Nitric oxide-induced lipophagic defects contribute to testosterone deficiency in rats with spinal cord injury.

Introduction: Males with acute spinal cord injury (SCI) frequently exhibit testosterone deficiency and reproductive dysfunction. While such incidence rates are high in chronic patients, the underlying mechanisms remain elusive. Methods and results: Herein, we generated a rat SCI model, which recapitulated complications in human males, including low testosterone levels and spermatogenic disorders. Proteomics analyses showed that the differentially expressed proteins were mostly enriched in lipid metabolism and steroid metabolism and biosynthesis. In SCI rats, we observed that testicular nitric oxide (NO) levels were elevated and lipid droplet-autophagosome co-localization in testicular interstitial cells was decreased. We hypothesized that NO impaired lipophagy in Leydig cells (LCs) to disrupt testosterone biosynthesis and spermatogenesis. As postulated, exogenous NO donor (S-nitroso-N-acetylpenicillamine (SNAP)) treatment markedly raised NO levels and disturbed lipophagy via the AMPK/mTOR/ULK1 pathway, and ultimately impaired testosterone production in mouse LCs. However, such alterations were not fully observed when cells were treated with an endogenous NO donor (L-arginine), suggesting that mouse LCs were devoid of an endogenous NO-production system. Alternatively, activated (M1) macrophages were predominant NO sources, as inducible NO synthase inhibition attenuated lipophagic defects and testosterone insufficiency in LCs in a macrophage-LC co-culture system. In scavenging NO (2-4-carboxyphenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (CPTIO)) we effectively restored lipophagy and testosterone levels both in vitro and in vivo, and importantly, spermatogenesis in vivo. Autophagy activation by LYN-1604 also promoted lipid degradation and testosterone synthesis. Discussion: In summary, we showed that NO-disrupted-lipophagy caused testosterone deficiency following SCI, and NO clearance or autophagy activation could be effective in preventing reproductive dysfunction in males with SCI.

The effect of revenue diversification on bank profitability and risk during the COVID-19 pandemic.

Banks can potentially reduce the variability of their revenue by diversifying beyond traditional lending activities into noninterest revenue sources. We investigate the effect of the COVID-19 pandemic on the relation between the use of noninterest income and bank profit and risk. The economic effect of the pandemic resulted in tightened credit standards and reduced demand for many types of loans. We find that noninterest revenue sources are positively related to performance but inversely related to risk. These results are consistent with a beneficial diversification effect during the pandemic from banks expanding beyond traditional lending sources of revenue.

[Inhibition of sanguinarine on S180 subcutaneously implanted tumors in mice].

OBJECTIVE: To investigate the inhibition of sanguinarine on S180 sarcoma in mice and the effect of angiogenesis. METHODS: S180 subcutaneous implanted tumor model mice were randomly divided into six groups: control group, cyclophosphamide (CTX) group, sanguinarine (10, 20 and 40 mg/kg) groups and combination group. The mice were sacrificed on the 10th day to measure the tumor weight and volumes, and caculate the tumor growth inhibition. Histopathology was performed, while immunohistochemistry was applied for assessment of MVD (microvascular density) and the expression of VEGF (vascular endothelial growth factor). RESULTS: The growth of tumors were significantly inhibited in the treatment groups (CTX group, sanguinarine 20 and 40 mg/kg groups, and combination group). HE staining showed tumor cell atypia and pathologic micosis were lower than that of the control group. Scattered and fusion of the slice necrosis foci were observed in the treatment groups. CTX, sanguinarine (20 and 40 mg/kg) and combination significantly reduced the expression of MVD and VEGF compared with the control group (P < 0.01, P < 0.05). CONCLUSION: Sanguinarine can effectively inhibit the growth of S180 implanted tumors via reducing MVD and the expression of VEGF, which is associated with its anti-angiogenesis.