Valproic acid use is associated with diminished risk of contracting COVID-19, and diminished disease severity: Epidemiologic and in vitro analysis reveal mechanistic insights.

The SARS-CoV-2 pandemic has caused unprecedented worldwide infections from persistent mutant variants with various degrees of infectivity and virulence. The elusiveness of a highly penetrant, worldwide vaccination strategy suggests that the complete eradication of SARS-CoV-2 is unlikely. Even with the advent of new antiviral agents, the disease burden worldwide continues to exceed current preventative and therapeutic strategies.

RNA sequencing in a penile cancer cohort: an investigation of biomarkers of cisplatin resistance and potential therapeutic drug targets.

Objective: Chemoresistance in distant micrometastatic lesions may account for diminished durable response rates in advanced penile cancer. However, there are limited studies on new therapeutic targets and the identification of biomarkers that predict chemotherapy response in this population. Thus, we examine the expression of candidate biomarkers of cisplatin resistance, ERCC1 and E2F1, and perform next-generation sequencing on the cancer transcriptome in a penile cancer cohort.

A novel role of snail in regulating tuberin/AMPK pathways to promote renal fibrosis in the new mouse model of type II diabetes.

Epithelial-mesenchymal transition (EMT) plays an important role in tissue fibrosis following chronic exposure to hyperglycemia. This study investigates the role of chronic diabetes in regulating tuberin/snail/AMPK to enhance EMT and increase renal fibrosis. A new mouse model of db/db/ was generated by backcrossing db/db mice and mice.

TP63 Is Significantly Upregulated in Diabetic Kidney.

The role of tumor protein 63 (TP63) in regulating insulin receptor substrate 1 (IRS-1) and other downstream signal proteins in diabetes has not been characterized. RNAs extracted from kidneys of diabetic mice (db/db) were sequenced to identify genes that are involved in kidney complications. RNA sequence analysis showed more than 4- to 6-fold increases in TP63 expression in the diabetic mice's kidneys, compared to wild-type mice at age 10 and 12 months old.

Mapping and Identification of Native Proteins of Developing Teeth in Mouse Mandibles.

Mass spectrometry imaging is a powerful tool of increasing utility due to its ability to spatially resolve molecular biomarkers directly from sectioned tissues. One hindrance to its universality is that no single protocol is sufficient for every tissue type, fixation, and pretreatment. Mineralized tissues are uniquely challenging as extensive decalcification protocols are necessary to achieve thin sections.

A new drug combination significantly reduces kidney tumor progression in kidney mouse model.

Tuberous sclerosis complex (TSC) disease is associated with tumors in many organs, particularly angiomyolipoma (AML) in the kidneys. Loss or inactivation of results in high levels of HIF-α activity and VEGF expression. mTOR inhibitor (rapamycin) and the AMPK activator 5-aminoimidazole-4-carboxamide (AICA)-riboside (AICAR) are currently used separately to treat cancer patients.

Preclinical evidence of the enhanced effectiveness of combined rapamycin and AICAR in reducing kidney cancer.

Loss of Von Hippel-Lindau in renal carcinoma cells results in upregulation of the activity of hypoxia-inducible factor (HIF-α), a major transcription factor involved in kidney cancer. Rapamycin as mammalian target of rapamycin inhibitor and 5-aminoimidazole-4-carboxamide-riboside (AICAR) as AMPK activator are used separately to treat cancer patients. In the current study, the possible additive effect of drug combinations in reducing kidney tumorigenesis was investigated.

Galectin-1 is a new fibrosis protein in type 1 and type 2 diabetes.

Chronic exposure of tubular renal cells to high glucose contributes to tubulointerstitial changes in diabetic nephropathy. In the present study, we identified a new fibrosis gene called galectin-1 (Gal-1), which is highly expressed in tubular cells of kidneys of type 1 and type 2 diabetic mouse models. Gal-1 protein and mRNA expression showed significant increase in kidney cortex of heterozygous Akita and db/db mice compared with wild-type mice.

Glutamine Addiction in Kidney Cancer Suppresses Oxidative Stress and Can Be Exploited for Real-Time Imaging.

Many cancers appear to activate intrinsic antioxidant systems as a means to counteract oxidative stress. Some cancers, such as clear cell renal cell carcinoma (ccRCC), require exogenous glutamine for growth and exhibit reprogrammed glutamine metabolism, at least in part due to the glutathione pathway, an efficient cellular buffering system that counteracts reactive oxygen species and other oxidants. We show here that ccRCC xenograft tumors under the renal capsule exhibit enhanced oxidative stress compared with adjacent normal tissue and the contralateral kidney.

Novel protective mechanism of reducing renal cell damage in diabetes: Activation AMPK by AICAR increased NRF2/OGG1 proteins and reduced oxidative DNA damage.

Exposure of renal cells to high glucose (HG) during diabetes has been recently proposed to be involved in renal injury. In the present study, we investigated a potential mechanism by which AICAR treatment regulates the DNA repair enzyme, 8-oxoG-DNA glycosylase (OGG1) in renal proximal tubular mouse cells exposed to HG and in kidney of db/db mice. Cells treated with HG for 2 days show inhibition in OGG1 promoter activity as well as OGG1 and Nrf2 protein expression.

Is mTOR Inhibitor Good Enough for Treatment All Tumors in TSC Patients?

Tuberous sclerosis complex (TSC) is an autosomal dominant and multi-system genetic disorder in humans. TSC affects around 25,000 to 40,000 individuals in the United States and about 1 to 2 million individuals worldwide, with an estimated prevalence of one in 6,000 newborns. TSC occurs in all races and ethnic groups, and in both genders.

Novel mechanism of transcriptional regulation of cell matrix protein through CREB.

The transcription mechanism(s) of renal cell matrix accumulation in diabetes does not explored. Phosphorylation of the transcription factor cAMP-responsive element binding protein (CREB) significantly increased in cells treated with high glucose (HG) compared to cell grown in normal glucose (NG). Cells pretreated with rapamycin before exposure to HG showed significant decrease phosphorylation of CREB, increase in AMPK activity and decrease protein/mRNA and promoter activity of fibronectin.

Microarray profile of human kidney from diabetes, renal cell carcinoma and renal cell carcinoma with diabetes.

Recent study from our laboratory showed that patients with diabetes are at a higher risk of developing kidney cancer. In the current study, we have screened whole human DNA genome from healthy control, patients with diabetes or renal cell carcinoma (RCC) or RCC+diabetes. We found that 883 genes gain/163 genes loss of copy number in RCC+diabetes group, 669 genes gain/307 genes loss in RCC group and 458 genes gain/38 genes loss of copy number in diabetes group, after removing gain/loss genes obtained from healthy control group.

Tuberin-deficiency downregulates N-cadherin and upregulates vimentin in kidney tumor of TSC patients.

Angiomyolipomas (AMLs) are associated with cell fibrosis in kidney of Tuberous Sclerosis Complex patients. The mechanism by which the fibrotic proteins accumulated in AMLs has not been explored. In the present study, we investigated the role of Akt/tuberin/mTOR pathway in the regulation cell fibrosis proteins.

Hyperactivation of Akt/mTOR and deficiency in tuberin increased the oxidative DNA damage in kidney cancer patients with diabetes.

Recent study from our laboratory showed that patients with diabetes are at a higher risk of developing kidney cancer. In the current study, we have explored one of the mechanisms by which diabetes accelerates tumorigenesis in the kidney. Kidney cancer tissue from patients with diabetes showed a higher activity of Akt and decreased in total protein of tuberin compared to kidney cancer patient without diabetes or diabetes alone.

Inhibition of hedgehog and androgen receptor signaling pathways produced synergistic suppression of castration-resistant prostate cancer progression.

Unlabelled: Metastatic prostate cancer is initially treated with androgen ablation therapy, which causes regression of androgen-dependent tumors. However, these tumors eventually relapse resulting in recurrent castration-resistant prostate cancer (CRPC). Currently, there is no effective therapy for CRPC and the molecular mechanisms that lead to the development of CRPC are not well understood.

Novel mechanism of regulation of fibrosis in kidney tumor with tuberous sclerosis.

Background: Deficiency in tuberin results in activation the mTOR pathway and leads to accumulation of cell matrix proteins. The mechanisms by which tuberin regulates fibrosis in kidney angiomyolipomas (AMLs) of tuberous sclerosis patients are not fully known.

Method: In the present study, we investigated the potential role of tuberin/mTOR pathway in the regulation of cell fibrosis in AML cells and kidney tumor tissue from tuberous sclerosis complex (TSC) patients.

Resistance to experimental tumorigenesis in cells of a long-lived mammal, the naked mole-rat (Heterocephalus glaber).

The naked mole-rat (NMR, Heterocephalus glaber) is a long-lived mammal in which spontaneous cancer has not been observed. To investigate possible mechanisms for cancer resistance in this species, we studied the properties of skin fibroblasts from the NMR following transduction with oncogenes that cause cells of other mammalian species to form malignant tumors. Naked mole-rat fibroblasts were transduced with a retrovirus encoding SV40 large T antigen and oncogenic Ras(G12V).

Neoplastic conversion of human colon smooth muscle cells: No requirement for telomerase.

The role of telomerase as an essential requirement for the neoplastic conversion of human cells has been controversial. In the model of conversion of normal human cells to cancer cells by the combination of simian virus 40 (SV40) early region genes and oncogenic Ras (H-Ras(G12V)), telomerase (hTERT) was originally described as essential in conjunction with these other genes. Here we used primary cultures of colon smooth muscle cells isolated from surgical specimens.

Improving cell therapy--experiments using transplanted telomerase-immortalized cells in immunodeficient mice.

Cell therapy is the use of stem cells and other types of cells in various therapies for age-related diseases. Two issues that must be addressed before cell therapy could be used routinely in medicine are improved efficacy of the transplanted cells and demonstrated long-term safety. Desirable genetic modifications that could be made to cells to be used for cell therapy include immortalization with human telomerase reverse transcriptase (hTERT).

Trans-activation of EphA4 and FGF receptors mediated by direct interactions between their cytoplasmic domains.

A yeast two-hybrid analysis has shown that the juxtamembrane region of FGF receptor 3 (FGFR3) interacts with the cytoplasmic domain of EphA4, which is a member of the largest family of receptor tyrosine kinases. Complex formation between the two receptors was shown to be mediated by direct interactions between the juxtamembrane domain of FGFR1, FGFR2, FGFR3, or FGFR4 and the N-terminal portion of the tyrosine kinase domain of EphA4. Activation of FGFR1 in transfected cells resulted in tyrosine phosphorylation of a kinase-negative EphA4 mutant and activation of EphA4 led to tyrosine phosphorylation of a kinase-negative FGFR1 mutant.

Fibroblast growth factor 23 reduces expression of type IIa Na+/Pi co-transporter by signaling through a receptor functionally distinct from the known FGFRs in opossum kidney cells.

Fibroblast growth factor (FGF) 23 is an important phosphaturic factor that inhibits inorganic phosphate (Pi) reabsorption from the renal proximal tubule. Its overproduction and proteolysis-resistant mutation such as R179Q cause tumor-induced osteomalacia and autosomal dominant hypophosphatemic rickets, respectively. To clarify the signaling mechanisms of FGF23 that mediate the reduction of Pi reabsorption, we inhibited the function of the known FGFRs in opossum kidney (OK-E) cells by expressing a dominant-negative (DN) form of FGFR.