Research Spotlight

Peng, W., X. Wu, D. Feng, Y. Zhang, X. Chen, C. Ma, H. Shen, X. Li, H. Li, J. Zhang and G. Chen (2020). “Cerebral cavernous malformation 3 relieves subarachnoid hemorrhage-induced neuroinflammation in rats through inhibiting NF-kB signaling pathway.” Brain Res Bull 160: 74-84.

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Subarachnoid hemorrhage (SAH) is a severe acute cerebrovascular disease with high rates of disability and death. In recent years, a large number of studies has shown that early brain injury (EBI) may be a crucial cause of the poor prognosis of SAH and that microglia-mediated neuroinflammation is an important pathological process in EBI. Previous studies have indicated that tumor necrosis factor receptor-associated factor 6 (TRAF6) is involved in microglia-mediated neuroinflammation after SAH. In addition, it has been reported that cerebral cavernous malformation 3/mammalian sterile20-like kinase 4 (CCM3/MST4) directly phosphorylates TRAF6 to inhibit its ubiquitination and to limit inflammatory responses. However, the association between CCM3/MST4 and SAH has not been reported. In our present study, we established a SAH model in adult male rats through injecting autologous arterial blood into the prechiasmatic cistern. Additionally, BV-2 cells, as well as primary microglial cultures from rats treated with oxygen hemoglobin (OxyHb) for 24 h, were used as in vitro models of SAH. Then, western blot, immunofluorescence, Fluoro-JadeC staining and Enzyme-linked immunosorbent assay (ELISA) and behavioral tests was applied in this study. We observed no significant change in the level of CCM3/MST4 in brain tissues, but a markedly decline of CCM3 in microglia of rats. We also found that the protein level of CCM3 was decreased in BV-2 cells after OxyHb treatment, reaching the lowest point at 6 h post-treatment. In contrast, there was no significant change in the protein level of MST4. Additionally, we recapitulated decreased expression of CCM3 and changes in subcellular localization of CCM3 in vitro model of SAH with primary microglial cultures treated with OxyHb. Overexpression of CCM3 decreased cellular degeneration, neurocognitive impairment, NF-kappaB p65 level in the nuclear, and inflammatory factors level (TNF-a and IL-1beta). These results suggest that overexpression of CCM3 alleviated brain injury and neurological damage through the NF-kappaB signaling pathway.

Papp, K., A. Menter, C. Leonardi, J. Soung, S. Weiss, R. Pillai and A. Jacobson (2020). “Long-term efficacy and safety of brodalumab in psoriasis through 120 weeks and after withdrawal and retreatment: subgroup analysis of a randomised phase 3 trial (AMAGINE-1).” Br J Dermatol Apr 14. [Epub ahead of print].

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BACKGROUND: Brodalumab is efficacious for the treatment of moderate-to-severe plaque psoriasis through 52 weeks. OBJECTIVE: To evaluate the efficacy and safety of brodalumab through 120 weeks, including following withdrawal and retreatment. METHODS: At baseline, patients were randomized to brodalumab (n=222) or placebo (n=220). At week 12, patients achieving static physician’s global assessment score of 0 or 1 (sPGA 0/1) with brodalumab were re-randomized to brodalumab (n=83) or placebo (n=84; later re-treated with brodalumab if sPGA >/=3 occurred), and patients receiving placebo switched to brodalumab (n=208). Safety was assessed by treatment-emergent adverse events. RESULTS: Among those who achieved sPGA 0/1 at week 12 and were re-randomized to brodalumab, 95.7% and 79.5% using observed data, respectively, and 73.9% and 61.4% using nonresponder imputation, respectively, achieved 75% improvement in psoriasis area and severity index (PASI 75) and PASI 100 at week 120. Following withdrawal from brodalumab, return of disease occurred after a mean (standard deviation) of 74.7 (50.5) days. Among those who switched from brodalumab to placebo at week 12, PASI 75 rates using observed data and nonresponder imputation were 55.1% and 51.2% at week 20, respectively, and 94.0% and 75.0% at week 120, respectively; PASI 100 rates at week 120 were 74.6% and 59.5%, respectively. Efficacy was maintained through week 120 in those receiving brodalumab after placebo. No new safety signals were observed. CONCLUSIONS: These findings indicate that brodalumab is efficacious and safe for continuous long-term treatment of psoriasis and support potential for response after discontinuation and retreatment.

Packer, M. (2020). “Role of Impaired Nutrient and Oxygen Deprivation Signaling and Deficient Autophagic Flux in Diabetic CKD Development: Implications for Understanding the Effects of Sodium-Glucose Cotransporter 2-Inhibitors.” J Am Soc Nephrol 31(5): 907-919.

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Growing evidence indicates that oxidative and endoplasmic reticular stress, which trigger changes in ion channels and inflammatory pathways that may undermine cellular homeostasis and survival, are critical determinants of injury in the diabetic kidney. Cells are normally able to mitigate these cellular stresses by maintaining high levels of autophagy, an intracellular lysosome-dependent degradative pathway that clears the cytoplasm of dysfunctional organelles. However, the capacity for autophagy in both podocytes and renal tubular cells is markedly impaired in type 2 diabetes, and this deficiency contributes importantly to the intensity of renal injury. The primary drivers of autophagy in states of nutrient and oxygen deprivation-sirtuin-1 (SIRT1), AMP-activated protein kinase (AMPK), and hypoxia-inducible factors (HIF-1alpha and HIF-2alpha)-can exert renoprotective effects by promoting autophagic flux and by exerting direct effects on sodium transport and inflammasome activation. Type 2 diabetes is characterized by marked suppression of SIRT1 and AMPK, leading to a diminution in autophagic flux in glomerular podocytes and renal tubules and markedly increasing their susceptibility to renal injury. Importantly, because insulin acts to depress autophagic flux, these derangements in nutrient deprivation signaling are not ameliorated by antihyperglycemic drugs that enhance insulin secretion or signaling. Metformin is an established AMPK agonist that can promote autophagy, but its effects on the course of CKD have been demonstrated only in the experimental setting. In contrast, the effects of sodium-glucose cotransporter-2 (SGLT2) inhibitors may be related primarily to enhanced SIRT1 and HIF-2alpha signaling; this can explain the effects of SGLT2 inhibitors to promote ketonemia and erythrocytosis and potentially underlies their actions to increase autophagy and mute inflammation in the diabetic kidney. These distinctions may contribute importantly to the consistent benefit of SGLT2 inhibitors to slow the deterioration in glomerular function and reduce the risk of ESKD in large-scale randomized clinical trials of patients with type 2 diabetes.

Packer, M. (2020). “Interplay of adenosine monophosphate-activated protein kinase/sirtuin-1 activation and sodium influx inhibition mediates the renal benefits of sodium-glucose co-transporter-2 inhibitors in type 2 diabetes: A novel conceptual framework.” Diabetes Obes Metab 22(5): 734-742.

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Long-term treatment with sodium-glucose co-transporter-2 (SGLT2) inhibitors slows the deterioration of renal function in patients with diabetes. This benefit cannot be ascribed to an action on blood glucose, ketone utilization, uric acid or systolic blood pressure. SGLT2 inhibitors produce a striking amelioration of glomerular hyperfiltration. Although initially ascribed to an action of these drugs to inhibit proximal tubular glucose reabsorption, SGLT2 inhibitors exert renoprotective effects, even in patients with meaningfully impaired levels of glomerular function that are sufficient to abolish their glycosuric actions. Instead, the reduction in intraglomerular pressures may be related to an action of SGLT2 inhibitors to interfere with the activity of sodium-hydrogen exchanger isoform 3, thereby inhibiting proximal tubular sodium reabsorption and promoting tubuloglomerular feedback. Yet, experimentally, such an effect may not be sufficient to prevent renal injury. It is therefore noteworthy that the diabetic kidney exhibits an important defect in adenosine monophosphate-activated protein kinase (AMPK) and sirtuin-1 (SIRT1) signalling, which may contribute to the development of nephropathy. These transcription factors exert direct effects to mute oxidative stress and inflammation, and they also stimulate autophagy, a lysosomally mediated degradative pathway that maintains cellular homeostasis in the kidney. SGLT2 inhibitors induce both AMPK and SIRT1, and they have been shown to stimulate autophagy, thereby ameliorating cellular stress and glomerular and tubular injury. Enhanced AMPK/SIRT1 signalling may also contribute to the action of SGLT2 inhibitors to interfere with sodium transport mechanisms. The dual effects of SGLT2 inhibitors on AMPK/SIRT1 activation and renal tubular sodium transport may explain the protective effects of these drugs on the kidney in type 2 diabetes.

Packer, M. (2020). “Are the benefits of SGLT2 inhibitors in heart failure and a reduced ejection fraction influenced by background therapy? Expectations and realities of a new standard of care.” Eur Heart J Apr 29. pii: ehaa344. [Epub ahead of print].

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With the completion of two large-scale trials of SGLT2 inhibitors in patients with chronic heart failure and a reduced ejection fraction, we are poised to add yet another drug to our portfolio of cardioprotective agents. These disease-modifying drugs target important, but distinct, pathways that promote cardiomyocyte dysfunction and demise, and it is critical that physicians prescribe all of them in combination to all appropriate patients who do not have demonstrable intolerance. Yet, <1% of patients with chronic heart failure are receiving currently recommended drugs at doses that have been shown to prolong life.1 According to modelling estimates, when compared with no neurohormonal blockade, the use of a broad-based combination of disease-modifying drugs at target doses may reduce the risk of death by as much as 75%. It is time that physicians who treat patients with heart failure took notice. (Excerpt from text; no abstract available.)