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Objective·To investigate the effect of hypoxia inducible factor-1α (HIF-1α) inhibitor YC-1 on the progression of diabetic nephropathy (DN) in mice and the potential mechanism.Methods·Ten-week-old male db/db mice (DN model) and their nondiabetic wild-type (WT) littermates were divided into 4 groups (n=6) according to whether treated with YC-1 or not: WT group, WT+YC-1 group, DB group, and DB+YC-1 group. The treatment groups were intraperitoneally injected with YC-1 (20 mg·kg-1) once a day, while the non-treatment groups received the same volumes of DMSO injection. After a total of 8 weeks of intervention, blood glucose, body weight, and kidney weight of all mice were measured. Serum, urine and kidney tissue samples were harvested. Serum creatinine, urinary albumin-to-creatinine ratio (UACR), and urine neutropil gelatinase-associated lipocalin (NGAL) levels were detected. The kidneys were stained with ‎hemat‎oxyli‎n-eosin (H-E) and periodic acid-Schiff (PAS) to observe the pathological changes. Masson staining was used to detect fibrosis, collagen-Ⅰ was detected by immunohistochemistry, and α-smooth muscle actin (α-SMA) was detected by Western blotting. The expression of HIF-1α was detected by both Western blotting and immunohistochemistry. TUNEL staining and Western blotting for apoptosis-related proteins were used to observe the cell apoptosis level. Superoxide dismutase (SOD) activity and malondialdehyde (MDA) level were detected by the kits. Endoplasmic reticulum stress (ERS) markers, including immunoglobulin heavy chain binding protein (BiP, also known as GRP78), phospho-protein kinase R-like endoplasmic reticulum kinase (p-PERK), total PERK, phospho-eukaryotic initiation factor 2α (p-eIF2α), total eIF2α, activating transcription factor 4 (ATF4), and C/EBP homologous protein (CHOP), were determined by Western blotting.Results·Compared with the WT group, the DB group showed significant rise of blood glucose, loss of renal function, severe kidney histopathology injuries and kidney fibrosis, increase of renal HIF-1α expression, and aggravated oxidative stress and ERS. Whilst there were no significant changes in blood glucose, YC-1 treatment notably reduced kidney weight/body weight ratio, serum creatinine, UACR, and urine NGAL levels in db/db mice. YC-1 treatment ameliorated kidney histopathology injuries and kidney fibrosis, and decreased the expressions of collagen-Ⅰ and α-SMA. YC-1 treatment also reduced the number of TUNEL positive cells, the expression of HIF-1α and pro-apoptotic proteins including BAX and cleaved caspase-3, and MDA level in the kidneys of db/db mice, while promoting anti-apoptotic protein BCL-2 expression and SOD activity. The expressions of ERS markers GRP78, p-PERK, p-eIF2α, ATF4, and CHOP were likewise significantly decreased in DB+YC-1 group.Conclusion·HIF-1α inhibitor YC-1 inhibits oxidative stress and abnormal activation of ERS, improving cell apoptosis and fibrosis in the kidneys of DN mice, which would attenuate the aggravation of pathological damage and loss of kidney function.

Pástor and Stambaugh (2012) find that from a forward-looking perspective, stocks are more volatile in the long run than they are in the short run. We demonstrate that when the nonnegative equity premium (NEP) condition is imposed on predictive regressions, stocks are in fact less volatile in the long run, even after taking estimation risk and uncertainties into account. The reason is that the NEP provides an additional parameter identification condition and prior information for future returns. Combined with the mean reversion of stock returns, this condition substantially reduces uncertainty on future returns and leads to lower long-run predictive variance. [ABSTRACT FROM AUTHOR]

This paper aims to investigate how different emotions affect the subsequent index futures returns. We test the forecasting regressions which predict the S&P 500 index futures returns with lagged text‐based emotion (anger, joy, fear, optimism, and gloom) indices and find asymmetric forecasting power exists between pessimism and optimism emotion indices. We show that only the text‐based anger index could reliably perform at predicting index futures return in‐sample and outperform the prevailing unconditional mean out‐of‐sample. Notably, the predictive power of the text‐based anger index persists after controlling for other emotion indices, investor sentiment indices, and fundamental variables known to predict the futures market. And the asset allocation conditioning on text‐based anger index can generate substantial economic benefits. Furthermore, the anger index influences the index futures return through both the discount rate and cash flow channels. [ABSTRACT FROM AUTHOR]

This article examines the cross-country asset pricing implications of disaster risk concerns. We construct a new disaster risk index, relying on six news-implied rare disaster proxies of Manela and Moreira (2017), and show that this index is a powerful predictor for stock returns and other asset returns in international markets both in and out of sample. By further disentangling a global common component from our rare disaster index, we find evidence supporting theories that emphasize globally shared disaster risk as the important driving force of asset price fluctuations. Moreover, we conduct a return decomposition analysis and find that the global disaster risk drives stock returns primarily through the discount rate channel. This paper was accepted by Karl Diether, finance. Funding: This work was supported by National Natural Science Foundation of China [72132002, 71903112, 72192842, U1811462, and 71502152], the Basic Scientific Center of National Science Foundation of China [71988101], the National Social Science Foundation [21&ZD088 and 20&ZD102], SIIFE [2018110262], and the Shanghai University of Finance and Economics [2018110698]. Supplemental Material: The data files and e-companion are available at https://doi.org/10.1287/mnsc.2022.4328. [ABSTRACT FROM AUTHOR]

Analyst recommendations convey valuable market‐wide information which implies analyst rating should generate reliable predictability for future market returns. This paper examines the predictive regressions which forecast the S&P 500 index futures return and volatility with lagged text‐based analyst rating index (TAR index). Empirical evidence shows that the TAR index generates superior in‐sample predictability. This substantial predictability remains after controlling the business cycles, macroeconomic factors, and economic conditions. Also, the TAR index outperforms the prevailing mean out‐of‐sample and generates significant economic performance. Notably, the TAR index also delivers consistent predictive gains on the volatility of index futures returns. [ABSTRACT FROM AUTHOR]

Based on hand‐collected data on Chinese listed non‐state‐owned enterprises (hereafter, non‐SOEs), this paper investigates how political connection and family involvement affect firms' IPO underpricing. We find that political connection and family involvement, serving as common compensatory mechanisms for institutional deficiencies, can significantly alleviate the IPO underpricing of non‐SOEs. Moreover, evidence shows that in regions with a well‐developed institutional environment, political connection significantly reduces the degree of IPO underpricing. But for companies located in regions with a poorer institutional environment, family involvement helps to achieve lower underpricing. The effects also vary with firm size. Political connection significantly mitigates underpricing of large firms. But for small firms, only family involvement plays a significant role in lowering IPO underpricing. Finally, we find that instead of increasing the offering price, the effect works in another way. Non‐SOEs with political connection and family involvement are no longer growth firms, for which the influence of the regulatory bar set by the China Security Regulatory Committee (CSRC) decreases. These firms tend to experience poorer long‐term performance after the IPO. This may lead to a relatively lower price in the secondary market, resulting in a lower level of IPO underpricing. [ABSTRACT FROM AUTHOR]

In this paper, we show that the individual skewness, defined as the average of monthly skewness across firms, performs very well at predicting the return of S&P 500 index futures. This result holds after controlling for the liquidity risk or for the current business cycle conditions. We also find that individual skewness performs very well at predicting index futures returns out‐of‐sample. [ABSTRACT FROM AUTHOR]

Mitochondrial abnormalities play critical roles in diabetic tubular injury progression. Dipeptidyl peptidase‐4 (DPP4) inhibitors are widely used antihyperglycemic agents that exert renal protective and positive effects against mitochondrial dysfunction in diabetic kidney disease (DKD). However, their underlying mechanism remains unclear. In this study, DPP4 upregulation, mitochondrial fragmentation, and altered mitochondrial dynamics‐associated protein expression were observed in the tubules of DBA2/J (D2) diabetic mice with unilateral nephrectomy and in albumin‐stimulated tubular cells. The inhibition of DPP4 by sitagliptin (Sita) ameliorated these mitochondrial perturbations both in vivo and in vitro, whereas DPP4 overexpression aggravated mitochondrial fusion‐fission disorder and tubular cell injury in albumin‐treated HK‐2 cells. Downstream of DPP4, the SDF‐1α/CXCR4 pathway was significantly suppressed in diabetic tubules. After Sita treatment, this signaling pathway was restored, and the mitochondrial dynamics was improved. Furthermore, a direct interaction between STAT3 and OPA1 was found in the mitochondria of tubular cells, and this effect was weakened by overloading albumin and by CXCR4 siRNA treatment, suggesting a possible link between DPP4‐mediated SDF‐1α/CXCR4/STAT3 signaling and mitochondrial dysfunction in diabetic tubular cells. The results suggest that a novel mechanism links the DPP4 enzyme to impaired mitochondrial dynamics homeostasis during tubular injury in DKD and highlight that the SDF‐1α/CXCR4/STAT3 signaling pathway could become a potential target for managing DKD. [ABSTRACT FROM AUTHOR]

Background: Despite the high mortality of cardiovascular disease (CVD) in diabetic patients with renal injury, few studies have compared cardiovascular characteristics and outcomes between patients with diabetic nephropathy (DN) and non-diabetic renal disease (NDRD). Methods: A total of 326 type 2 diabetes mellitus patients with renal biopsy were assigned to DN and NDRD groups. Echocardiography and Doppler ultrasound were performed to evaluate left ventricular hypertrophy (LVH) and peripheral atherosclerosis disease (PAD). Renal and cardiovascular survival rates were compared between the DN and NDRD groups by Kaplan-Meier analysis. Risk factors for renal and cardiovascular events in DN patients were identified by a Cox proportional hazards model. Results: In total, 179 patients entered the DN group (54.9%) and 147 made up the NDRD group (45.1%). The presence of diabetic retinopathy, family history of diabetes, and dependence on insulin therapy were associated with the presence of DN. DN patients had more CVD with more severe LVH and PAD. Poorer renal (log-rank χ2 = 26.534, p < 0.001) and cardiovascular (log-rank χ2 = 16.257, p < 0.001) prognoses were seen in the DN group. DR (HR 1.539, 95% CI 1.332–1.842), eGFR (HR 0.943, 95% CI 0.919–0.961), and 24-h proteinuria (HR 1.211, 95% CI 1.132–1.387) were identified as risk factors for renal endpoints. Age (HR 1.672, 95% CI 1.487–1.821), HbA1C (HR 1.398, 95% CI 1.197–1.876), and 24-h proteinuria (HR 1.453, 95% CI 1.289–1.672) were associated with cardiovascular endpoints. Conclusion: Patients with DN had more severe CVD along with poorer renal and cardiovascular prognoses than those with NDRD. [ABSTRACT FROM AUTHOR]

Ischemia reperfusion injury (IRI) is one of the most common causes of acute kidney injury (AKI). However, the pathogenesis and biomarkers predicting the progression of IRI-induced AKI to chronic kidney disease (CKD) remain unclear. A side-by-side comparison between different IRI animal models with variable ischemic duration and episodes was performed. The dynamic changes of KIM-1 and NGAL continuously from AKI to CKD phases were studied as well. Short-term duration of ischemia induced mild renal tubule-interstitial injury which was completely reversed at acute phase of kidney injury, while long-term duration of ischemia caused severe tubular damage, cell apoptosis and inflammatory infiltration at early disease stage, leading to permanent chronic kidney fibrosis at the late stage. Repeated attacks of moderate IRI accelerated the progression of AKI to CKD. Different from serum and urine levels of KIM-1 that increased at acute phase of IRI then declined gradually in chronic phase, NGAL increased continuously during AKI-to-CKD transition. Severity and frequency of ischemia injury determines the progression and outcome of ischemia-induced AKI. Inflammation, apoptosis and fibrogenesis likely participate in the progression of AKI to CKD. Both KIM-1 and NGAL enable noninvasive and early detection of AKI, but NGAL is associated better with the process of AKI-to-CKD progression. [ABSTRACT FROM AUTHOR]

Background/Aims: Previously we have shown that activation of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-antioxidant response element (ARE) attenuated hyperglycemia-induced damage in podocytes, but the molecular mechanism remains unknown. Methods: Tert-butylhydroquinone (t-BHQ) and small interfering RNAs (siRNAs) were used to regulate Nrf2 expression, while nicotinamide and siRNAs were used to regulate sirtuin 1 (Sirt1) activity and expression, respectively. Mitochondrial superoxide, membrane potential and ATP levels were measured to assess changes in mitochondrial function. Nephrin and synaptopodin expression were measured by western blot analysis. Human podocytes and db/db diabetic mice were used in this study. Results: t-BHQ pretreatment of human podocytes exposed to high glucose (HG) alleviated mitochondrial dysfunction, enhanced the expression of Sirt1, nephrin and synaptopodin and lowered BSA permeability compared with podocytes exposed to HG without t-BHQ pretreatment (p< 0.05). Human podocytes exposed to HG had more severe mitochondrial dysfunction, lower expression of Sirt1, synaptopodin and nephrin and higher BSA permeability than podocytes exposed to HG when Nrf2 expression was downregulated by siRNAs (p< 0.05). The protection provided by activation of the Nrf-ARE pathway in podocytes exposed to HG was partially diminished when Sirt1 expression or activity was decreased by siRNAs or inhibitor compared with podocytes exposed to HG and pretreated with t-BHQ (p< 0.05). When nicotinamide and t-BHQ were both administered to db/db mice, we observed higher levels of urinary albumin/creatinine, lower nephrin and synaptopodin expression, more severe mesangial matrix deposition, collagen deposition on pathological slides and mitochondrial structural damage in podocytes compared to db/db mice treated only with t-BHQ. Conclusions: Our findings suggest that crosstalk between Sirt1 and the Nrf2-ARE anti-oxidative pathway forms a positive feedback loop and that protection provided by t-BHQ activation of the Nrf2-ARE pathway in db/db mice is partly dependent on Sirt1. [ABSTRACT FROM AUTHOR]

Using a broad sample of earnings announcements, we show that the initial stock market's response substantially increases and the post‐earnings announcement drift becomes much weaker in the presence of more active pre‐earnings option trading. We find that the strongest initial stock market's response originates from those announcements with higher pre‐earnings option trading, fewer competing announcements, and made on non‐Fridays. Our interpretation is that the heightened investor attention, as captured by higher pre‐earnings option trading, fewer competing announcements, and non‐Friday announcements, accelerates the stock market's response and mitigates the stock market under‐reaction. [ABSTRACT FROM AUTHOR]

Objective To investigate the relationship of soluble CD146 (sCD146) with atherosclerosis and future cardiovascular events in patients with diabetic kidney disease (DKD). Methods A total of 105 DKD patients at chronic kidney disease(CKD) (68 male, 37 female) stage 1-3 were enrolled and another 94 type 2 diabetes mellitus patients without DKD (64 male, 30 female) entered the control group from January 2013 to December 2015 in our hospital. Plasma concentration of sCD146 was measured. Doppler ultrasounds of carotid and lower extremity artery were performed. All the DKD patients were retrospectively followed up (medium follow-up 28 months) .The differences of sCD146 between DKD patients and control group was analyzed and the relationship between sCD146 and proteinuria and renal function was evaluated in DKD patients. The association between sCD146 and atherosclerosis was explored in DKD patients. Kaplan-Meier method was used to evaluate the predictive value of sCD146 in future cardiovascular events. Results The level of sCD146 in diabetes mellitus patients was lower than that of DKD group [the level of sCD146 was (435± 150) and (602 ± 274) µg/L, respectively, t=-5.246, P<0.001]. Spearman analysis showed the positive association between sCD146 and serum creatinine (r=0.36, P<0.001), urinary albumino-to-creatinine ratio (r= 0.225, P=0.001) and its negative correlation with eGFR (r=-0.376, P<0.001). The elevation of sCD146 was further associated with the progression of CKD [the levels of sCD146 in patients of CKD stage 1, 2 and 3 were (472 ± 172), (590 ± 223), (685 ± 340) µg/L, respectively, F=164.203, P<0.001]. In DKD group, the upregulation of sCD146 was associated with both the increase of carotid intima-media thickness (r=0.577, P< 0.001) and femoral intima-media thickness (r=0.765, P<0.001). Patients with higher level of sCD146 tended to have more carotid plaques [OR(95%CI)=17.302(2.752-108.780), P=0.002], unstable carotid plaques [OR (95%CI)=6.404(1.036-39.608), P=0.046] and unstable plaques in lower extremity arteries [OR(95%CI)= 13.641(1.942- 95.825), P=0.009] after the adjustment of other cardiovascular risks. Patients with higher concentration of sCD146 tended to have poorer cardiovascular outcomes (Log rank χ²=9.366, P=0.049). Conclusions The measurement of plasma sCD146 is a noninvasive way which can sensitively reflect the progression of renal function and atherosclerosis, and it can also be a good marker to predict cardiovascular outcomes in DKD patients at CKD stage 1-3. [ABSTRACT FROM AUTHOR]

Patients with both hypertension and hyperhomocysteinemia, termed H-type hypertension, have a high risk for cardiocerebrovascular diseases. However, little is known about the prevalence of H-type hypertension or its role in target organ damage in patients with chronic kidney disease (CKD). The authors recruited 1042 patients with CKD who were admitted to their hospital division. Multiple linear regression analyses were used to evaluate the association between H-type hypertension and renal/cardiovascular parameters. A total of 460 (44.14%) CKD patients had H-type hypertension. Multivariate logistic regression analysis showed that H-type hypertension is associated with serum albumin, uric acid, estimated glomerular filtration rate (eGFR), and 24-hour systolic blood pressure. Patients with H-type hypertension had the worst renal function and left ventricular hypertrophy among all patients, while the levels of carotid intima-media thickness (cIMT) in patients with H-type hypertension were only slightly higher than in patients with normotension and normohomocysteinemia (P<.05). H-type hypertension was associated with eGFR, left ventricular mass index, and cIMT according to multiple linear regression analyses. The prevalence of H-type hypertension was high and H-type hypertension was associated with target organ damage in patients with CKD. [ABSTRACT FROM AUTHOR]

A correction is presented to the article "Comparison of Kidney Transcriptomic Profiles of Early and Advanced Diabetic Nephropathy Reveals Potential New Mechanisms for Disease Progression" which appeared in the December, 2019 issue.

Renal ischemia reperfusion injury (IRI) has become a growing concern in clinical practice with high morbidity and mortality rates. There is currently no effective prophylactic regimen available to prevent its occurrence and to improve its clinical prognosis. Dl-3-n-butylphthalide (NBP) has been used for stroke treatment in China for years. Little is known about its role in preventing kidney injury. The kidneys of male C57BL/6J mice were subjected to 33 min of ischemia followed by 24 h of reperfusion. NBP was administered by gavage prior to surgery. The reno-protective effect of NBP was evaluated by serum creatinine, kidney injury markers and renal pathological changes. Furthermore, the inflammation, oxidative stress, and apoptosis markers in kidney tissue were examined. In vitro, HK2 cells were treated prophylactically with NBP and then exposed to hypoxia/reoxygenation (H/R). Cell viability and apoptosis related protein were quantified to verify the protective effect of NBP. Pro-inflammation genes expression as well as ROS generation were further investigated also. NBP pretreatment significantly improved renal dysfunction and alleviated pathological injury, renal inflammation response, oxidative stress and cell apoptosis. Consistently, NBP attenuated H/R induced increases in ROS, pro-inflammatory genes expression, apoptosis and cleaved caspase-3 levels in HK2 cells. Our promising results validated for the first time that NBP could ameliorate renal IRI via attenuating inflammation, oxidative stress, and apoptosis, which indicated that NBP might be a good candidate against AKI. • We demonstrated that dl-3-n-butylphthalide could ameliorate renal IRI in vivo and in vitro. • dl-3-n-butylphthalide could attenuated renal inflammation response, oxidative stress and cell apoptosis in IRI mice. • dl-3-n-butylphthalide could decrease H/R-induced cell death and suppress pro-inflammatory cytokine release and ROS production in HK2 cells. • Our study validated for the first time that dl-3-n-butylphthalide might represent as a good candidate for overcoming renal IRI. [ABSTRACT FROM AUTHOR]