Unraveling the Nephroprotective Potential of Papaverine against Cisplatin Toxicity through Mitigating Oxidative Stress and Inflammation: Insights from In Silico, In Vitro, and In Vivo Investigations.

Cisplatin is a potent compound in anti-tumor chemotherapy; however, its clinical utility is hampered by dose-limiting nephrotoxicity. This study investigated whether papaverine could mitigate cisplatin-induced kidney damage while preserving its chemotherapeutic efficacy. Integrative bioinformatics analysis predicted papaverine modulation of the mechanistic pathways related to cisplatin renal toxicity; notably, mitogen-activated protein kinase 1 (MAPK1) signaling. We validated protective effects in normal kidney cells without interfering with cisplatin cytotoxicity on a cancer cell line. Concurrent in vivo administration of papaverine alongside cisplatin in rats prevented elevations in nephrotoxicity markers, including serum creatinine, blood urea nitrogen, and renal oxidative stress markers (malondialdehyde, inducible nitric oxide synthase (iNOS), and pro-inflammatory cytokines), as tumor necrosis factor alpha (TNF-α), monocyte chemoattractant protein 1 (MCP-1), and interleukin-6 (IL-6). Papaverine also reduced apoptosis markers such as Bcl2 and Bcl-2-associated X protein (Bax) and kidney injury molecule-1 (KIM-1), and histological damage. In addition, it upregulates antioxidant enzymes like catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx) while boosting anti-inflammatory signaling interleukin-10 (IL-10). These effects were underlined by the ability of Papaverine to downregulate MAPK-1 expression. Overall, these findings show papaverine could protect against cisplatin kidney damage without reducing its cytotoxic activity. Further research would allow the transition of these results to clinical practice.

OMA1 and YME1L as a Diagnostic Panel in Hepatocellular Carcinoma.

Identifying new hepatocellular carcinoma (HCC)-driven signaling molecules and discovering their molecular mechanisms are crucial for efficient and better outcomes. Recently, OMA1 and YME1L, the inner mitochondrial proteases, were displayed to be associated with tumor progression in various cancers; however, their role in HCC has not yet been studied. Therefore, we evaluated the possible role of OMA1/YME1L in HCC staging and discussed their potential role in cellular apoptosis and proliferation. Our study was performed using four groups of male albino rats: a normal control and three diethyl nitrosamine-treated groups for 8, 16, and 24 weeks. The OMA1 and YME1L, matrix-metalloproteinase-9 (MMP-9), and cyclin D1 content were measured in liver tissues, while alpha-fetoprotein (AFP) level was assessed in serum. Additionally, Ki-67 expression was evaluated by immunohistochemistry. The relative hepatic expression of Bax, and tissue inhibitor matrix metalloproteinase (TIMP-3) was measured. Herein, we confirmed for the first time that OMA1 is down-regulated while YME1L is up-regulated in HCC in the three studied stages with subsequent inhibition of apoptosis and cell cycle progression. Furthermore, these proteases have a possible role in metastasis. These newly recognized results suggested OMA1 and YME1L as possible diagnostic tools and therapeutic targets for HCC management.

Dual regulating of mitochondrial fusion and Timp-3 by leflunomide and diallyl disulfide combination suppresses diethylnitrosamine-induced hepatocellular tumorigenesis in rats.

AIMS: Hepatocellular carcinoma (HCC) is considered one of the main causes of cancer-related death globally. Combination therapy targeting different pathways can improve the efficacy of HCC management. Mitofusin 2 (Mfn2), a mitochondrial fusion protein, and a tissue inhibitor of matrix metalloproteinase 3 (Timp-3) were found to be downregulated in various cancers, including HCC. Our study aimed to evaluate the possible antineoplastic effect of a novel combination in the treatment of HCC through targeting mitochondrial fusion and metastatic proteins. MAIN METHODS: HCC induction was performed using a single intraperitoneal dose of diethylnitrosamine (200 mg/kg), followed by adding phenobarbital sodium (0.05%) to the drinking water for successive 18 weeks. Then, leflunomide (LF, 10 mg/kg) was administered orally for 28 days. Diallyl disulfide (DADS, 50 mg/kg) was also given orally for 28 days, either alone or in combination with LF. KEY FINDINGS: Treatment with LF or DADS could alleviate the HCC- induced histological and biochemical variations, including liver enzyme activities (ALT, AST), alpha-fetoprotein, Bax, cyclin D1, Ki67, malondialdehyde, and reduced glutathione. They could shift the mitochondrial dynamics toward mitochondrial fusion through upregulating the expression of Mfn2 and also exhibited antimetastatic activity through upregulating the expression of Timp-3 and decreasing hepatic MMP9 content. SIGNIFICANCE: the treatment with a combination of LF and DADS displayed a more potent effect than the treatment with each drug alone. Our results suggest that the combined use of LF and a naturally occurring DADS can be used as a promising novel combination in managing HCC.

Matrix metalloproteinase contribution in management of cancer proliferation, metastasis and drug targeting.

Matrix metalloproteinases (MMPs) or matrixins, are members of a zinc-dependent endopeptidase family. They cause remodeling of the extracellular matrix (ECM) leading to numerous diseases. MMPs subfamilies possess: collagenases, gelatinases, stromelysins and membrane-type MMPs (MT-MMP). They consist of several domains; pro-peptide, catalytic, linker peptide and the hemopexin (Hpx) domains. MMPs are involved in initiation, proliferation and metastasis of cancer through the breakdown of ECM physical barriers. Overexpression of MMPs is associated with poor prognosis of cancer. This review will discuss both types of MMPs and current inhibitors, which target them in different aspects, including, biosynthesis, activation, secretion and catalytic activity. Several synthetic and natural inhibitors of MMPs (MMPIs) that can bind the catalytic domain of MMPs have been designed including; peptidomimetic, non-peptidomimetic, tetracycline derivatives, off-target MMPI, natural products, microRNAs and monoclonal antibodies.

Expression of thioredoxin and glutaredoxin in experimental hepatocellular carcinoma-Relevance for prognostic and diagnostic evaluation.

Hepatocellular carcinoma (HCC), represents more than 85% of liver cancers. The diagnosis of HCC may be delayed due to the absence of early, sensitive and specific biomarkers. This study was conducted to investigate whether the expression of thioredoxin (Trx) and glutaredoxin (Grx) is helpful for HCC diagnosis in an experimental model. Twenty male albino rats were equally divided into two groups (HCC and control). Hepatocarcinogenesis was performed by single intraperitoneal (i.p) injection of 200 mg/kg of diethylnitrosamine (DENA). Two weeks later, 0.05% of phenobarbital (PB) was supplied in the drinking water for other 14 weeks. HCC was diagnosed by measuring serum alpha-fetoprotein (AFP) level and histopathological examination. Our results found that hepatic indices alanine transaminase (ALT), aspartate transaminase (AST), total bilirubin were elevated but decreased total protein level. Lipid peroxidation was elevated through increasing hepatic content of MDA with decreased antioxidant parameters like hepatic SOD, CAT activities and GSH. The current study also found that Trx and Grx tissue genes were overexpressed in HCC group significantly, compared to control group. This study substantiated that increased expression of these enzymes may be predictive of outcomes in HCC.

Herbal management of hepatocellular carcinoma through cutting the pathways of the common risk factors.

Hepatocellular carcinoma (HCC) is considered the most frequent tumor that associated with high mortality rate. Several risk factors contribute to the pathogenesis of HCC, such as chronic persistent infection with hepatitis C virus or hepatitis B virus, chronic untreated inflammation of liver with different etiology, oxidative stress and fatty liver disease. Several treatment protocols are used in the treatment of HCC but they also associated with diverse side effects. Many natural products are helpful in the co-treatment and prevention of HCC. Several mechanisms are involved in the action of these herbal products and their bioactive compounds in the prevention and co-treatment of HCC. They can inhibit the liver cancer development and progression in several ways as protecting against liver carcinogens, enhancing effects of chemotherapeutic drugs, inhibiting tumor cell growth and metastasis, and suppression of oxidative stress and chronic inflammation. In this review, we will discuss the utility of diverse natural products in the prevention and co-treatment of HCC, through its capturing of the common risk factors known to lead to HCC and shed the light on their possible mechanisms of action. Our theory assumes that shutting down the risk factor to cancer development pathways is a critical strategy in cancer prevention and management. We recommend the use of these plants side by side to recent chemical medications and after stopping these chemicals, as a maintenance therapy to avoid HCC progression and decrease its global incidence.

Chemosensitizing effect of Alpinia officinarum rhizome extract in cisplatin-treated rats with hepatocellular carcinoma.

This study was conducted to estimate the preventing and sensitizing efficiency of Alpinia officinarum rhizome extract (AORE) in an experimental model of hepatocellular carcinoma (HCC) +/- cisplatin. HCC was induced by a single intraperitoneal (i.p) dose of diethylnitrosamine (DENA, 200mg/kg). After 14 days, phenobarbitone (PB, 0.05%) was added to drinking water for 14 weeks to promote hepatocarcinogenesis. Cisplatin (CP) was given in a dose of 1.5 mg/kg (i.p), twice a week, alone or with AORE (400 mg/kg daily, orally) for 21 days. AORE was tried as a protective before the induction of HCC for three weeks as well. Results revealed that DENA/PB elevated hepatic indices as ALT and AST and total bilirubin with declining serum total protein. It increased oxidative stress, as hepatic malondialdehyde (MDA) with depressed hepatic reduced glutathione (GSH) contents, superoxide dismutase (SOD) and catalase activities. This was accompanied by an increase in hepatic expression of antioxidant genes (thioredoxin and glutaredoxin). Hepatocarcinogenesis was detected by histopathological changes in liver sections and the elevation of serum alpha-fetoprotein (AFP) level. Treatment with CP partially restored altered hepatic functions and oxidative stress markers. It also showed a partial decrease in the expression of antioxidant genes, improving histopathological changes in the liver and AFP level in serum. The treatment with AORE alone or AORE+CP enhanced hepatic function and oxidative stress markers. It also caused a decrease in the expression of antioxidant genes and improved histopathological changes in liver and serum AFP level. This effect is more potent than the treatment with CP alone. Our study suggested that AORE can be used as a promising natural chemoprevention or a chemosensitizing agent against hepatocarcinogenesis.