under curve of 0.84 (95% confidence interval of 0.74-0.94).

Conclusion: Estimation of serum miRNA 21 expression has potential to be used as liquid biopsy for the diagnosis of NSCLC. Further studies with large sample sizes are warranted to confirm the diagnostic accuracy of serum miRNA 21 expression.
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http://dx.doi.org/10.4103/lungindia.lungindia_100_20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7879878PMC
November 2020

In vitro and in vivo studies on potentiation of curcumin-induced lysosomal-dependent apoptosis upon silencing of cathepsin C in colorectal cancer cells.

Pharmacol Res 2020 11 22;161:105156. Epub 2020 Aug 22.

Department of Biotechnology, Daegu University, Gyeongsan, Gyeongbuk, 38453, Republic of Korea. Electronic address:

Cathepsins are lysosomal acid hydrolases that make crucial contributions to tumor progression through a variety of signaling mechanisms, including autophagy, cell survival, chemotherapeutic resistance, and metastasis. Herein, we report that cathepsin C (CTSC) silencing upregulates the anticancer potential of curcumin in colorectal cancer cells (CRCs) both in vitro and in athymic mice xenografts. Curcumin treatment enhances CTSC level in CRCs; however, CTSC silencing with subsequent curcumin treatment (sequential treatment) induces ER stress and autophagic dysregulation accompanied by lysosomal permeabilization and ROS generation. This lysosomal permeabilization triggered the cytosolic CTSB mediated BID-dependent mitochondrial membrane permeabilization and thereby caspase-dependent apoptosis. This phenotype can be rescued by CTSB inhibition and NAC, which further supported the involvement of ROS and CTSB in apoptosis following sequential treatment. Indeed, the sequential CTSC silencing and curcumin treatment also significantly curtailed tumor volume as well as ameliorated cytosolic cyt c and tBID protein levels in tumor tissues compared to those in control and individual treatments of CTSC targeting and on curcumin treatment in nude mice xenografts. The results reveal that CTSC can controls the curcumin-induced cytotoxic insult through autophagy maintenance both in vitro and in athymic mice xenografts, thereby providing an insight into the role of CTSC in chemoprevention of CRCs.
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http://dx.doi.org/10.1016/j.phrs.2020.105156DOI Listing
November 2020

Wnt-induced, TRP53-mediated Cell Cycle Arrest of Precursors Underlies Interstitial Cell of Cajal Depletion During Aging.

Cell Mol Gastroenterol Hepatol 2021 7;11(1):117-145. Epub 2020 Aug 7.

Enteric Neuroscience Program and Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota; Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota; Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota. Electronic address:

Background & Aims: Gastric dysfunction in the elderly may cause reduced food intake, frailty, and increased mortality. The pacemaker and neuromodulator cells interstitial cells of Cajal (ICC) decline with age in humans, and their loss contributes to gastric dysfunction in progeric klotho mice hypomorphic for the anti-aging Klotho protein. The mechanisms of ICC depletion remain unclear. Klotho attenuates Wnt (wingless-type MMTV integration site) signaling. Here, we examined whether unopposed Wnt signaling could underlie aging-associated ICC loss by up-regulating transformation related protein TRP53 in ICC stem cells (ICC-SC).

Methods: Mice aged 1-107 weeks, klotho mice, APC mice with overactive Wnt signaling, mouse ICC-SC, and human gastric smooth muscles were studied by RNA sequencing, reverse transcription-polymerase chain reaction, immunoblots, immunofluorescence, histochemistry, flow cytometry, and methyltetrazolium, ethynyl/bromodeoxyuridine incorporation, and ex-vivo gastric compliance assays. Cells were manipulated pharmacologically and by gene overexpression and RNA interference.

Results: The klotho and aged mice showed similar ICC loss and impaired gastric compliance. ICC-SC decline preceded ICC depletion. Canonical Wnt signaling and TRP53 increased in gastric muscles of klotho and aged mice and middle-aged humans. Overstimulated canonical Wnt signaling increased DNA damage response and TRP53 and reduced ICC-SC self-renewal and gastric ICC. TRP53 induction persistently inhibited G/S and G/M cell cycle phase transitions without activating apoptosis, autophagy, cellular quiescence, or canonical markers/mediators of senescence. G/S block reflected increased cyclin-dependent kinase inhibitor 1B and reduced cyclin D1 from reduced extracellular signal-regulated kinase activity.

Conclusions: Increased Wnt signaling causes age-related ICC loss by up-regulating TRP53, which induces persistent ICC-SC cell cycle arrest without up-regulating canonical senescence markers.
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http://dx.doi.org/10.1016/j.jcmgh.2020.07.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672319PMC
August 2020

Cancer surgery in the era of COVID-19 pandemic: Changing dynamics.

J Surg Oncol 2020 Nov 5;122(6):1262-1263. Epub 2020 Aug 5.

Department of Surgical Oncology, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India.

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http://dx.doi.org/10.1002/jso.26156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7436129PMC
November 2020

Discordance of COVID-19 guidelines for patients with cancer: A systematic review.

J Surg Oncol 2020 Jul 15. Epub 2020 Jul 15.

Department of Thoracic Surgery, Roswell Park Cancer Institute, Buffalo, New York.

This review was aimed to systematically evaluate the available literature on the impact of COVID-19 on cancer care and to critically analyze the diagnostic and therapeutic strategies suggested by various healthcare providers, societies, and institutions. Majority guidelines for various types of cancers favored a delay in treatment or a nonsurgical approach wherever feasible. These guidelines are based on a low level of evidence and have significant discordance for the role and timing of surgery, especially in early tumors.
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http://dx.doi.org/10.1002/jso.26110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405271PMC
July 2020

Lymph node ratio in oral cavity cancer and its impact on mortality and disease recurrence.

Oral Oncol 2020 12 10;111:104880. Epub 2020 Jul 10.

Department of Surgical Oncology, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India. Electronic address:

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http://dx.doi.org/10.1016/j.oraloncology.2020.104880DOI Listing
December 2020

Patient participation in decision making-undisputed fact.

Head Neck 2020 09 17;42(9):2242-2243. Epub 2020 Jun 17.

Department of Surgical Oncology, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, 249203, India.

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http://dx.doi.org/10.1002/hed.26316DOI Listing
September 2020

Methotrexate based oral chemotherapy for advanced oral cancer during COVID-19 pandemic: Another option in the therapeutic armamentarium.

Oral Oncol 2020 08 4;107:104839. Epub 2020 Jun 4.

Department of Surgical Oncology, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India. Electronic address:

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http://dx.doi.org/10.1016/j.oraloncology.2020.104839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269919PMC
August 2020

Grade as prognostic variable in early tongue cancer patients: Are we getting off the track?

Oral Oncol 2020 11 26;110:104812. Epub 2020 May 26.

Department of Pathology, All India Institute of Medical Sciences, Rishikesh, India.

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http://dx.doi.org/10.1016/j.oraloncology.2020.104812DOI Listing
November 2020

Baffling posterior belly of digastric muscle during neck dissection.

Oral Oncol 2020 11 12;110:104783. Epub 2020 May 12.

Department of Surgical Oncology, All India Institute of Medical Sciences, Rishikesh, India. Electronic address:

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http://dx.doi.org/10.1016/j.oraloncology.2020.104783DOI Listing
November 2020

Letter to the Editor: Relevance of Level IIb Neck Dissection in Patients with Head and Neck Squamous Cell Carcinomas.

World J Surg 2020 05;44(5):1691-1692

Department of Surgical Oncology, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, 249203, India.

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http://dx.doi.org/10.1007/s00268-020-05448-8DOI Listing
May 2020

Cell Intrinsic Deregulated ß-Catenin Signaling Promotes Expansion of Bone Marrow Derived Connective Tissue Type Mast Cells, Systemic Inflammation, and Colon Cancer.

Front Immunol 2019 3;10:2777. Epub 2019 Dec 3.

Department of Immunology, Mayo Clinic, Rochester, MN, United States.

Mast cells constitutively express ß-catenin and expand in solid tumors such as colon and skin cancer. However, the role of ß-catenin signaling in mast cells and the cause or effect of mast cell expansion and tumor growth has yet to be established. In earlier studies we used mast cell depletion and protease staining approaches, to provide evidence for a causative role of mast cells in small bowel polyposis, and related specific phenotypes and distributions of tumor infiltrating mast cells to stages of tumor growth. Here we report that, stabilization of ß-catenin expands mast cells to promote high incidence of colon polyposis and infrequent small bowel polyps and skin cancer. Expression of a dominant acting ß-catenin in mast cells (5CreCAT) stimulated maturation and expression of granule stored proteases. Both mucosal and connective tissue type mast cells accumulated in colonic small bowel polyps independent of gender, and mice developed chronic systemic inflammation with splenomegaly. Reconstitution of polyposis-prone mice with bone marrow from 5CreCAT mice resulted in focal expansion of connective tissue like mast cells, which are normally rare in benign polyps and characteristically expand during adenoma-to-carcinoma transition. Our findings highlight a hitherto unknown contribution of ß-catenin signaling in mast cells to their maturation and to increased risk of colon cancer.
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http://dx.doi.org/10.3389/fimmu.2019.02777DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6902090PMC
November 2020

Morin Hydrate Reverses Cisplatin Resistance by Impairing PARP1/HMGB1-Dependent Autophagy in Hepatocellular Carcinoma.

Cancers (Basel) 2019 Jul 15;11(7). Epub 2019 Jul 15.

Department of Biotechnology, College of Engineering, Daegu University, Gyeongsan, Gyeongbuk 38453, Korea.

Chemoresistance is a major obstacle that limits the benefits of cisplatin-based chemotherapy in various cancers, including hepatocellular carcinoma. De-regulation of the poly(ADP-ribose) polymerase 1 (PARP1)/high-mobility group box 1 (HMGB1) signaling pathway has been proposed as an important mechanism involved in cisplatin-resistance. In this study, we investigated therapeutic potential of a natural flavonoid Morin hydrate against cisplatin-induced toxicity using the HepG2 multi-drug resistant cell line, which is derived from the HepG2 human hepatocellular carcinoma cell line. HepG2 cells were exposed to cisplatin and Morin hydrate alone or together after which autophagy and apoptotic signaling pathways were monitored by fluorometric assay and Western blot analysis. Xenograft mouse models were performed to confirm the in vitro effect of Morin hydrate. PARP1 was hyper activated in cisplatin-resistant HepG2 cells. Cisplatin-induced PARP1 activation resulted in chemoresistance via increased autophagy. The cisplatin/Morin hydrate combination was effective in the reversal of the HepG2 cell resistance via suppression of PARP1-mediated autophagy by regulating the HMGB1 and microtubule-associated protein 1A/1B light chain 3B (LC3) I/II. Moreover, PARP1 inhibition by 4-amino-1,8-naphthalimide or autophagy inhibition by a knockdown of the autophagy-related 5 () gene resulted in sensitizing the HepG2 cells to cisplatin (CP) through activation of the c-Jun N-terminal kinase (JNK) pathway. In a mouse xenograft model, the treatment of cisplatin with Morin hydrate reversed the increased expression of PARP and HMGB1 and significantly suppressed tumor growth. These findings indicate dysregulated expression of PARP1 confers cisplatin-resistance via autophagy activation in HepG2 cells. Morin hydrate inhibits cisplatin-mediated autophagy induction, resulting in increased susceptibility of HepG2 cells to cisplatin cytotoxicity. The combination of Morin hydrate with cisplatin may be a promising therapeutic strategy to enhance the efficacy of conventional chemotherapeutic drugs.
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http://dx.doi.org/10.3390/cancers11070986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678360PMC
July 2019

Fumonisin B1 actuates oxidative stress-associated colonic damage via apoptosis and autophagy activation in murine model.

J Biochem Mol Toxicol 2018 May 22:e22161. Epub 2018 May 22.

Department of Biotechnology, College of Engineering, Daegu University Gyeongsan, Gyeongbuk, 38453, Republic of Korea.

In the present study, we investigated the cytotoxic mechanism of Fumonisin B1 (FB1) in mice colonic region in a time course manner. Herein, after consecutive 4 days of exposure to FBI (2.5 mg/kg body weight), we observed disintegration of mice colon, as evidenced by histopathological analysis. FB1 significantly increased alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase activities in serum and plasma, decreased ceramide level, increased sphinganine level, and increased lipid peroxidase level along with the breakdown of the antioxidant system. Further, FB1-induced ER stress caused apoptosis and autophagy activation in mice colon, evidenced by increased expression of IRE1-α, p-JNK, Casp3, and LC3I/II. In addition, we also noticed a reduced protein kinase C expression in mice colon exposed to FB1, suggesting its role in ER stress-induced cell death. Taken together, study suggests both physiologically and biochemically, FB1 toxicity to mice colon induced by oxidative stress-associated apoptosis and autophagy activation.
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http://dx.doi.org/10.1002/jbt.22161DOI Listing
May 2018

Targeting of cathepsin C induces autophagic dysregulation that directs ER stress mediated cellular cytotoxicity in colorectal cancer cells.

Cell Signal 2018 06 1;46:92-102. Epub 2018 Mar 1.

Department of Biotechnology, Daegu University, Gyeongsan, Gyeongbuk 38453, Republic of Korea. Electronic address:

As Autophagy is a pivotal mechanism of cancer cell survival and the development of chemotherapeutic resistance; therefore, new approaches are warranted for its targeting which may be fulfilled by cathepsins regulation. Amongst cathepsins, cathepsin C (CTSC) is highly expressed in various cancers and possesses significant therapeutic potential in autoimmune disorders; however, its role in colorectal cancer has not been explored. Herein, we aimed to investigate the role of CTSC in autophagy regulation mediated colorectal carcinoma cell proliferation. Cathepsin C targeting through inhibitors/siRNA leads to the accumulation of light chain 3 II and p62 without affecting the lysosomal integrity, revealed dysfunctional autolysosomal degradation which is also substantiated by proteolytic studies. Cathepsin C inhibition showed comparable autophagy blockade with E64d and augmented the autophagy blockade mediated by bafilomycin. Loss of CTSC function also induced ER stress-mediated JNK phosphorylation accompanied by the translocation of mitochondrial cyt c followed by apoptotic cell death in colorectal carcinoma cells. Taken together, the study reveals that CTSC targeting plays a key role in the regulation of autophagy mediated colorectal cancer cell proliferation. Further investigations are required to determine the functional role of CTSC in other tumors also which may have implications for the therapeutic prevention of cancer in the future.
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http://dx.doi.org/10.1016/j.cellsig.2018.02.017DOI Listing
June 2018

Morin hydrate ameliorates cisplatin-induced ER stress, inflammation and autophagy in HEK-293 cells and mice kidney via PARP-1 regulation.

Int Immunopharmacol 2018 Mar 3;56:156-167. Epub 2018 Feb 3.

Department of Biotechnology, Daegu University, Gyeongsan, Gyeongbuk 38453, Republic of Korea. Electronic address:

The present study assessed the possible therapeutic potential of a natural flavonoid morin hydrate (MH), against cisplatin (CP) induced toxicity in HEK-293 cells and mice kidney. Herein, we observed that exposure of HEK-293 cells to CP (20 μM, 24 h) reduced the cell viability, and increased the intracellular ROS generation, nuclear DNA damage, Ca release, and accumulation of acidic vacuoles. Concomitantly, acute exposure of CP (30 mg/kg, 72 h) to male ICR mice induced histopathological changes in kidney tissue, and alterations in serum creatinine and blood urea nitrogen (BUN) levels. Oxidative stress mediated ER-stress was evidenced by the reduced expression of antioxidant enzymes such as SOD-1, SOD-2, GR, and Trx, and increased expression levels of CytP450, IRE1-α, PERK, and CHOP. The expression levels of major inflammatory response markers such as NF-κB, TNF-α, IL-1β, COX-2 and iNOS were significantly increased in the HEK-293 cells and mice kidney. Temporal up-regulation of p-AMPK and LC3I/II, and down regulation of mTOR was also noticed after CP treatment. CP-induced DNA damage led to activation of PARP-1, which plays a crucial role in inflammation, apoptosis and autophagy activation. Concurrently, co-treatment of CP-MH and CP-ANI (PARP-1 inhibitor) significantly attenuated the expression level of PARP-1, reduced cellular death, alleviated inflammatory responses, and inhibited autophagy stimulation in HEK-293 cells and mice kidney. On the basis of above findings, we suggest MH as a potential therapeutic agent against CP-induced nephrotoxicity.
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http://dx.doi.org/10.1016/j.intimp.2018.01.031DOI Listing
March 2018

Endoplasmic reticulum stress-mediated autophagy activation attenuates fumonisin B1 induced hepatotoxicity in vitro and in vivo.

Food Chem Toxicol 2017 Dec 31;110:371-382. Epub 2017 Oct 31.

Department of Biotechnology, Daegu University, Gyeongsan, Gyeongbuk, 38453, Republic of Korea. Electronic address:

Although pathological characteristics of fumonisin B1 are known to induce hepatic injury over prolonged periods, the cellular defense mechanisms against the detrimental effects of FB1 are still unknown. The underlying mechanisms of FB1 toxicity are thought to be related with the inhibition of ceramide synthase, causing an accumulation of sphingoid bases, which in turn cause development of oxidative stress. Herein, we investigated whether autophagy, a cellular defense mechanism, protects liver cells from FB1 exposure. To accomplish this, we utilized HepG2 cells and a mouse model to study the effects of FB1 in the autophagy pathway. FB1 was capable of inducing autophagy via the generation of ROS, induction of endoplasmic reticulum stress, phosphorylation of JNK, suppression of mTOR and activation of LC3I/II in HepG2 cells and mice livers. Treatment of HepG2 cells with the ROS scavenger N-acetyl-l-cysteine alleviated ER stress stimulation and induced HepG2 cell death. Moreover, suppression of autophagy with 3-Methyladenine enhanced HepG2 cells apoptosis. Concurrently, four consecutive days exposure of mice livers to FB1 altered the levels of sphingoid bases, hepatic enzymes and induced histopathological changes. Moreover, the expression levels of major ER stress and autophagy-related markers such as PERK, IRE1-α, and LC3I/II also increased. Autophagy activation protected HepG2 cells and mice livers from the lethal effects of FB1. Hence, these findings specify that, the compounds that modify autophagy might be useful therapeutic agents for treatment of patients with FB1 induced liver ailments.
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http://dx.doi.org/10.1016/j.fct.2017.10.054DOI Listing
December 2017

CJK-7, a Novel Flavonoid from Paulownia tomentosa Triggers Cell Death Cascades in HCT-116 Human Colon Carcinoma Cells via Redox Signaling.

Anticancer Agents Med Chem 2018 ;18(3):428-437

Department of Biotechnology, Collage of Engineering, Daegu University, Gyeongsan, Gyeongbuk, 38453, Korea.

Background: Colon cancer is the second most common cancer to cause death worldwide. About half of colon cancers patients require adjuvant therapy to control relapse following surgical resection. Therefore, abolition of tumor cell progression using an effective chemotherapeutic agent holds a feasible approach to treat patients suffering from colon cancer. In the present study, we evaluated the effects of geranylated flavonoid CJK-7, isolated from Paulownia tomentosa on HCT-116 human colon carcinoma cells.

Materials And Methods: The effects of CJK-7 as an active component on HCT-116 cells programmed cell death and its underlying molecular mechanism were examined by using MTT assay, morphological assessment, H2DCFDA staining, Fura-2AM staining, Hoechst-33342 staining, comet assay, Acridine orange staining, mitochondrial membrane potential (ΔΨm) assay and Western blot analyses.

Results And Conclusion: The results revealed that, CJK-7 was capable of inducing caspase-dependent cell death events in cancer cells. Moreover, it was involved in up-regulation of autophagy signaling as evidenced by enhanced expression of LC3I/II. We also noticed stimulated expression of endoplasmic reticulum stress markers and phosphorylation of c-Jun NH2-terminal kinase (JNK), which was associated with up-regulated expression of p53, PUMA, Atg5 and Beclin-1, and down-regulation of Bcl-2, stressing the interaction of ROS on the aforementioned signaling. Furthermore, exposure to ROS scavengers (N-acetyl-l-cysteine (NAC), and JNK-specific inhibitor SP600125) significantly reversed the effects of CJK-7 by down-regulating apoptosis and autophagy signatures in HCT-116 cancer cells. Collectively our findings clarify the ROS-dependent regulatory effect of CJK-7 on programmed cell death signaling events in HCT-116 cancer cells while depicting its virile pro-oxidant capacity.
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http://dx.doi.org/10.2174/1871520617666171026170009DOI Listing
July 2019

3',5-dihydroxy-3,4',7-trimethoxyflavone-induces ER-stress-associated HCT-116 programmed cell death via redox signaling.

Biomed Pharmacother 2017 Apr 16;88:151-161. Epub 2017 Jan 16.

Department of Biotechnology, Daegu University, Gyeongsan, Gyeongbuk, 38453, Republic of Korea. Electronic address:

Quercetin, a well cognized bioactive flavone possessing great medicinal value, has limited usage. The rapid gastrointestinal digestion of quercetin is also a major obstacle for its clinical implementation due to low bioavailability and poor aqueous solubility. 3',5-dihydroxy-3,4',7-trimethoxyflavone (DTMF), a novel semi-synthetic derivative of quercetin, is known to modulate several biological activities. Therefore, in the present study we examined the cytotoxic mechanism of DTMF in concentration-dependent manner (25, 50, and 100μM; 24h) against HCT-116 human colon carcinoma cells. The cytotoxic potential of DTMF was characterized based on deformed cell morphology, increased ROS accumulation, loss of mitochondrial membrane potential (ΔѰm), increased mitochondrial mass, chromatin condensation, and typical DNA-fragmentation in HCT-116 cells. The results showed that DTMF-induced enhanced ROS production at higher concentration (100μM) as evidenced by upregulated expression of ER stress and apoptotic proteins with concomitant increase in PERK, CHOP, and JNK levels, when compared to N-acetyl cysteine (NAC, ROS inhibitor) treated HCT-116 cells, which depicts that DTMF might act as a crucial mediator of apoptosis signaling. Collectively, our results suggest that DTMF stimulates ROS-mediated oxidative stress, which in turn induces PERK-CHOP and JNK pathway of apoptosis to promote HCT-116 cell death.
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http://dx.doi.org/10.1016/j.biopha.2017.01.027DOI Listing
April 2017

Biological activity of a small molecule indole analog, 1-[(1H-indol-3-yl)methylene]-2-phenylhydrazine (HMPH), in chronic inflammation.

Chem Biol Interact 2016 Jan 5;244:71-83. Epub 2015 Nov 5.

Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal University, Karnataka, Manipal, 576104, India. Electronic address:

A synthetic small molecule, 1-[(1H-indol-3-yl)methylene]-2-phenylhydrazine (HMPH) was conveniently synthesised by a one-step reaction, purified and characterised by chromatographic and spectroscopic methods. HMPH scavenged free radicals and inhibited lipopolysaccharide (LPS)-induced ROS generation and NO release in RAW-264.7 cells without signs of any detectable cytotoxicity. HMPH inhibited lipid peroxidation (LPO) with IC50 of 135 ± 9 as against 58 ± 8 μM for α-tocopherol. Further, HMPH (>50 μM) significantly reduced the LPS-induced TNF-α release in mouse peritoneal macrophages and in human peripheral blood mononuclear cells (PBMCs). HMPH did not show any visible signs of toxicity in rats up to 400 mg/kg/intraperitoneal and 2000 mg/kg/oral. HMPH at 25 and 50 mg/kg attenuated neutrophil infiltration in air-pouch lavage and bronchoalveolar lavage (BAL) in rat models. HMPH also reduced myeloperoxidase (MPO), nitrite and TNF-α in air-pouch lavage in addition to MPO in plasma. HMPH reduced acute paw-inflammation in carrageenan-induced paw-edema. HMPH consistently decreased both ipsilateral and contralateral paw inflammation, minimised the clinical scores of arthritis, prevented body weight (B.wt.) loss, attenuated serum C-reactive protein (C-RP) and rheumatoid factors (RF) in rat model of adjuvant-induced arthritis. Histopathology and radio-graphical reports show that HMPH reduced bone erosion in both ipsilateral and contralateral paw joints. Failure to inhibit COX suggests that effectiveness of HMPH in both acute and chronic inflammation is mediated by a multimodal mechanism involving modulation of immunity, attenuating TNF-α, protecting bone attrition and reducing oxidative stress.
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http://dx.doi.org/10.1016/j.cbi.2015.10.024DOI Listing
January 2016

Morin hydrate attenuates the acrylamide-induced imbalance in antioxidant enzymes in a murine model.

Int J Mol Med 2015 Oct 7;36(4):992-1000. Epub 2015 Aug 7.

Department of Biotechnology, Daegu University, Gyeongsan, Gyeongbuk 712-714, Republic of Korea.

Liver diseases are among the most serious health issues nowadays. Hepatocellular carcinoma, one of the most lethal types of cancer worldwide, can be caused by chemically-induced oxidative stress. In the present study, we aimed to evaluate the protective effects of morin hydrate (MH) against acrylamide (AA)-induced hepatotoxicity in male ICR mice. The mice were randomly allocated into 4 groups [the control, the group subcutaneously injected with AA alone (50 mg/kg body weight), the group subcutaneously injected with AA (50 mg/kg body weight) and MH (5 mg/kg body weight) and the group subcutaneously injected with AA (50 mg/kg body weight) and MH (15 mg/kg body weight) for 5 consecutive days]. Histopathological evaluations were performed and the levels of serum hepatic enzymes were analyzed to determine initial liver injury, and the mice in the AA-treated groups were compared with the mice receiving no treatment and with the mice administered MH in combination with AA. Furthermore, oxidative stress, hepatic inflammation and the levels of DNA damage-related markers were evaluated to determine the extent of liver damage induced by AA within a short-term period. The subcutaneous administration of AA induced severe hepatic injury, and combined treatment with AA and MH resulted in a significant improvement in all evaluated parameters. This recovery was most obvious in the group receiving AA and 15 mg/kg body weight dose of MH. The findings of our study demonstrated that MH protected mice from severe hepatic injury induced by AA. Moreover, MH is a natural polyphenolic compound, and thus it has potential for use in the treatment of severe liver diseases, in place of many synthetic drugs.
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http://dx.doi.org/10.3892/ijmm.2015.2306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4564079PMC
October 2015

Supramolecular insulin assembly II for a sustained treatment of type 1 diabetes mellitus.

Proc Natl Acad Sci U S A 2010 Jul 13;107(30):13246-51. Epub 2010 Jul 13.

National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India.

Diabetes is a chronic disease requiring continuous medical supervision and patient education to prevent acute secondary complications. In this study, we have harnessed the inherent property of insulin to aggregate into an oligomeric intermediate on the pathway to amyloid formation, to generate a form that exhibits controlled and sustained release for extended periods. Administration of a single dose of the insulin oligomer, defined here as the supramolecular insulin assembly II (SIA-II), to experimental animals rendered diabetic by streptozotocin or alloxan, released the hormone capable of maintaining physiologic glucose levels for >120 days for bovine and >140 days for recombinant human insulin without fasting hypoglycemia. Moreover, the novel SIA-II described here not only improved the glycemic control, but also reduced the extent of secondary diabetic complications.
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http://dx.doi.org/10.1073/pnas.1005704107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2922159PMC
July 2010

Treadmill exercise-dependent tumor growth retardation in T-cell lymphoma-bearing host displays gender dimorphism.

Oncol Res 2010 ;18(7):293-304

School of Biotechnology, Banaras Hindu University, Varanasi-221 005, UP India.

A number of previous investigations have reported that physical exercise renders immunopotentiating and antitumor therapeutic benefits to the tumor-bearing host. As these effects of physical exercise are mainly mediated through the modulation of hormonal and cytokine repertoire, it remains unclear if male and female tumor-bearing hosts show a gender-dependent differential response to the therapeutic action of physical exercise in tumor growth retardation. In the present investigation tumor growth retardation, following physical exercise was investigated in a gender-specific manner in a murine tumor model of a T-cell lymphoma designated as Dalton's lymphoma (DL). The results of the present investigation show that physical exercise of a tumor-bearing host on a treadmill results in a better retardation of tumor progression along with prolongation of survival time in male compared to female tumor-bearing host. Such gender dimorphism of the therapeutic benefits of physical exercise in tumor-bearing host was found to be associated with a gender-dependent variation in cell survival and induction of apoptosis in tumor cells. Moreover, expression of cell growth regulatory proteins-selectin, Hsp70, p53, CAD, SOCS, and IL-2 receptor-was found to vary in a gender-specific manner following physical exercise. The investigation also indicates the role of cytokines and macrophages in manifestation of gender dimorphism in the response of tumor-bearing mice to physical exercise. Thus, the observations of the present investigation suggest for the first time that the beneficial effects of physical exercise in a tumor-bearing host may be variable depending on the gender of the host.
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http://dx.doi.org/10.3727/096504010x12629634366142DOI Listing
May 2010

Effect of physical exercise on tumor growth regulating factors of tumor microenvironment: implications in exercise-dependent tumor growth retardation.

Immunopharmacol Immunotoxicol 2009 Jun;31(2):274-82

School of Biotechnology, Banaras Hindu University, Varanasi, India.

Recently, we reported that treadmill exercise renders survival benefits in a murine tumor model of a transplantable lymphoma of spontaneous origin, designated as Dalton's lymphoma (DL), owing to an augmented apoptosis of tumor cells. However, the underlying the mechanisms of the same remained unclear with respect to the role alterations if any in the components of tumor microenvironment following physical exercise. Therefore, in the present we investigated the role of oxygen, pH, lactate and cytokines of tumor micro-environment associated with physical exercise-dependent alteration in the growth properties of tumor cells to explore their contribution in modulation of tumor. Physical exercise of tumor-bearing host resulted in a decreased angiogenesis in the vicinity of tumor. This was also found to be accompanied by a decrease in erythrocyte count and increase in the level of oxygen while the content of lactate showed a concomitant decrease in the tumor microenvironment along with normalization of pH. Moreover, physical exercise also resulted in an inhibition of VEGF expression which was correlated to an altered expression of cytokines: IL-1, IL-4, IL-10, TGF-beta and IFN-gamma. Ascitic fluid of tumor-bearing host subjected to physical exercise showed an increase in nitric oxide content along with an increase in the expression of inducible nitric oxide synthase (iNOS). The study discusses the possible role of the aforesaid alterations in constituents of tumor microenvironment of tumor-bearing host following physical exercise in retardation of tumor growth.
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http://dx.doi.org/10.1080/08923970802562042DOI Listing
June 2009
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