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

The transcription factor TCF-1 is essential for the development and function of regulatory T (Treg) 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 Treg cells with differential expression of Klf2 and memory and activation markers. TCF-1 deficiency did not change the core Treg cell transcriptional signature, but promoted alternative signaling pathways whereby Treg cells became activated and gained gut-homing properties and characteristics of the TH17 subset of helper T cells. TCF-1-deficient Treg cells strongly suppressed T cell proliferation and cytotoxicity, but were compromised in controlling CD4+ T cell polarization and inflammation. In mice with polyposis, Treg cell-specific TCF-1 deficiency promoted tumor growth. Consistently, tumor-infiltrating Treg cells of patients with colorectal cancer showed lower TCF-1 expression and increased TH17 expression signatures compared to adjacent normal tissue and circulating T cells. Thus, Treg cell-specific TCF-1 expression differentially regulates TH17-mediated inflammation and T cell cytotoxicity, and can determine colorectal cancer outcome.

Financial toxicity and mental well-being of the oral cancer survivors residing in a developing country in the era of COVID 19 pandemic - A cross-sectional study.

OBJECTIVES: The primary outcome measures evaluated the financial toxicity and mental well-being of the oral cancer survivors. METHODS: A cross-sectional study of oral cancer survivors who were disease-free for more than 6 months after treatment and visited the hospital for a routine follow-up is included in the study. Mental well-being and financial toxicity were evaluated using the Depression, Anxiety, and Stress Scale - 21 (DASS 21) and Comprehensive Score for financial Toxicity (COST- Functional Assessment of Chronic Illness Therapy) questionnaires. A literature review was done to compare the results with financial toxicity and mental health in cancer patients from the pre-pandemic era. RESULTS: A total of 79 oral cancer survivors were included in the study, predominantly males (M: F = 10:1). The age ranged from 26 to 75 years (The median age is 49). The full-time employment dropped from 83.5% in the pre-treatment period to 21.5% post-treatment. Depression was observed in 58.2% and anxiety in 72.2%. Unemployed survivors were observed to have more depression (OR = 1.3, 95% confidence interval (CI) = 0.3-5.4, p = 0.6), anxiety (OR = 3.5, 95% CI = 0.3-21.2, p = 0.1) and stress (OR = 1.6, 95% CI = 0.3-6.6, p = 0.5) than rest of the cohort. On univariate analysis, unemployed survivors (M = 11.8 ± 3.8, p = 0.01) had significantly poorer financial toxicity scores. Survivors with depression (M = 16.4 ± 7.1, p = 0.06) and stress (M = 14.4 ± 6.8, p = 0.002) had poor financial toxicity scores. On multifactorial analysis of variance, current employment (p = 0.04) and treatment modality (p = 0.05) were significant factors impacting the financial toxicity. CONCLUSION: There is a trend towards increased incidence of depression, anxiety, and stress among oral cancer survivors compared to the literature from the pre-COVID era. There is significant financial toxicity among either unemployed or part-time workers. This calls for urgent public/government intervention to prevent the long-term impact of financial toxicity on survival and quality of life.

Radiological tumor thickness as a clinical predictor of pathological depth of invasion in oral squamous cell carcinoma: a retrospective analysis.

PURPOSE: Inclusion of depth of invasion (DOI) in the recent AJCC/UICC TNM staging for oral cancer has incorporated the concept of tumor third dimension and its prognostic importance. However, there is no uniform consensus about measuring DOI at clinical setting at present. For more practical reasons, radiological tumor thickness (rTT) is a simple and practical measurement which can be used as a clinical predictor of pDOI. METHODS: We compared rTT and pathological DOI (pDOI) of 179 patients with OSCC who underwent curative surgery from April 2018 to April 2020 at AIIMS Rishikesh, India. Spearman correlation was used to determine correlation between rTT and pDOI. ROC curve was used to determine inter-group cutoff values. RESULTS: Overall, rTT showed a strong correlation with pDOI (rho = 0.74; 95% CI 0.667-0.8; p < 0.001). The inter-group cutoff value for rTT were 8 mm (Sn 89.1%; Sp 53.2%) between Group A (pDOI ≤ 5 mm) and B (pDOI > 5 mm, ≤ 10 mm), and 14 mm (Sn 89.5%; Sp 78.3%) between Group B and C (pDOI > 10 mm), respectively. CONCLUSIONS: rTT is a clinical predictor of pDOI in OSCC, and may be considered as a surrogate of DOI in the clinical setting.

Au@Zr-based metal-organic framework composite as an immunosensing platform for determination of hepatitis B virus surface antigen.

An ultrasensitive electrochemical immunosensor has been prepared using an immunofunctionalized zirconium (Zr)-based metal-organic framework (MOF) with gold (Au) decoration Au@UiO-66(NH2) 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(NH2). The electrochemical sensing performance of the immunofunctionalized Au@UiO-66(NH2)/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-1-100 ng mL-1 (R2 = 0.999) with a detection limit of 1.13 fg mL-1. 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-1) 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.

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

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.

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

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.

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

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.

Recent advances in targeting autophagy in cancer.

Autophagy is a cellular homeostasis mechanism that fuels the proliferation and survival of advanced cancers by degrading and recycling organelles and proteins. Preclinical studies have identified that within an established tumor, tumor cell autophagy and host cell autophagy conspire to support tumor growth. A growing body of evidence suggests that autophagy inhibition can augment the efficacy of chemotherapy, targeted therapy, or immunotherapy to enhance tumor shrinkage. First-generation autophagy inhibition trials in cancer using the lysosomal inhibitor hydroxychloroquine (HCQ) have produced mixed results but have guided the way for the development of more potent and specific autophagy inhibitors in clinical trials. In this review, we will discuss the role of autophagy in cancer, newly discovered molecular mechanisms of the autophagy pathway, the effects of autophagy modulation in cancer and host cells, and novel autophagy inhibitors that are entering clinical trials.

Lysosomal lipid peroxidation regulates tumor immunity.

Lysosomal inhibition elicited by palmitoyl-protein thioesterase 1 (PPT1) inhibitors such as DC661 can produce cell death, but the mechanism for this is not completely understood. Programmed cell death pathways (autophagy, apoptosis, necroptosis, ferroptosis, and pyroptosis) were not required to achieve the cytotoxic effect of DC661. Inhibition of cathepsins, or iron or calcium chelation, did not rescue DC661-induced cytotoxicity. PPT1 inhibition induced lysosomal lipid peroxidation (LLP), which led to lysosomal membrane permeabilization and cell death that could be reversed by the antioxidant N-acetylcysteine (NAC) but not by other lipid peroxidation antioxidants. The lysosomal cysteine transporter MFSD12 was required for intralysosomal transport of NAC and rescue of LLP. PPT1 inhibition produced cell-intrinsic immunogenicity with surface expression of calreticulin that could only be reversed with NAC. DC661-treated cells primed naive T cells and enhanced T cell-mediated toxicity. Mice vaccinated with DC661-treated cells engendered adaptive immunity and tumor rejection in "immune hot" tumors but not in "immune cold" tumors. These findings demonstrate that LLP drives lysosomal cell death, a unique immunogenic form of cell death, pointing the way to rational combinations of immunotherapy and lysosomal inhibition that can be tested in clinical trials.

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

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.

Social taboos: a formidable challenge in cancer care.

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.

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

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, APCΔ468 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 G1/S and G2/M cell cycle phase transitions without activating apoptosis, autophagy, cellular quiescence, or canonical markers/mediators of senescence. G1/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.

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

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.

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

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.

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

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.

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

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 HepG2DR multi-drug resistant cell line, which is derived from the HepG2 human hepatocellular carcinoma cell line. HepG2DR 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 HepG2DR cells. Cisplatin-induced PARP1 activation resulted in chemoresistance via increased autophagy. The cisplatin/Morin hydrate combination was effective in the reversal of the HepG2DR 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 (Atg5) gene resulted in sensitizing the HepG2DR 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 HepG2DR cells. Morin hydrate inhibits cisplatin-mediated autophagy induction, resulting in increased susceptibility of HepG2DR 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.

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

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.

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

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-1ß, 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.