The Laparoscopic Right-lower Quadrant Approach for the Treatment of Right-sided Colon Cancer Offers Advantages Such as Shorter Surgical Time and Less Blood Loss.

Objective: This study aims to compare the therapeutic efficacy of laparoscopic right-lower quadrant and midline approaches for the treatment of right-sided colon cancer and evaluate the analgesic effect of parecoxib sodium. Methods: Sixty patients with right-sided colon cancer admitted to Hospital of Lin 'an District between January 2019 and November 2022 were selected. They were divided into the study group A (n=30) with a right-lower quadrant approach and the study group B (n=30) with a midline approach. All patients received parecoxib sodium. Surgical time, blood loss, postoperative complications, and other relevant indicators were recorded and compared between the two groups. Additionally, a control group of 60 right-sided colon cancer patients who underwent conventional non-exclusive analgesic laparoscopic surgery during the same period was included to compare the analgesic effects between the study and control groups. Results: The surgical time (RR = 0.608, 95%CI 0.51, 1.53, P = .042), blood loss (RR = 0.798, 95%CI 0.52, 1.02, P < .001), time for bowel function recovery (RR = 0.808, 95%CI 0.50, 1.77, P = .007), and length of hospital stay (RR = 0.766, 95%CI 0.56, 1.72, P =.052) were significantly lower in group A than in group B, while the number of lymph node dissections was higher in group A (RR = 0.803, 95%CI 0.62, 1.52, P = .047). The postoperative levels of tumor-specific growth factor (TSGF) (RR = 0.710, 95%CI 0.50, 1.55, P < .001) and carcinoembryonic antigen (CEA) (RR = 0.803, 95%CI 0.62, 1.52, P < .001) were significantly decreased in both groups A and B, with no significant difference between the groups (P > .05). The incidence of complications in group A was significantly lower than in group B (RR = 0.167, 95%CI 0.17, 0.63, P = .044). The VAS scores of the study group at 2/4/6/8 hours postoperatively were significantly lower than those of the control group (RR = 0.702, 95%CI 0.52, 1.62, P < .001). The SF-36 scores of the study group were significantly higher than those of the control group (RR = 0.753, 95%CI 0.56, 1.82, P < .001). Conclusions: The Laparoscopic right-lower quadrant approach for the treatment of right-sided colon cancer offers advantages such as shorter surgical time and less blood loss. It demonstrates significant clinical efficacy and reduces the incidence of postoperative complications. Parecoxib sodium enhances postoperative analgesic effect, effectively alleviating patient pain, promoting recovery, and improving quality of life. It is worth promoting in clinical practice.

Revealing the Incidence-Angle-Independent Frequency Shift in the Acoustic Rotational Doppler Effect.

The Doppler effect is a universal wave phenomenon that has inspired various applications due to the induced frequency shift. In the case of the linear Doppler effect, the frequency shift depends on the incident frequency and angle. Here, we unveil the frequency shift dependence induced by the acoustic rotational Doppler effect in the wave-object scattering process. We experimentally demonstrate that this frequency shift is exclusively determined by the angular speed and rotational symmetry of the spinning scatterer while remaining independent of the incident angular momentum and angle. We derive the analytical relationship between the frequency shift and the scatterer's helicity, presenting a novel approach for helical feature recognition. The angle-independent nature of the frequency shift inherently prevents spectrum broadening and offers a solution for precise motion measurement through the rotational Doppler effect. This work provides a rigorous and comprehensive understanding of the acoustic Doppler effect, enriching its applications in helicity and motion detection.

Gate-Tunable Quantum Acoustoelectric Transport in Graphene.

Transport probes the motion of quasi-particles in response to external excitations. Apart from the well-known electric and thermoelectric transport, acoustoelectric transport induced by traveling acoustic waves has rarely been explored. Here, by adopting hybrid nanodevices integrated with piezoelectric substrates, we establish a simple design of acoustoelectric transport with gate tunability. We fabricate dual-gated acoustoelectric devices based on hBN-encapsulated graphene on LiNbO3. Longitudinal and transverse acoustoelectric voltages are generated by launching a pulsed surface acoustic wave. The gate dependence of zero-field longitudinal acoustoelectric signal presents strikingly similar profiles to that of Hall resistivity, providing a valid approach for extracting carrier density without magnetic field. In magnetic fields, acoustoelectric quantum oscillations appear due to Landau quantization, which are more robust and pronounced than Shubnikov-de Haas oscillations. Our work demonstrates a feasible acoustoelectric setup with gate tunability, which can be extended to the broad scope of various van der Waals materials.

Allelic reprogramming of chromatin states in human early embryos.

The reprogramming of parental epigenomes in human early embryos remains elusive. To what extent the characteristics of parental epigenomes are conserved between humans and mice is currently unknown. Here, we mapped parental haploid epigenomes using human parthenogenetic and androgenetic embryos. Human embryos have a larger portion of genome with parentally specific epigenetic states than mouse embryos. The allelic patterns of epigenetic states for orthologous regions are not conserved between humans and mice. Nevertheless, it is conserved that maternal DNA methylation and paternal H3K27me3 are associated with the repression of two alleles in humans and mice. In addition, for DNA-methylation-dependent imprinting, we report 19 novel imprinted genes and their associated germline differentially methylated regions. Unlike in mice, H3K27me3-dependent imprinting is not observed in human early embryos. Collectively, allele-specific epigenomic reprogramming is different in humans and mice.

2-bromoacetamide exposure impairs oocyte maturation in mice and humans primarily via disrupting the cytoskeleton.

2-bromoacetamide (BAcAm) is an emerging class of unregulated disinfection by-products (DBPs), with potent cytogenetic and developmental toxicity in animals. However, whether BAcAm exerts toxic effects on mammalian oocyte quality remains to be elucidate. In this research, we investigated the effect of BAcAm on mouse and human oocyte maturation with an in vitro culture system. Our results revealed that BAcAm exposure hindered the extrusion of the first polar body, disrupted the spindle organization and reduced the competence of embryo development after fertilization in the mouse oocytes. Results of single-cell RNA sequencing (scRNA-seq) showed that 605 differentially expressed genes (DEGs) were identified in the BAcAm exposed mouse oocytes, among which 366 were up-regulated and 239 were down-regulated. Gene Ontology (GO) analysis further revealed that DEGs were mainly enriched in mitochondrial functions, oxidative stress, cytoskeleton, endoplasmic reticulum (ER), Golgi and protein synthesis, DNA damage and apoptosis. We then conducted further tests in these aspects and discovered that BAcAm exposure principally perturbed the function of microtubule and actin cytoskeleton. This finding was confirmed in human oocytes. Overall, our data suggest that BAcAm exposure disturbs the cytoskeleton function, thus impairing oocyte maturation. These data, for the first time, provide a comprehensive view for the toxic effects of BAcAm on oocyte maturation.

NLRP14 deficiency causes female infertility with oocyte maturation defects and early embryonic arrest by impairing cytoplasmic UHRF1 abundance.

Oocyte maturation is vital to attain full competence required for fertilization and embryogenesis. NLRP14 is preferentially expressed in mammalian oocytes and early embryos. Yet, the role and molecular mechanism of NLRP14 in oocyte maturation and early embryogenesis are poorly understood, and whether NLRP14 deficiency accounts for human infertility is unknown. Here, we found that maternal loss of Nlrp14 resulted in sterility with oocyte maturation defects and early embryonic arrest (EEA). Nlrp14 ablation compromised oocyte competence due to impaired cytoplasmic and nuclear maturation. Importantly, we revealed that NLRP14 maintained cytoplasmic UHRF1 abundance by protecting it from proteasome-dependent degradation and anchoring it from nuclear translocation in the oocyte. Furthermore, we identified compound heterozygous NLRP14 variants in women affected by infertility with EEA, which interrupted the NLRP14-UHRF1 interaction and decreased UHRF1 levels. Our data demonstrate NLRP14 as a cytoplasm-specific regulator of UHRF1 during oocyte maturation, providing insights into genetic diagnosis for female infertility.

Distinct thermal effect on biological tissues using subwavelength ultrasound metalens at megahertz.

Ultrasound focusing plays an important role in biomedical therapy and diagnosis. Acoustic metalens has showcased remarkable focusing performance but yet to be implemented to the practical ultrasound therapeutic applications. We design a planar metalens operating at megahertz and experimentally demonstrate the distinct thermal effect on biological tissues induced by the high-resolution focusing. A prominent temperature rise of 50°C is experimentally observed in the biological phantom, with a much lower input ultrasound power of 4 W compared with the traditional methods. We further study the thermal effect on fresh porcine liver and investigate the morphological changes under different physical parameters. Visible lesions are observed in in vitro tissues at the lowest input ultrasound power of 2.6 W within 10 s. This study facilitates the practical biomedical application of acoustic metalens, providing a feasible approach for the precise, safe, and reliable therapeutic ultrasound with the simple and compact metalens.

Environmentally relevant concentrations of Mn2+ disrupts the endocrine regulation of growth in juvenile Yunlong groupers (Epinephelus moara♀×Epinephelus lanceolatus♂).

Even though manganese is a bioelement essential for metabolism, excessive manganese levels in water can be detrimental to fish development and growth. Therefore, the aim of this study was to evaluate the effects of Mn2+ (0, 0.5,1, 2, and 4 mg·L-1) exposure for 30 d on the growth performance, growth hormone/insulin-like growth factor (GH/IGF) axis, hypothalamic-pituitary-thyroid (HPT) axis, and monoaminergic neurotransmitters of Epinephelus moara♀×Epinephelus lanceolatus♂(Yunlong grouper). Compared with the control and low Mn2+concentration groups of (0.5 and 1 mg·L-1), the high concentration of Mn2+ (4 mg·L-1) significantly reduced body weight (BW), body length (BL), weight gain rate (WGR), and specific growth rate (SGR), increased the feed coefficient rate (FCR) and mortality of Yunlong groupers (P < 0.05). Further, the levels of GH and IGF, along with the expression of ghra and ghrb were significantly reduced after exposure to 2 and 4 mg·L-1 Mn2+for 30 d, whereas the expression of sst5 was significantly up-regulated after exposure to 2 and 4 mg·L-1 Mn2+for 20 and 30 days. Moreover, Mn2+exposure increased thyroid hormone (T3) and thyroid stimulating hormone (TSH) contents, accompanied by increased mRNA levels of dio1 and dio2, however, the T4 level was decreased. Finally, dopamine (DA) and serotonin (5-HT) levels significantly decreased after long-term exposure to higher concentrations of Mn2+, and the levels their metabolites changed as well, suggesting that the synthesis and metabolism of DA and 5-HT were affected. Accordingly, changes in the GH/IGF and HPT axes-related parameters may be the cause of growth inhibition in juvenile groupers under Mn2+ exposure, indicating that the relationship between endocrine disorder and growth inhibition should not be ignored.

Post-ovulatory aging affects mitochondria, spindle and protein metabolism in mouse oocytes.

In brief: Post-ovulatory aging (POA) results in a decline in oocyte quality and embryonic developmental capacity although the underlying mechanisms remain elusive. This study provides comprehensive mRNA expression profiles of fresh and aging oocytes in mice for the first time. Abstract: POA impairs the quality of mammalian oocytes with harmful effects on the developmental potential of the embryo. This is a major problem for humans since it is associated with low rate of natural fertility, with high rate of spontaneous abortion and low efficiency of in vitro fertilization. However, the molecular mechanisms underlying this process remain unclear and new methods are demanded to control POA. In this study, we performed single-cell RNA-sequencing (scRNA-seq) analysis on fresh and aging MII mouse oocytes and compared their global RNA transcription patterns. Nine hundred and twenty-one differentially expressed genes (DEGs) were identified. Five hundred and sixty-nine genes were downregulated, while 356 were upregulated in the group of aging oocytes. Gene ontology (GO) enrichment analysis demonstrated that a series of DEGs were significantly enriched involving mitochondrial functions, spindle functions and protein metabolism. The results of qPCR and a series of functional tests further confirmed that the disorder of mitochondrial functions, spindle functions and impairment of protein metabolism were actually involved in the progression of POA. In this study, panoramic mRNA expression profiles of fresh and aging oocytes were depicted and fully validated. Our data will provide a useful resource for further research on the regulation of gene expression of POA and suggest potential strategies to delay and reverse POA.

Developmental toxicity of 2-bromoacetamide on peri- and early post-implantation mouse embryos in vitro.

2-bromoacetamide (BAcAm), a new class of disinfection by-products (DBPs), is widely detected in drinking water across the world. Reports of the high cytogenetic toxicity of BAcAm have aroused public attention concerning its toxic effects on early embryonic development. In this study, we optimized an in vitro culture (IVC) system for peri- and early post-implantation mouse embryos and used this system to determine the developmental toxicity of BAcAm. We found that exposure to BAcAm caused a reduction in egg cylinder formation rate and abnormal lineage differentiation in a dose-dependent manner. Transcriptomic analysis further revealed that BAcAm exposure at early developmental stages altered the abundance of transcripts related to a variety of biological processes including gene expression, metabolism, cell proliferation, cell death and embryonic development, thus indicating its toxic effects on embryonic development. Thus, we developed a robust tool for studying the toxicology of chemicals at the early stages of embryonic development and demonstrated the developmental toxicity of BAcAm in the early embryonic development of mammals.

Spatiotemporal Acoustic Communication by a Single Sensor via Rotational Doppler Effect.

A longstanding pursuit in information communication is to increase transmission capacity and accuracy, with multiplexing technology playing as a promising solution. To overcome the challenges of limited spatial information density and systematic complexity in acoustic communication, here real-time spatiotemporal communication is proposed and experimentally demonstrated by a single sensor based on the rotational Doppler effect. The information carried in multiplexed orbital-angular-momentum (OAM) channels is transformed into the physical quantities of the temporal harmonic waveform and simultaneously detected by a single sensor. This single-sensor configuration is independent of the channel number and encoding scheme. The parallel transmission of complicated images is demonstrated by multiplexing eight OAM channels and achieving an extremely-low bit error rate (BER) exceeding 0.02%, owing to the intrinsic discrete frequency shift of the rotational Doppler effect. The immunity to inner-mode crosstalk and robustness to noise of the simple and low-cost communication paradigm offers promising potential to promote relevant fields.

Human zygotic genome activation is initiated from paternal genome.

Although parental genomes undergo extensive epigenetic reprogramming to be equalized after fertilization, whether they play different roles in human zygotic genome activation (ZGA) remains unknown. Here, we mapped parental transcriptomes by using human parthenogenetic (PG) and androgenetic (AG) embryos during ZGA. Our data show that human ZGA is launched at the 8-cell stage in AG and bi-parental embryos, but at the morula stage in PG embryos. In contrast, mouse ZGA occurs at the same stage in PG and AG embryos. Mechanistically, primate-specific ZNF675 with AG-specific expression plays a role in human ZGA initiated from paternal genome at the 8-cell stage. AG-specifically expressed LSM1 is also critical for human maternal RNA degradation (MRD) and ZGA. The allelic expressions of ZNF675 and LSM1 are associated with their allelically epigenetic states. Notably, the paternally specific expressions of ZNF675 and LSM1 are also observed in diploid embryos. Collectively, human ZGA is initiated from paternal genome.

Timing of angiography and outcomes in patients with non-ST-segment elevation myocardial infarction: Insights from the evaluation and management of patients with acute chest pain in China registry.

Objective: Although an invasive strategy has been recommended within 24 h for patients with non-ST-segment elevation myocardial infarction (NSTEMI), the optimal timing of the invasive strategy remains controversial. We sought to investigate the association between the different timings of invasive strategies and clinical outcomes in patients with NSTEMI. Materials and methods: Patients admitted with NSTEMI from the Evaluation and Management of Patients with Acute ChesT pain in China (EMPACT) registry between January 2016 and September 2017 were included. The primary outcomes were major adverse cardiac events (MACEs) within 30 days. Multivariable logistic regression was performed to assess independent risk factors for MACEs. Results: A total of 969 patients with NSTEMI from the EMPACT Registry were eligible for this study. Coronary angiography (CAG) was performed in 501 patients [<24 h, n = 150 (15.5%); ≥ 24 h, n = 351 (36.2%)]. The rate of MACEs at 30 days in all patients was 9.2%, including 54 (5.6%) deaths. Patients who underwent CAG had a lower rate of MACEs and mortality than those who did not receive CAG (MACEs: 5.6% vs. 13.0%, P < 0.001; mortality: 1.6% vs. 9.8%, P < 0.001). Nonetheless, no statistically significant difference was found in the rates of MACEs and mortality between the early (< 24 h) and delayed (≥ 24 h) CAG groups. Older age (OR: 1.036, 95% CI: 1.007, 1.065, P = 0.014), and acute heart failure (OR: 2.431, 95% CI: 1.244, 4.749, P = 0.009) increased the risk of MACEs and protective factors were underwent CAG (OR: 0.427, 95% CI: 0.219, 0.832, P = 0.012) or PCI (OR: 0.376, 95% CI: 0.163, 0.868, P = 0.022). In the multilevel logistic regression, older age (OR: 0.944, 95% CI: 0.932, 0.957, P < 0.001), cardiogenic shock (OR: 0.233, 95% CI: 0.079, 0.629, P = 0.009), pulmonary moist rales (OR: 0.368, 95% CI: 0.197, 0.686, P = 0.002), and prior chronic kidney disease (OR: 0.070, 95% CI: 0.018, 0.273, P < 0.001) was negatively associated with CAG. Conclusion: This real-world cohort study of NSTEMI patients confirmed that the early invasive strategy did not reduce the incidence of MACEs and mortality within 30 days compared with the delayed invasive strategy in NSTEMI patients.

Proteomic analysis implicates that postovulatory aging leads to aberrant gene expression, biosynthesis, RNA metabolism and cell cycle in mouse oocytes.

BACKGROUND: In mammals, oocytes display compromised quality after experiencing a process of postovulatory aging. However, the mechanisms underlying are not yet fully understood. Here, we portrayed a protein expression profile of fresh and aging metaphase II (MII) mouse oocytes by means of four-dimensional label-free quantification mass spectrometry (4D-LFQ). RESULTS: The analysis of 4D-LFQ data illustrated that there were seventy-six differentially expressed proteins (DEPs) between two groups of MII stage oocytes. Fifty-three DEPs were up-regulated while twenty-three DEPs were down-regulated in the MII oocytes of the aging group, and Gene Ontology (GO) analysis revealed that these DEPs were mainly enriched in regulation of gene expression, biosynthesis, RNA metabolism and cell cycle. Our detailed analysis revealed that the expression of proteins that related to gene expression processes such as transcription, translation, post-translational modifications and epigenome was changed; the relative protein expression of RNA metabolic processes, such as RNA alternative splicing, RNA export from nucleus and negative regulation of transcription from RNA polymerase II promoter was also altered. CONCLUSION: In conclusion, we identified considerable DEPs and discussed how they agreed with previous researches illustrating altered protein expression associated with the quality of oocytes. Our research provided a new perspective on the mechanisms of postovulatory aging and established a theoretical support for practical methods to control and reverse postovulatory aging.

Translatome and transcriptome co-profiling reveals a role of TPRXs in human zygotic genome activation.

Translational regulation plays a critical role during the oocyte-to-embryo transition (OET) and zygotic genome activation (ZGA). Here, we integrated ultra-low-input ribosome profiling (Ribo-lite) with messenger RNA sequencing to co-profile the translatome and transcriptome in human oocytes and early embryos. Comparison with mouse counterparts identified widespread differentially translated gene functioning in epigenetic reprogramming, transposon defense, and small RNA biogenesis, in part driven by species-specific regulatory elements in 3' untranslated regions. Moreover, PRD-like homeobox transcription factors, including TPRXL, TPRX1, and TPRX2, are highly translated around ZGA. TPRX1/2/L knockdown leads to defective ZGA and preimplantation development. Ectopically expressed TPRXs bind and activate key ZGA genes in human embryonic stem cells. These data reveal the conservation and divergence of translation landscapes during OET and identify critical regulators of human ZGA.

Functional substitution of zona pellucida with modified sodium hyaluronate gel in human embryos.

PURPOSE: Zona pellucida-free (ZP-free) embryos often fail to achieve good developmental outcomes and are routinely discarded in assisted reproductive laboratories. Existing attempts to rescue ZP-free embryos are not widely used due to operational complexity and high technical requirements. To handle cases with missing ZP, we applied modified sodium hyaluronate gel (MSHG) to embryo culture to determine if it can function as a substitute for human zona pellucida. METHODS: The developmental process and the blastocyst formation rate of embryos were analyzed in both mouse and human. The first clinical application of MSHG was reported, and the pregnancy outcome was continuously followed up. RESULTS: Human and mouse ZP-free embryos cultured with MSHG showed a blastocyst formation rate similar to ZP-intact embryos. MSHG improves blastocysts formation rate by maintaining blastomere spatial arrangement at early stages. Compared to ZP-free embryos, the proportion of tetrahedrally arranged blastomeres at the 4-cell stage increased significantly in embryos cultured with MSHG in humans. A ZP-free blastocyst cultured in MSHG with the highest score was successfully implanted after day 5 transplantation and developed normally. CONCLUSION: These data demonstrate that MSHG can substitute the function of zona pellucida and rescue human ZP-free embryos during assisted reproductive technology.

Activin receptor-like kinase 7 promotes apoptosis of vascular smooth muscle cells via activating Smad2/3 signaling in diabetic atherosclerosis.

Vascular smooth muscle cells (VSMCs) is a vital accelerator in the late phase of diabetic atherosclerosis, but the underlying mechanism remains unclear. The aim of our study was to investigate whether activin receptor-like kinase 7 (ALK7)-Smad2/3 pathway plays an important role in VSMC apoptosis of diabetic atherosclerosis. It was shown that ALK7 expression was obviously elevated in the aorta of ApoE-/- mice with type 2 diabetes mellitus. Inhibition of ALK7 expression significantly improved the stability of atherosclerotic plaques and reduced cell apoptosis. Further experiments showed that ALK7 knockdown stabilized atherosclerotic plaques by reducing VSMC apoptosis via activating Smad2/3. Our study uncovered the important role of ALK7-Smad2/3 signaling in VSMCs apoptosis, which might be a potential therapeutic target in diabetic atherosclerosis.

Community-Acquired Stenotrophomonas Maltophilia Infection in a Child: A Case Report and Literature Review.

Background: Stenotrophomonas maltophilia (S. maltophilia) is a pathogen causing opportunistic and nosocomial infections that are invasive and fatal, especially in hospitalized and immunocompromised patients. However, community-acquired S. maltophilia is rarely reported in children with normal immunity. S. maltophilia is a multi-drug-resistant bacterium, and the preferred drug is trimethoprim/sulfamethoxazole (TMP/SMX), which has greater side effects in children. Case Presentation: Herein, we reported the case of a child with clinical manifestations of fever, high C-reactive protein (CRP) and white blood cells, and severe pneumonia. The blood culture yielded S. maltophilia. The initial treatment regimen was meropenem IV, which was subsequently changed to ceftazidime IV, and finally to oral cefixime, which has less side effects in children. The child recovered completely. At the 1-month follow-up, anteroposterior chest X-ray was normal, and the child was in good general health. Conclusion: Although community-acquired S. maltophilia infection in children is rare, it can occur. The doctor encountered such a child in clinical work. This child has a normal immune system, his disease comes from a community infection and has lobar pneumonia located in the lower lung area. At the same time, the child's white blood cells and CRP values are high, the doctor should be concerned that the child may have S. maltophilia infection. When treating patients, doctors can try to use drugs empirically, such as ceftazidime, instead of using ciprofloxacin, SMZ and other drugs that have relatively large side effects in children. It is worth mentioning that doctors also need to adjust the medication in a timely manner according to the efficacy evaluation and drug sensitivity of the children after the medication, so as to minimize the drug resistance of community-acquired infections. This will prevent the misuse of Meropenem, which has been given in a community patient and that too in a child. Its important to prevent this malpractise.

Structures of the ADGRG2-Gs complex in apo and ligand-bound forms.

Adhesion G protein-coupled receptors are elusive in terms of their structural information and ligands. Here, we solved the cryogenic-electron microscopy (cryo-EM) structure of apo-ADGRG2, an essential membrane receptor for maintaining male fertility, in complex with a Gs trimer. Whereas the formations of two kinks were determinants of the active state, identification of a potential ligand-binding pocket in ADGRG2 facilitated the screening and identification of dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate and deoxycorticosterone as potential ligands of ADGRG2. The cryo-EM structures of DHEA-ADGRG2-Gs provided interaction details for DHEA within the seven transmembrane domains of ADGRG2. Collectively, our data provide a structural basis for the activation and signaling of ADGRG2, as well as characterization of steroid hormones as ADGRG2 ligands, which might be used as useful tools for further functional studies of the orphan ADGRG2.

Adenosine Kinase Inhibition Prevents Severe Acute Pancreatitis via Suppressing Inflammation and Acinar Cell Necroptosis.

Background: Inflammatory disorder and acinar cell death contribute to the initiation and progression of severe acute pancreatitis (SAP). Adenosine kinase (ADK) has potential effects on both inflammation and cell death. However, the role of ADK in SAP remains to be explored. Methods: To establish an experimental SAP model, male C57BL/6 mice were intraperitoneally injected with cerulein (50 µg/kg, seven doses at hourly intervals) and LPS (10 mg/kg, at the last cerulein injection). For ADK inhibition, ABT702 (1.5 mg/kg) was intraperitoneally injected 1 h before cerulein treatment. The pancreas and serum were collected and analyzed to determine the severity of pancreatic injury and explore the potential pathophysiological mechanisms. Pancreatic acinar cells (AR42J) were used to explore the in vitro effects of ADK inhibition on cerulein-induced inflammation and necroptotic cell death. Results: ADK inhibition notably attenuated the severity of SAP, as indicated by the decreased serum amylase (7,416.76 ± 1,457.76 vs. 4,581.89 ± 1,175.04 U/L) and lipase (46.51 ± 11.50 vs. 32.94 ± 11.46 U/L) levels and fewer pancreatic histopathological alterations (histological scores: 6.433 ± 0.60 vs. 3.77 ± 0.70). MOMA-2 and CD11b staining confirmed that ADK inhibition prevented the infiltration of neutrophils and macrophages. The phosphorylation of nuclear factor-κB (NF-κB) was also reduced by ADK inhibition. ADK inhibition markedly limited the necrotic area of the pancreas and prevented the activation of the necroptotic signaling pathway. Endoplasmic reticulum (ER) stress was activated in the pancreas using the SAP model and cerulein-treated AR42J cells whereas ADK inhibition reversed the activation of ER stress both in vivo and in vitro. Moreover, the alleviating effects of ADK inhibition on ER stress, inflammation, and cell necroptosis were eliminated by the adenosine A2A receptor antagonist. Conclusion: ADK inhibition reduced inflammation and necroptotic acinar cell death in SAP via the adenosine A2A receptor/ER stress pathway, suggesting that ADK might be a potential therapeutic target for SAP.