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Ischemia/reperfusion is a common cause of acute kidney injury (AKI). However, mechanisms underlying the sudden loss in kidney function and tissue injury remain to be fully elucidated. Here, we investigated the role of peptidyl arginine deiminase-4 (PAD4), which converts arginine to citrulline and plays a role in epigenetic regulation and inflammation, in renal ischemia/reperfusion injury. PAD4 expression was highly induced in infiltrating leukocytes 24 hours following renal ischemia and reperfusion. This induction was accompanied by citrullination of histone H3 and formation of neutrophil extracellular traps in kidneys of wild-type mice. By contrast, PAD4-deficient mice did not form neutrophil extracellular traps, expressed lower levels of pro-inflammatory cytokines and were partially protected from renal ischemia/reperfusion-induced AKI. Furthermore, PAD4-deficient mice recovered kidney function 48 hours after ischemia/reperfusion, whereas kidney function in the wild-type mice progressively worsened. Administration of DNase I, which degrades neutrophil extracellular traps or the PAD-specific inhibitor YW3-56 before ischemia, partially prevented renal ischemia/reperfusion-induced AKI. Notably, transfer of neutrophils from wild-type, but not from PAD4-deficient mice, was sufficient to restore renal neutrophil extracellular trap formation and impair kidney function following renal ischemia/reperfusion. Thus, neutrophil PAD4 plays a pivotal role in renal ischemia/reperfusion-induced AKI.

<b><i>Background:</i></b> There is a growing interest in the use of cannabis (and its extracts), as well as CBD oil (hemp extracts containing cannabidiol), for therapeutic purposes. While there is reason to believe that cannabinoids may be efficacious for a number of different diseases and syndromes, there exist limited objective data supporting the use of crude materials (CBD oil, cannabis extracts, and/or cannabis itself). <b><i>Summary:</i></b> In the present review, we examined data for pure cannabinoid compounds (dronabinol, nabilone, and CBD), as well as partially purified medicinal cannabis extracts (nabiximols), to provide guidance on the potential therapeutic uses of high-THC cannabis and CBD oil. In general, data support a role for cannabis/cannabinoids in pain, seizure disorders, appetite stimulation, muscle spasticity, and treatment of nausea/vomiting. Given the biological activities of the cannabinoids, there may be utility in treatment of central nervous system disorders (such as neurodegenerative diseases, PTSD, and addiction) or for the treatment of cancer. However, those data are much less compelling. <b><i>Key Message:</i></b> On balance, there are reasons to support the potential use of medical cannabis and cannabis extract (Δ⁹-THC-dominant or CBD-dominant), but much more careful research is required.

Deregulated Wnt/b-catenin signaling promotes colorectal cancer (CRC) by activating expression of the c-MYC protooncogene (MYC). In the nucleus, the b-catenin transcriptional co-activator binds T-cell factor (TCF) transcription factors, and together TCF/b-catenin complexes activate MYC expression through Wnt responsive DNA regulatory elements (WREs). The MYC 3' WRE maps 1.4-kb downstream from the MYC transcription stop site and binds TCF4/b-catenin transcription complexes to activate MYC. However, the underlying mechanisms for how this element operates are not fully understood. Here, we report that the TCF family member, TCF3, plays an important role in regulating MYC expression in CRCs. We demonstrate that TCF3 binds the MYC 3 0 WRE to repress MYC. When TCF3 is depleted using shRNAs, the MYC 3 0 WRE is more available to bind TCF4/b-catenin complexes. Stimulating downstream Wnt/b-catenin signaling by inhibiting GSK3b causes an exchange of TCF3 with TCF4/b-catenin complexes to activate MYC. Finally, this transcription factor switch at the MYC 3 0 WRE controls MYC expression as quiescent cells re-enter the cell cycle and progress to S phase. These results indicate that a dynamic interplay of TCF transcription factors governs MYC gene expression in CRCs.

Introduction: Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide, and new therapeutic strategies are still required. Here we screened a synthetic cannabinoid library to identify compounds that uniformly reduce the viability of seven CRC cell lines.Material and Methods: Seven distinct CRC cell lines were treated with 10 μM cannabinoid compounds (from a library of 370 molecules) for 48 h, and cell viability was subsequently measured with MTS assay. Dose–response curves were conducted for compounds that were found to reproducibly reduce cell viability of one or more cell lines.Results: We identified 10 compounds from the library that were able to reduce cell viability of CRC cell lines (with an IC50 ≤ 30 μM). Of these compounds, seven were specific for CRC cells, and six were effective in all CRC cell lines tested. Treatment with traditional phytocannabinoids (THC or CBD) was either ineffective or much less potent and only partially efficacious. Treatment with antagonists for the known cannabinoid receptors (alone or in combination) failed to block the activity of the most potent of identified compounds.Conclusion: We identified three families of cannabinoid compounds that reduce CRC cell viability through a noncanonical receptor mechanism. Future modification of these compounds may lead to the development of novel therapies to treat this disease.

Inflammation is a central pathophysiologic mechanism that contributes to diabetes mellitus and diabetic nephropathy. Recently, we showed that macrophages directly contribute to diabetic renal injury, and that pharmacological blockade or genetic deficiency of chemokine (C-C motif) receptor 2 (CCR2) confers kidney protection in diabetic nephropathy. However, the direct role of CCR2 in kidney-derived cells such as podocytes in diabetic nephropathy remains unclear. To study this, we developed a transgenic mouse model expressing CCR2 specifically in podocytes (Tg(NPHS2-Ccr2)) on a nephropathy prone (DBA/2J) and CCR2 deficient (Ccr2−/−) background with heterozygous Ccr2+/− littermate controls. Diabetes was induced by streptozotocin. As expected, absence of CCR2 conferred kidney protection after nine weeks of diabetes. In contrast, transgenic CCR2 over expression in the podocytes of Ccr2−/− mice resulted in significantly increased albuminuria, blood urea nitrogen, histopathologic changes, kidney fibronectin and type-1 collagen expression, podocyte loss, and glomerular apoptosis after nine weeks of streptozotocin-induced diabetes. Interestingly, there was no concurrent increase in kidney macrophage recruitment or inflammatory cytokine levels in the mice. These findings support a direct role for CCR2 expression in podocytes to mediate diabetic renal injury, independent of monocyte/macrophage recruitment. Thus, targeting the CCR2 signaling cascade in podocytes could be a novel therapeutic approach for treatment of diabetic nephropathy.

By inducing Myc expression in the colonic epithelium, lithium promotes colonic regeneration after DSS-induced colitis. Therefore, the use of lithium may be of therapeutic value to manage individuals afflicted by UC.

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