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.

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.

Doping Engineering to Modulate Lattice and Electronic Structure for Enhanced Piezocatalytic Therapy and Ferroptosis.

Piezocatalytic therapy, which generates reactive oxygen species (ROS) under mechanical force, has garnered extensive attention for its use in cancer therapy owing to its deep tissue penetration depth and less O2 -dependence. However, the piezocatalytic therapeutic efficiency is limited owing to the poor piezoresponse, low separation of electron-hole pairs, and complicated tumor microenvironment (TME). Herein, a biodegradable, porous Mn-doped ZnO (Mn-ZnO) nanocluster with enhanced piezoelectric effect is constructed via doping engineering. Mn-doping not only induces lattice distortion to increase polarization but also creates rich oxygen vacancies (OV ) for suppressing the recombination of electron-hole pairs, leading to high-efficiency generation of ROS under ultrasound irradiation. Moreover, Mn-doped ZnO shows TME-responsive multienzyme-mimicking activity and glutathione (GSH) depletion ability owing to the mixed valence of Mn (II/III), further aggravating oxidative stress. Density functional theory calculations show that Mn-doping can improve the piezocatalytic performance and enzyme activity of Mn-ZnO due to the presence of OV . Benefiting from the boosting of ROS generation and GSH depletion ability, Mn-ZnO can significantly accelerate the accumulation of lipid peroxide and inactivate glutathione peroxidase 4 (GPX4) to induce ferroptosis. The work may provide new guidance for exploring novel piezoelectric sonosensitizers for tumor therapy.

Acute Kidney Injury Induced by Immune Checkpoint Inhibitors.

Background: Recent advances in immune therapy have focused on several agents that target tumor suppression; specifically, use of immune checkpoint inhibitors (ICIs), such as ipilimumab, pembrolizumab, and nivolumab, has become an important strategy in cancer therapy as they improve outcomes in malignant disease. However, the incidence of renal complications arising from the widespread use of ICIs may be underestimated. Summary: The most frequently reported renal condition caused by ICI use is acute interstitial nephritis, and for clinicians, the crucial question is how to effectively manage patients who develop renal side effects due to cancer treatment. Currently, treatment of kidney injury associated with ICIs adheres to clinical guidelines described in Kidney Disease Improving Global Outcomes, which entails drug withdrawal and glucocorticoids or combined immunosuppressant use based on disease stage; however, there is no consensus on renal biopsy. Key Messages: Despite significant progress in prevention and treatment, the incidence and mortality of ICI-induced acute kidney injury (AKI) remain very high. This article will discuss the general clinical manifestations, mechanisms of toxicity, renal complications of ICI therapy, and related biomarkers of renal damage. It is envisaged that this information would help clinicians effectively manage AKI due to ICI therapy.

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.

[Clinical investigation of the diagnostic value of interferon-gamma, interleukin-12 and adenosine deaminase isoenzyme in tuberculous pleurisy].

OBJECTIVE: To investigate the diagnostic value of interferon-gamma (IFN-gamma), interleukin-12 (IL-12) and adenosine deaminase isoenzymes (ADA(2)) in tuberculous pleural effusions. METHODS: One hundred and ninety specimens of pleural effusion were collected from 190 patients with pleural effusion in Peking University People's Hospital, Beijing Chest Hospital, and Beijing Tuberculosis and Thoracic Tumor Institute, from March 2002 to February 2003. Of them 141 pleural specimens were diagnosed as tuberculous, and 49 as malignant. IFN-gamma and IL-12 concentrations and ADA isoenzyme activity in all the specimens were determined by ELISA and enzyme kinetic analytical method respectively. RESULTS: (1) ADA(2) activity (47.9 +/- 6.9) U/L in tuberculous effusions was significantly higher than that in malignant effusion (13.2 +/- 3.2) U/L (P < 0.01). The IFN-gamma level (112.1 +/- 45.8) ng/L in tuberculous effusion was significantly higher than that in malignant diseases (24.8 +/- 5.9) ng/L (P < 0.01). The IL-12 level (104.3 +/- 32.3) ng/L in tuberculous effusions was significantly higher than that in malignant diseases (61.8 +/- 10.8) ng/L (P < 0.05). (2) By analysis of ROC curves, the cut-off values for IFN-gamma, IL-12 and ADA(2) were defined. The sensitivity and specificity of IFN-gamma for tuberculous effusion were 84.4% and 95.9% respectively. Those of IL-12 for tuberculous effusion were 85.1% and 65.3% respectively, while those of ADA(2) were 84.4% and 91.8%. CONCLUSIONS: IFN-gamma and IL-12 could be used as valuable parameters for the differentiation of tuberculous effusion from malignant, and IFN-gamma was more sensitive and specific for tuberculous effusion than IL-12 and ADA(2).