Sensing of mitochondrial DNA by ZBP1 promotes RIPK3-mediated necroptosis and ferroptosis in response to diquat poisoning.

Diquat (DQ) poisoning is a severe medical condition associated with life-threatening implications and multiorgan dysfunction. Despite its clinical significance, the precise underlying mechanism remains inadequately understood. This study elucidates that DQ induces instability in the mitochondrial genome of endothelial cells, resulting in the accumulation of Z-form DNA. This process activates Z-DNA binding protein 1 (ZBP1), which then interacts with receptor-interacting protein kinase 3 (RIPK3), ultimately leading to RIPK3-dependent necroptotic and ferroptotic signaling cascades. Specific deletion of either Zbp1 or Ripk3 in endothelial cells simultaneously inhibits both necroptosis and ferroptosis. This dual inhibition significantly reduces organ damage and lowers mortality rate. Notably, our investigation reveals that RIPK3 has a dual role. It not only phosphorylates MLKL to induce necroptosis but also phosphorylates FSP1 to inhibit its enzymatic activity, promoting ferroptosis. The study further shows that deletion of mixed lineage kinase domain-like (Mlkl) and the augmentation of ferroptosis suppressor protein 1 (FSP1)-dependent non-canonical vitamin K cycling can provide partial protection against DQ-induced organ damage. Combining Mlkl deletion with vitamin K treatment demonstrates a heightened efficacy in ameliorating multiorgan damage and lethality induced by DQ. Taken together, this study identifies ZBP1 as a crucial sensor for DQ-induced mitochondrial Z-form DNA, initiating RIPK3-dependent necroptosis and ferroptosis. These findings suggest that targeting the ZBP1/RIPK3-dependent necroptotic and ferroptotic pathways could be a promising approach for drug interventions aimed at mitigating the adverse consequences of DQ poisoning.

Synergistic cobalt­copper metal-organic framework anchored amino-functionalized cellulose for antibiotic degradation: Interfacial engineering and mechanism insight.

Improving electron transfer rate of Co species and inhibiting aggregation of metal-organic frameworks (MOFs) particles are essential prerequisites for activating advanced oxidation process in wastewater treatment field. Here, we exploit Cu species with variable valence states to accelerate electron transfer of Co species and then to boost the unsatisfactory degradation efficiency for refractory pharmaceuticals via in-situ growth of copper and cobalt species on l-lysine functionalized carboxylated cellulose nanofibers. Utilizing the synergistic interplay of Co sites and deliberately exposed Cu0/Cu1+ atoms, the subtly designed catalyst exhibited a surprising degradation efficiency (~100 %) toward tetracycline hydrochloride within 10 min (corresponding to a catalytic capacity of 267.71 mg/g) without adjusting temperature and pH. Meanwhile, the catalyst displays good recyclability, well tolerance for coexisting ions and excellent antibacterial performance derived from the intrinsic antibacterial property of Cu-MOF. This research provided a novel strategy to construct MOFs-cellulose materials toward degrading various stubborn antibiotic pollutants.

Design of amphoteric MOFs-cellulose based composite for wastewater remediation: Adsorption and catalysis.

Water pollution remains a serious problem for aquatic organism and human beings. Developing an efficient material which can simultaneously remove and convert pollutants into low or no harmful compounds is an essential issue. Targeting at this goal, a multifunctional and amphoteric wastewater treatment material of Co-MOF and functionalized cellulose-based composite (CMC/SA/PEI/ZIF-67) was designed and prepared. Carboxymethyl cellulose (CMC) and sodium alginate (SA) were selected as support to construct an interpenetrating network structure and made it crosslinked with polyethyleneimine (PEI) for further in situ growth of ZIF-67 with good dispersion. The material was characterized using an appropriate set of spectroscopic and analytical techniques. When applied in the adsorption of heavy metal oxyanions with no adjustment of pH, the adsorbent could completely decontaminate Cr(VI) at both low and high initial concentrations with good reduction rates. The adsorbent maintained good reusability after five cycles. Meanwhile, the cobalt species of CMC/SA/PEI/ZIF-67 can activate peroxymonosulfate to generate high oxidizing substances (such as SO4-· and ·OH- radicals) to degrade cationic rhodamine B dye within 120 min, thus indicating the amphoteric and catalytic nature of our CMC/SA/PEI/ZIF-67 adsorbent. The mechanism of the adsorption and catalytic process was also discussed based with the assistance of different characterization analysis.

Single-cell sequencing reveals homogeneity and heterogeneity of the cytopathological mechanisms in different etiology-induced AKI.

Homogeneity and heterogeneity of the cytopathological mechanisms in different etiology-induced acute kidney injury (AKI) are poorly understood. Here, we performed single-cell sequencing (scRNA) on mouse kidneys with five common AKI etiologies (CP-Cisplatin, IRI-Ischemia-reperfusion injury, UUO-Unilateral ureteral obstruction, FA-Folic acid, and SO-Sodium oxalate). We constructed a potent multi-model AKI scRNA atlas containing 20 celltypes with 80,689 high-quality cells. The data suggest that compared to IRI and CP-AKI, FA- and SO-AKI exhibit injury characteristics more similar to UUO-AKI, which may due to tiny crystal-induced intrarenal obstruction. Through scRNA atlas, 7 different functional proximal tubular cell (PTC) subtypes were identified, we found that Maladaptive PTCs and classical Havcr1 PTCs but not novel Krt20 PTCs affect the pro-inflammatory and pro-fibrotic levels in different AKI models. And cell death and cytoskeletal remodeling events are widespread patterns of injury in PTCs. Moreover, we found that programmed cell death predominated in PTCs, whereas apoptosis and autophagy prevailed in the remaining renal tubules. We also identified S100a6 as a novel AKI-endothelial injury biomarker. Furthermore, we revealed that the dynamic and active immune (especially Arg1 Macro_2 cells) -parenchymal cell interactions are important features of AKI. Taken together, our study provides a potent resource for understanding the pathogenesis of AKI and early intervention in AKI progression at single-cell resolution.

Assessment of cerebrovascular reserve impairment using the breath-holding index in patients with leukoaraiosis.

Many studies have demonstrated that leukoaraiosis is associated with impaired cerebrovascular reserve function. However, the definitive hemodynamic changes that occur in leukoaraiosis are not clear, and there are many controversies. This study aimed to investigate hemodynamic changes in symptomatic leukoaraiosis using transcranial Doppler ultrasonography and the breath-holding test in a Chinese Han population, from northern China. A total of 203 patients who were diagnosed with ischemic stroke or clinical chronic progressive ischemic symptoms were enrolled in this study, including 97 males and 106 females, with an age range of 43-93 years. The severity of leukoaraiosis was evaluated according to the Fazekas grading scale, and patients were divided into four groups accordingly. Grade 0 was no leukoaraiosis, and grades I, II, and III were mild, moderate, and severe leukoaraiosis, respectively, with 44, 79, 44, and 36 cases in each group. Transcranial Doppler ultrasonography and the breath-holding test were performed. The mean blood flow velocity of the bilateral middle cerebral artery was measured and the breath-holding index was calculated. The breath holding index was correlated with leukoaraiosis severity and cognitive impairment. Patients with a low breath holding index presented poor performance in the Montreal Cognitive Assessment (MoCA) and executive function tests. That is, the lower the breath holding index, the lower the scores for the MoCA and the higher for the trail-making test Parts A and B. These results indicate that the breath-holding index is a useful parameter for the evaluation of cerebrovascular reserve impairment in patients with leukoaraiosis. In addition, the breath-holding index can reflect cognitive dysfunction, providing a new insight into the pathophysiology of leukoaraiosis. This study was approved by the Ethics Committee of the Fifth People's Hospital of Shenyang, China (approval No. 20160301) and registered in the Chinese Clinical Trial Registry (registration number: ChiCTR1800014421).

[Indications and contraindications of vaginal hysterectomy for non-prolapsed uterus].

OBJECTIVE: To study the indications and contraindications of vaginal hysterectomy for non-prolapsed uterus. METHODS: Totally 2086 patients underwent vaginal hysterectomy during the period of June 1992-June 2003 were analysed and the surgery quality and incidence of complications among patients with different sizes of uteri, with or without history of pelvic or abdominal surgery, with history of vaginal delivery and adnexectomy were compared. RESULTS: (1) The patients with uteri > 16 weeks of gestation were associated with longer operating time [(73 +/- 25) vs (42 +/- 16) min)], more blood loss [(237 +/- 86) vs (101 +/- 58) ml] and higher rate of pelvic infection (1.69% vs 0.78%) when compared to the patients with uteri < or = 16 weeks. The differences were statistically significant (P < 0.01). (2) There was no significant difference in the operating time and intraoperative blood loss between the patients with and without history of pelvic or abdominal surgery (P > 0.05), however, the surgery group had higher side injury rate during operation. In addition, 119 patients complicated with ovarian cyst underwent vaginal ovarian cystectomy successfully. CONCLUSION: Vaginal hysterectomy for patients with uteri < or = 16 weeks of gestation is safe and feasible. The procedure is relatively difficult for uteri > 16 weeks and should be determined according to the operator's experience and the patient's condition. A history of pelvic or abdominal operation increases the side injury rate in vaginal hysterectomy. The successful rate of vaginal hysterectomy in patients with uteri < or = 16 weeks of gestation is not affected by the history of vaginal delivery. During vaginal hysterectomy, ovarian cystectomy is feasible for the ovarian cyst < or = 6 cm. Skillful operator and use of appropriate instrument expand the indication of vaginal hysterectomy.