Kidney injury molecule-1 (KIM-1)/T cell Ig and mucin domain-containing protein-1 (TIM-1) is upregulated more than other proteins after AKI, and it is highly expressed in renal damage of various etiologies. In this capacity, KIM-1/TIM-1 acts as a phosphatidylserine receptor on the surface of injured proximal tubular epithelial cells, mediating phagocytosis of apoptotic cells, and it may also act as a costimulatory molecule for immune cells. Despite recognition of KIM-1 as an important therapeutic target for kidney disease, the regulators of KIM-1 transcription in the kidney remain unknown. Using a bioinformatics approach, we identified upstream regulators of KIM-1 after AKI. In response to tubular injury in rat and human kidneys or oxidant stress in human proximal tubular epithelial cells (HPTECs), KIM-1 expression increased significantly in a manner that corresponded temporally and regionally with increased phosphorylation of checkpoint kinase 1 (Chk1) and STAT3. Both ischemic and oxidant stress resulted in a dramatic increase in reactive oxygen species that phosphorylated and activated Chk1, which subsequently bound to STAT3, phosphorylating it at S727. Furthermore, STAT3 bound to the KIM-1 promoter after ischemic and oxidant stress, and pharmacological or genetic induction of STAT3 in HPTECs increased KIM-1 mRNA and protein levels. Conversely, inhibition of STAT3 using siRNAs or dominant negative mutants reduced KIM-1 expression in a kidney cancer cell line (769-P) that expresses high basal levels of KIM-1. These observations highlight Chk1 and STAT3 as critical upstream regulators of KIM-1 expression after AKI and may suggest novel approaches for therapeutic intervention.

Glucocorticoids (GCs) are anti-inflammatory and immunosuppressive steroid molecules secreted by the adrenal gland and regulated by the hypothalamic–pituitary–adrenal (HPA) axis. GCs present a circadian release pattern under normal conditions; they increase their release under stress conditions. Their mechanism of action can be via the receptor-independent or receptor-dependent pathway. The receptor-dependent pathway translocates to the nucleus, where the ligand-receptor complex binds to specific sequences in the DNA to modulate the transcription of specific genes. The glucocorticoid receptor (GR) and its endogenous ligand cortisol (CORT) in humans, and corticosterone in rodents or its exogenous ligand, dexamethasone (DEX), have been extensively studied in breast cancer. Its clinical utility in oncology has mainly focused on using DEX as an antiemetic to prevent chemotherapy-induced nausea and vomiting. In this review, we compile the results reported in the literature in recent years, highlighting current trends and unresolved controversies in this field. Specifically, in breast cancer, GR is considered a marker of poor prognosis, and a therapeutic target for the triple-negative breast cancer (TNBC) subtype, and efforts are being made to develop better GR antagonists with fewer side effects. It is necessary to know the type of breast cancer to differentiate the treatment for estrogen receptor (ER)-positive, ER-negative, and TNBC, to implement therapies that include the use of GCs.

Cereal Chem. 94(1):117-123The objective of this study was to evaluate the antihypertensive potential of common bean protein hydrolysate. Protein concentrates were obtained, followed by Alcalase enzymatic hydrolysis, and then ultrafiltrated (3,000 molecular weight cutoff); the lyophilized product was named BP3. The angiotensin converting enzyme (ACE) inhibitory activity was determined as IC 50 (3.68 ± 0.07 µg/mL). The antihypertensive effect was evaluated in spontaneously hypertensive rats (SHR) by two assays; Captopril ACE inhibitor was used as a reference compound and water as a control. A short-term assay showed a maximum decrease in mean arterial pressure of -41 ± 5 mmHg in SHR, 3 h after oral administration of 500 mg of BP3/kg of body weight (bw). In a long-term assay, a significant decrease in systolic blood pressure of -24 ± 5 mmHg was observed in SHR, after 45 days of oral administration of 500 mg of BP3/kg of bw/12 h. In both assays, BP3 treatment showed antihypertensive effect over SHR, similar to Captopril treatment. The sequences of the most abundant peptides present in BP3, determined by mass spectrometry, were identified as KFPWVK, GADFRKK, and PQSPCKRVNRHS. These peptides are reported for the first time in Azufrado Higuera common beans, and they are most likely responsible for the antihypertensive effect of BP3. † Corresponding author. Phone: +52 687 87 2 96 26.

Chronic kidney disease (CKD) is a health problem that is constantly growing. This disease presents a diverse symptomatology that implies complex therapeutic management. One of its characteristic symptoms is dyslipidemia, which becomes a risk factor for developing cardiovascular diseases and increases the mortality of CKD patients. Various drugs, particularly those used for dyslipidemia, consumed in the course of CKD lead to side effects that delay the patient’s recovery. Therefore, it is necessary to implement new therapies with natural compounds, such as curcuminoids (derived from the Curcuma longa plant), which can cushion the damage caused by the excessive use of medications. This manuscript aims to review the current evidence on the use of curcuminoids on dyslipidemia in CKD and CKD-induced cardiovascular disease (CVD). We first described oxidative stress, inflammation, fibrosis, and metabolic reprogramming as factors that induce dyslipidemia in CKD and their association with CVD development. We proposed the potential use of curcuminoids in CKD and their utilization in clinics to treat CKD-dyslipidemia.

Niacin and butyrate modulate cellular metabolism by several metabolic pathways. The niacin at therapeutic doses reduces blood lipid levels through the activation of its G protein receptor (GPR109), this vitamin is also a precursor of two important coenzymes involved in the cellular oxidation‐reduction processes (NAD(P)+/NAD(P)H). The consumption of butyrate in the diet produces a hypophagic effect in bovines. This effect was associated with an increase of leptin expression generating a loss of body weight. High fat diets supplemented with butyrate induce an improvement in insulin resistance in C57BL/6 mice. Butyrate also interacts with a G protein receptor (GPR 43). Both niacin and butyrate are substrates of the H+/monocarboxylate (MCT) and Na+/monocarboxylate (SMCT) transporters, these last being located in the lumen of the gastrointestinal tract and the proximal tubule of nephron. The physiological and molecular role of the receptors and transporters of the niacin and butyrate in body energy expenditure has been little studied.We used 80 C57BL/6 mice, 4 weeks old, divided into 8 groups (10 by group), were feed for 5 months with different diets with 10% kcal fat (control diets (C)) or with 45% kcal fat (high fat diet (HF)) both supplemented with 1% w/w niacin (N or HFN) or with 5% w/w butyrate (B or HFB) or with both monocarboxylates (BN; HFBN). Over the 5 month diet period were assessed weekly body weight changes with an analytical balance and monthly changes in body fat concentration with the EchoMRI ™ 4 in 1–500 small live animal body composition analyzers. The calorimetry analysis was performed with Columbus Instruments, Comprehensive Lab Animal Monitoring System: CLAMS. Several organs were extracted, including the kidneys for studies of protein and gene expression by WB and qPCR analysis respectively. The blood chemistry of the different groups was also evaluated. The renal function and physiology status of animals prior to slaughter was evaluated by the 24h urine collection in metabolic cages to evaluate various ions and metabolites.We observed that the co‐administration of butyrate and niacin prevents body weight gain. The calorimetric analysis showed that the energy expenditure in the HFBN group was higher than the HF group (P< 0.0001), similar situation was observed in the oxygen consumption (P< 0.039). The respiratory coefficient (RER) was 0.7 in HF and HFBN groups, suggesting an increase in fatty acid oxidation. In the body composition analysis the HFBN group gain a similar fat mass compared to C group with a maintained of fat free mass. The reduction of fat mass in HFBN group was significant compared with the HF group (P< 0.01). Interesting the mice groups that eat butyrate supplemented diets developed renal hyperplasia and hydronephrosis. The expressions of both SMCTs in the kidneys of BN and HFBN groups were significant reduced in contrast with C and HF groups. Also significant increment of UCP2 expression was observed in these groups.We conclude that the consumption of butyrate with niacin favors the oxidation of fatty acids and increased caloric expenditure that that modifies the expression of both SMCTs and UCP2 genes, however, as an adverse effect, butyrate diets causes a significant increase in serum creatinine and BUN and as observed in the histological analysis exist a loss of renal architecture. This effect is possibly caused by an obstruction in the renal tubules inducing a renal damage.Support or Funding InformationINCMSZ‐AI‐015 (CP) CONACYT 155700 (VR)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.