ß-Hydroxybutyrate Protects Against Cisplatin-Induced Renal Damage via Regulating Ferroptosis.

Cisplatin is a particularly potent antineoplastic drug. However, its usefulness is restricted due to the induction of nephrotoxicity. More recent research has indicated that ß-hydroxybutyrate (ß-HB) protects against acute or chronic organ damage as an efficient healing agent. Nonetheless, the therapeutic mechanisms of ß-HB in acute kidney damage caused by chemotherapeutic drugs remain unclear. Our study developed a model of cisplatin-induced acute kidney injury (AKI), which involved the administration of a ketogenic diet or ß-HB. We analyzed blood urea nitrogen (BUN) and creatinine (Cr) levels in serum, and used western blotting and immunohistochemical staining to assess ferroptosis and the calcium/calmodulin-dependent kinase kinase 2 (Camkk2)/AMPK pathway. The mitochondrial morphology and function were examined. Additionally, we conducted in vivo and in vitro experiments using selective Camkk2 inhibitor or activator to investigate the protective mechanism of ß-HB on cisplatin-induced AKI. Exogenous or endogenous ß-HB effectively alleviated cisplatin-induced abnormally elevated levels of BUN and Cr and renal tubular necrosis in vivo. Additionally, ß-HB reduced ferroptosis biomarkers and increased the levels of anti-ferroptosis biomarkers in the kidney. ß-HB also improved mitochondrial morphology and function. Moreover, ß-HB significantly attenuated cisplatin-induced cell ferroptosis and damage in vitro. Furthermore, western blotting and immunohistochemical staining indicated that ß-HB may prevent kidney injury by regulating the Camkk2-AMPK pathway. The use of the Camkk2 inhibitor or activator verified the involvement of Camkk2 in the renal protection by ß-HB. This study provided evidence of the protective effects of ß-HB against cisplatin-induced nephrotoxicity and identified inhibited ferroptosis and Camkk2 as potential molecular mechanisms.

ß-HB protects against cisplatin-induced renal damage both in vivo and in vitro.Moreover, ß-HB is effective in attenuating cisplatin-induced lipid peroxidation and ferroptosis.The regulation of energy metabolism, as well as the treatment involving ß-HB, is associated with Camkk2.

Longitudinal study of multidimensional factors influencing maternal and offspring health outcomes: a study protocol.

BACKGROUND: Reducing preventable adverse maternal and offspring outcomes is a global priority. The causes of adverse maternal and fetal outcomes are complex with multidimensional influencing factors. In addition, the Covid-19 epidemic has had a significant psychological and physical impact on people. China is now stepping into the post-epidemic era. We are curious about the psychological and physical situation of maternity in China at this stage. Therefore, we plan to initiate a prospective longitudinal study to investigate the multidimensional influences and mechanisms that affect maternal and offspring health. METHOD: We will recruit eligible pregnant women at Renmin Hospital of Hubei Province, China. The expected sample size is 1490. We will assess socio-demographics, Covid-19 related information, social capital, sleep, mental health and medical records, including clinical examination and biochemical tests. Eligible pregnant women will be enrolled in the study with less than 14 weeks of gestation. Participants will receive a total of nine follow-up visits between mid-pregnancy and one year postpartum. The offspring will be followed up at birth, 6 weeks, 3 months, 6 months and one year. In addition, a qualitative study will be conducted to understand the underlying causes that affect maternal and offspring health outcomes. DISCUSSION: This is the first longitudinal study of maternity in Wuhan, Hubei Province which integrates physical, psychological and social capital dimensions. Wuhan is the first city to be affected by Covid-19 in China. As China moves into the post-epidemic era, this study will provide us with a better understanding of the long-term impact of the epidemic on maternal and offspring health outcomes. We will implement a range of rigorous measures to enhance participants' retention rate and ensure the quality of data. The study will provide empirical results for maternal health in the post-epidemic era.

Optimal gestational weight gain in Chinese pregnant women with gestational diabetes mellitus: A large retrospective cohort study.

AIM: To examine the optimal gestational weight gain (GWG) for Chinese pregnant women with gestational diabetes mellitus (GDM) based on the Chinese-specific body mass index (BMI) classification. METHODS: A retrospective cohort study was conducted using the 2017-2020 data from pregnant women with GDM in a tertiary hospital. A quadratic function model and the total predicted probability of adverse pregnancy outcomes were developed to obtain the optimal GWG. Differences in the incidence of adverse pregnancy outcomes between our optimal GWG recommendations and the Institute of Medicine (IOM) 2009 GWG guidelines were also analyzed. RESULTS: A total of 8103 pregnant women with GDM were analyzed. Based on the Chinese-specific BMI classification, the optimal GWG range was 11.0-17.5 kg for underweight women, 3.7-9.7 kg for normal-weight women, -0.6 to 4.8 kg for overweight women, and - 9.8 to 4.2 kg for obese women. Excessive GWG had a higher risk of large for gestational age (LGA) (OR: 2.99, 95% CI: 2.42-3.70), macrosomia (OR: 2.35, 95% CI: 1.77-3.12), pre-eclampsia (OR: 1.91, 95% CI: 1.37-2.65), gestational hypertension (OR: 1.65, 95% CI: 1.24-2.19), cesarean section (OR: 1.29, 95% CI: 1.15-1.44), postpartum hemorrhage (OR: 1.29, 95% CI: 1.02-1.64); insufficient GWG had a higher risk of small for gestational age (OR: 1.82, 95% CI: 1.20-2.75). Compared to the IOM 2009 GWG guidelines, the prevalence of macrosomia, LGA, and postpartum hemorrhage were significantly lower in pregnant women following the implementation of our recommended GWG range (p < 0.05). CONCLUSIONS: Compared to the IOM 2009 GWG recommendations, our optimal GWG recommendations for Chinese pregnant women were more sensitive.

Clinical diagnostic value of IL-14, 1L-16 and SAA in periodontitis.

OBJECTIVES: Periodontitis is a chronic infectious disease, which leads to inflammatory destruction of periodontal supporting tissues. Interleukin 14 (IL-14), Interleukin 16 (IL-16) and serum amyloid A (SAA) have been demonstrated to be abnormally expressed in inflammatory diseases. Therefore, this study was performed to analyzed the expression and potential clinical values of IL-14, 1L-16 and SAA in periodontitis. MATERIALS AND METHODS: A total of 100 periodontitis patients and 100 healthy volunteers were recruited and the saliva and serum samples were collected. Then the C-reactive protein (CRP), procalcitonin (PCT), IL-14, 1L-16 and SAA levels in the saliva and serum of periodontitis patients were measured by Elisa kits. Besides, the significance of CRP, PCT, IL-14, 1L-16 and SAA in periodontitis patients were analyzed by receiver operating characteristic (ROC) analysis. RESULTS: The results showed that CRP, PCT, IL-14, 1L-16 and SAA levels were significantly increased in the the saliva and serum of the periodontitis patients. Additionally, the area under the curve (AUC) of saliva CRP, PCT, IL-14, 1L-16 and SAA for the diagnosis of periodontitis were 0.9035, 0.9435, 0.9508, 0.9500 and 0.9467, respectively. The AUC of serum CRP, PCT, IL-14, 1L-16 and SAA for the diagnosis of periodontitis were 0.9035, 0.9435, 0.9508, 0.9500 and 0.9467, respectively. What's more, the diagnostic value of IL-14, 1L-16 and SAA were enhanced when combining with CRP and PCT. CONCLUSION AND CLINICAL RELEVANCE: This study demonstrated that IL-14, IL-16 and SAA expressions were upregulated in periodontitis patients and exhibited a significant significance for periodontitis diagnosis.

Recent Progresses in Non-Dialysis Chronic Kidney Disease Patients with Hyperkalemia: Outcomes and Therapeutic Strategies.

Chronic kidney disease (CKD) affects about 10% of the world's population. Hyperkalemia is a life-threatening complication in patients with CKD, as it is associated with adverse cardiovascular and kidney outcomes. There are still many challenges and questions to address to improve the currently available therapeutic strategies to treat hyperkalemia, such as how to approach the emergency management of hyperkalemia. In recent years, in addition to novel oral potassium binders, great progress has been made in the application of novel kidney protective strategies, such as mineralocorticoid receptor antagonists and sodium-glucose cotransporter 2 inhibitors (SGLT2i) in hyperkalemia therapy. This review will discuss the recent advances from clinical trials in the effective management of hyperkalemia in non-dialysis CKD patients, enhancing the knowledge of physicians and internists concerning these newer agents and providing a helpful reference for clinical practice.

Is the Gestational Weight Gain Recommended by the National Academy of Medicine Guidelines Suitable for Chinese Twin-Pregnant Women with Gestational Diabetes Mellitus?

OBJECTIVES: This study aimed to assess the applicability of the National Academy of Medicine (NAM) interim guidelines for twin pregnancies to the specific population of gestational diabetes mellitus by exploring the relationship between gestational weight gain and adverse pregnancy outcomes in Chinese twin-pregnant women with gestational diabetes mellitus. STUDY DESIGN: This was a retrospective cohort study of women diagnosed with diabetes in pregnancy between July 2017 and December 2020 at the Maternal and Child Health Hospital in Chongqing, China. The primary variable of interest was maternal total gestational weight gain. The primary outcomes were perinatal outcomes, which included: preeclampsia, small for gestational age, large for gestational age, low birth weight, neonatal pneumonia, neonatal respiratory distress syndrome, and neonatal intensive unit admission, etc. The association between inappropriate gestational weight gain and adverse pregnancy outcomes was estimated using multiple logistic regression analysis. RESULTS: A total of 455 twin-pregnant women who had gestational diabetes mellitus were analyzed. Women with low gestational weight gain had reduced risk of preeclampsia (adjusted odds ratio [aOR], 0.32; 95% CI or confidence interval, 0.17-0.63; p = 0.001) and their infants had higher risks of small for gestational age (aOR, 1.93; 95% CI, 1.04-3.58; p = 0.037), low birth weight (aOR, 2.27; 95% CI, 1.32-3.90; p = 0.003), neonatal intensive unit admission (aOR, 3.29; 95% CI, 1.10-5.78; p = 0.038), pneumonia (aOR, 2.41; 95% CI, 1.08-5.33; p = 0.031), and neonatal respiratory distress syndrome (aOR, 2.29; 95% CI, 1.10-4.78; p = 0.027); the infants of women with excessive gestational weight gain had a higher risk of large for gestational age (aOR, 3.76; 95% CI, 1.42-9.96; p = 0.008). CONCLUSION: Gestational weight gain controlled within the range recommended by the NAM could reduce the risk of perinatal adverse outcomes. The 2009 NAM gestational weight gain recommendations can be used for Chinese twin-pregnant women with gestational diabetes mellitus. KEY POINTS: · Inappropriate gestational weight gain can lead to adverse perinatal outcomes in twin pregnancies.. · Gestational weight gain controlled within recommended range could reduce the risk of poor perinatal outcomes.. · The National Academy of Medicine recommendations are suitable for Chinese twin-pregnant women with GDM..

Glutathione Conjugation and Protein Adduction by Environmental Pollutant 2,4-Dichlorophenol In Vitro and In Vivo.

2,4-Dichlorophenol (2,4-DCP), an environmental pollutant, was reported to cause hepatotoxicity. The biochemical mechanisms of 2,4-DCP induced liver injury remain unknown. The present study showed that 2,4-DCP is chemically reactive and spontaneously reacts with GSH and bovine serum albumin to form GSH conjugates and BSA adducts. The observed conjugation/adduction apparently involved the addition of GSH and departure of chloride via the ipso substitution pathway. Two biliary GSH conjugates and one urinary N-acetyl cysteine conjugate were observed in rats given 2,4-DCP. The N-acetyl cysteine conjugate was chemically synthesized and characterized by mass spectrometry and NMR. As expected, 2,4-DCP was found to modify hepatic protein at cysteine residues in vivo by the same chemistry. The observed protein adduction reached its peak at 15 min and revealed dose dependency. The new findings allowed us to better understand the mechanisms of the toxic action of 2,4-DCP.

Mechanism of Rhodium(III)-Catalyzed C-H Activation/Annulation of Aromatic Amide with α-Allenol: A Computational Study.

With the help of DFT calculations, the reaction mechanisms of the rhodium(III)-catalyzed C-H activation/annulation between aromatic amide and α-allenol leading to the formation of isoindolinone have been theoretically investigated. Our calculated results show that the catalytic cycle consists of four stages: N-H deprotonation and C-H activation (Stage I), allene insertion, rearrangement and isomerization (Stage II), ß-H elimination and enol-keto tautomerism (Stage III), and catalyst regeneration resulting in the five-membered ring product (Stage IV). For stage IV, besides the reaction paths proposed by the experimentalists, i.e., the insertion and reductive elimination (labeled as path a) and the reductive elimination and hydroamination (labeled as path b), an alternative path which involves C-N and C-H reductive eliminations (labeled as path c) was proposed and examined. The computational results show that the newly established path c is more energetically favorable than the reaction paths proposed by the experimentalists (paths a and b). The allene (non-terminal double bond) insertion step contributes to the rate-determining step with an overall activation free energy of 24.6 kcal/mol. Our study is beneficial for a better comprehension of the reaction mechanisms and provides a significant suggestion for further development of similar reactions.

Lack of association between PAX6/SOSTDC1/FAM20B gene polymorphisms and mesiodens.

BACKGROUND: The purpose of this study was to analyze the association between the genetic polymorphism of genes (PAX6, SOSTDC1and FAM20B) and the susceptibility to mesiodens. METHODS: This study was carried out on 50 patients with mesiodens and 50 controls. The family history of each patient with mesiodens were recorded. Genomic DNA was extracted from saliva samples, and single nucleotide polymorphisms were detected in all exons and exon/intron boundaries of PAX6, SOSTDC1 and FAM20B using Sanger sequencing. The data were analyzed using pearson chi-square test with theoretical frequency ≥ 5. For theoretical frequency less than 5 but at least 1 (≤20% cell), the data were analyzed by continuity correction. For the rest, Fisher's Exact test was used. A P-value< 0.05 was considered statistically significant. The Odds ratio (OR) and confidence intervals (CI) were recorded. RESULTS: Three polymorphisms were detected in PAX6. Two polymorphisms were detected in SOSTDC1. Twenty-nine polymorphisms were detected in FAM20B. Although, the T allele of FAM20B (rs3766626) appears to be associated with mesiodens (P = 0.051), there were no significant differences of PAX6/SOSTDC1/FAM20B gene polymorphisms between the two groups. The T allele of FAM20B (rs3766626) was associated with susceptibility to two mesiodens (P < 0.001; OR = 8.333; CI = 2.516-27.600). CONCLUSIONS: Lack of association between PAX6/SOSTDC1/FAM20B gene polymorphisms and mesiodens in the population studied was detected. Further studies with large samples on T allele of FAM20B (rs3766626) are needed.

Gut microbiota mediates the protective effects of ß-hydroxybutyrate against cisplatin-induced acute kidney injury.

The gut microbiota has been reported to be perturbed by chemotherapeutic agents and to modulate side effects. However, the critical role of ß-hydroxybutyrate (BHB) in the regulation of the gut microbiota and the pathogenesis of chemotherapeutic agents related nephrotoxicity remains unknown. We conducted a comparative analysis of the composition and function of gut microbiota in healthy, cisplatin-challenged, BHB-treated, and high-fat diet-treated mice using 16 S rDNA gene sequencing. To understand the crucial involvement of intestinal flora in BHB's regulation of cisplatin -induced nephrotoxicity, we administered antibiotics to deplete the gut microbiota and performed fecal microbiota transplantation (FMT) before cisplatin administration. 16 S rDNA gene sequencing analysis demonstrated that both endogenous and exogenous BHB restored gut microbiota dysbiosis and cisplatin-induced intestinal barrier disruption in mice. Additionally, our findings suggested that the LPS/TLR4/NF-κB pathway was responsible for triggering renal inflammation in the gut-kidney axis. Furthermore, the ablation of the gut microbiota ablation using antibiotics eliminated the renoprotective effects of BHB against cisplatin-induced acute kidney injury. FMT also confirmed that administration of BHB-treated gut microbiota provided protection against cisplatin-induced nephrotoxicity. This study elucidated the mechanism by which BHB affects the gut microbiota mediation of cisplatin-induced nephrotoxicity by inhibiting the inflammatory response, which may help develop novel therapeutic approaches that target the composition of the microbiota.