An immunomodulatory role of Fc receptor γ chain independent of FcγR ligation by IgG in acute neuroinflammation triggered by MPTP intoxication.

Aberrant microglial activation is a prominent feature of neuroinflammation, which is implicated in the pathogenesis of neurological disorders. Fc receptor common γ-chain (FcRγ), one of the two immunoreceptor tyrosine-based activation motif-bearing adaptor proteins, is abundantly expressed in microglia. It couples with different receptors, such as receptors for the Fc portion of IgG. In this study, we observed increased FcRγ expression along with increased IgG-binding during acute neuroinflammation triggered by MPTP intoxication, where adaptive immune responses should not be involved. Notably, FcRγ was expressed not only in the cell membrane but also in the cytoplasm in the activated microglia. FcRγ deficiency exacerbated microglial activation, pro-inflammatory factor upregulation, nigral dopaminergic neuronal loss and motor deficits, implicating a beneficial role of FcRγ in this model. Blockade of Fcγ receptor ligation by IgG in mice by Endoglycosidase S treatment, a bacterial endo-ß-N-acetylglucosaminidase cleaving specifically the Asn297-linked glycan of IgG, or by using the mice deficient in mature B cells (muMT) with IgG production defects, did not show similar phenotypes to those observed in FcRγ-deficient mice, indicating that the beneficial effect mediated by FcRγ did not depend on FcγR ligation by IgG. Further, FcRγ knockout aggravated the expression and activation of STAT1 in microglia, suggesting FcRγ modulated neuroinflammation by dampening STAT1 signaling. Collectively, these results revealed that FcRγ-associated receptors could function as negative regulators of neuroinflammation and dopaminergic neurodegeneration.

Efficacy of nonopioid analgesics and regional techniques for perioperative pain management in laparoscopic gynecological surgery: a systematic review and network meta-analysis.

BACKGROUND: The optimal approach for perioperative pain management in laparoscopic gynecological surgery is unclear due to a lack of comprehensive analysis, which limits the development of evidence-based enhanced recovery after surgery protocols. This study aimed to conduct a systematic review and network meta-analysis to support clinical decision-making for optimal analgesia. MATERIALS AND METHODS: This study conducted a systematic literature search in PubMed, Embase, CENTRAL, Web of Science, and CINAHL from inception to 3 December 2021, and updated on 19 August 2022. Randomized controlled trials comparing the perioperative use of nonopioid analgesics and regional techniques in adults undergoing elective laparoscopic gynecological surgery under general anesthesia were included in the analysis, either alone or in combination. The co-analgesic interventions during the perioperative period for the intervention and control groups of each eligible study were also considered. We assessed the risk of bias using the Risk of Bias 2 tool and evaluated the certainty of evidence using the Confidence in Network Meta-Analysis (CINeMA) approach. A Bayesian network meta-analysis was used to estimate the efficacy of the analgesic strategies. The primary outcomes were pain score at rest and cumulative oral morphine milligram equivalents at 24 h postoperatively. RESULTS: Overall, 108 studies with 9582 participants and 35 different interventions were included. Compared with inert treatments, combinations of two or more interventions showed better efficacy and longer duration in reducing postoperative pain and opioid consumption within 24 h than monotherapies, and showed stepwise enhanced effects with increasing analgesic modes. In combination therapies, regional techniques that included peripheral nerve blocks and intraperitoneal local anesthetics, in combination with nonopioid systemic analgesics, or combining local anesthetics with adjuvant drugs, were found to be more effective. Monotherapies were found to be mostly ineffective. The most effective peripheral nerve blocks were found to be ultrasound-guided transversus abdominis plane block with adjuvant and ultrasound-guided quadratus lumborum block. CONCLUSIONS: These results provide robust evidence for the routine use of regional techniques in combination with nonopioid analgesics in perioperative pain management. However, further better quality and larger trials are needed, considering the low confidence levels for certain interventions.

Inhibition of JNK/c-Jun-ATF2 Overcomes Cisplatin Resistance in Liver Cancer through down-Regulating Galectin-1.

Due to drug resistance, the clinical response to cisplatin (CDDP) from patients with liver cancer is unsatisfactory. The alleviation or overcoming of CDDP resistance is an urgent problem to be solved in clinics. Tumor cells rapidly change signal pathways to mediate drug resistance under drug exposure. Here, multiple phosphor-kinase assays were performed and c-Jun N-terminal kinase (JNK) was activated in liver cancer cells treated with CDDP. The high activity of the JNK promotes poor progression and mediates cisplatin resistance in liver cancer, leading to a poor prognosis of liver cancer. Mechanistically, the highly activated JNK phosphorylated c-Jun and ATF2 formed a heterodimer to upregulate the expression of Galectin-1, leading to promoting cisplatin resistance in liver cancer. Importantly, we simulated the clinical evolution of drug resistance in liver cancer by continuous CDDP administration in vivo. In vivo bioluminescence imaging showed the activity of JNK gradually increased during this process. Moreover, the inhibition of JNK activity by small molecular or genetic inhibitors enhanced DNA damage and overcame CDDP resistance in vitro and in vivo. Collectively, our results underline that the high activity of JNK/c-Jun-ATF2/Galectin-1 mediates cisplatin resistance in liver cancer and provides an optional scheme for dynamic monitoring of molecular activity in vivo.

Cell type- and region-specific translatomes in an MPTP mouse model of Parkinson's disease.

Parkinson's disease (PD) is the most common neurodegenerative movement disorder, characterized by the progressive loss of nigrostriatal dopaminergic neurons (DANs), involving the dysregulation of both neurons and glial cells. Cell type- and region-specific gene expression profiles can provide an effective source for revealing the mechanisms of PD. In this study, we adopted the RiboTag approach to obtain cell type (DAN, microglia, astrocytes)- and brain region (substantia nigra, caudate-putamen)-specific translatomes at an early stage in an MPTP-induced mouse model of PD. Through DAN-specific translatome analysis, the glycosphingolipid biosynthetic process was identified as a significantly downregulated pathway in the MPTP-treated mice. ST8Sia6, a key downregulated gene related to glycosphingolipid biosynthesis, was confirmed to be downregulated in nigral DANs from postmortem brains of patients with PD. Specific expression of ST8Sia6 in DANs exerts anti-inflammatory and neuroprotective effects in MPTP-treated mice. Through cell type (microglia vs. astrocyte) and brain region (substantia nigra vs. caudate-putamen) comparisons, nigral microglia showed the most intense immune responses. Microglia and astrocytes in the substantia nigra showed similar levels of activation in interferon-related pathways and interferon gamma (IFNG) was identified as the top upstream regulator in both cell types. This work highlights that the glycosphingolipid metabolism pathway in the DAN is involved in neuroinflammation and neurodegeneration in an MPTP mouse model of PD and provides a new data source for elucidating the pathogenesis of PD.

[Effect and mechanism of Rho kinase inhibitor on intestinal injury in septic rats].

OBJECTIVE: To explore the effect of Rho kinase inhibitor on intestinal injury in septic rats and its possible mechanism. METHODS: Thirty-two male Sprague-Dawley (SD) rats were randomly divided into sham operation group (Sham group), Rho kinase inhibitor Y-27632 control group (Y+Sham group), sepsis model group [cecal ligation and puncture (CLP) group] and Y-27632 pretreatment group (Y+CLP group), with 8 rats in each group. Rat sepsis model was reproduced by CLP. The rats in the Sham group and Y+Sham group were only separated and moved the cecum without ligation and perforation. The rats in the Y+Sham group and Y+CLP group were pretreated with intraperitoneal injection of Y-27632 solution 5 mg/kg 15 minutes before operation; the rats in the Sham group and CLP group were intraperitoneally injected with the same amount of phosphate buffered saline (PBS). Twenty-four hours after operation, the heart blood was collected and the serum diamine oxidase (DAO) content was determined by enzyme-linked immunosorbent assay (ELISA). Then the small intestine tissue was collected, the pathological changes of the intestinal tissue were observed under the light microscope after hematoxylin-eosin (HE) staining, and Chiu's score was performed. The positive expressions of Rho-related coiled-coil kinase 1 (ROCK1) and nuclear factor-κB (NF-κB) in intestinal tissue were detected by immunohistochemistry. ELISA was used to detect the levels of tumor necrosis factor-α (TNF-α) and interleukin-10 (IL-10) in intestinal tissue homogenate. RESULTS: The intestinal tissue structure of the Sham group and Y+Sham group was intact and the mucosa was arranged neatly. Compared with the Sham group, the intestinal mucosa of the CLP group was arranged disorderly, with a large number of inflammatory cells infiltration, and the Chiu's score was significantly increased (3.83±0.27 vs. 0.12±0.11, P < 0.05), indicating that those rats suffered from septic intestinal injury. Compared with the CLP group, the degree of necrosis of intestinal epithelial cells in the Y+CLP group was reduced, a small amount of inflammatory cells infiltration was seen, and the Chiu's score was significantly decreased (2.85±0.21 vs. 3.83±0.27, P < 0.05), indicating that Y-27632 pretreatment could alleviate intestinal injury in septic rats. Compared with the Sham group, the positive expressions of intestinal tissue ROCK1 and NF-κB, the contents of serum DAO and intestinal homogenate TNF-α in the CLP group were significantly increased [ROCK1 expression (A value): 0.19 (0.18, 0.22) vs. 0.10 (0.09, 0.11), NF-κB expression (A value): 0.40±0.02 vs. 0.15±0.01, DAO (ng/L): 287.81±23.31 vs. 144.92±17.72, TNF-α (ng/L): 101.08±5.62 vs. 74.81±5.56, all P < 0.05], the level of intestinal homogenate IL-10 was significantly decreased (µg/L: 55.16±5.20 vs. 95.95±7.53, P < 0.05). Compared with the CLP group, the positive expressions of intestinal tissue ROCK1, NF-κB, the contents of serum DAO and intestinal homogenate TNF-α in the Y+CLP group were significantly decreased [ROCK1 expression (A value): 0.15 (0.13, 0.18) vs. 0.19 (0.18, 0.22), NF-κB expression (A value): 0.28±0.01 vs. 0.40±0.02, DAO (ng/L): 243.34±19.76 vs. 287.81±23.31, TNF-α (ng/L): 90.41±8.79 vs. 101.08±5.62, all P < 0.05], while the level of intestinal homogenate IL-10 was significantly increased (µg/L: 66.15±5.74 vs. 55.16±5.20, P < 0.05), indicating that the protective effect of Y-27632 pretreatment on sepsis intestinal injury rats might be related to the regulation of RhoA/ROCK1/NF-κB signaling pathway. CONCLUSIONS: Rho kinase inhibitors can reduce intestinal injury in septic rats, and the mechanism may be related to inhibiting RhoA/ROCK1/NF-κB signaling pathway and reducing intestinal inflammation in septic rats.

[Response of phenophase to meteorological conditions and flowering forecast model on Amygdalus communis in Shache County, Xinjiang, China].

Based on the phenophase data of Amygdalus communis and homochronous meteorological observation data at agrometeorological experimental station of Shache County during 2008-2013, the change characteristics of phenological period of A. communis and the effects of temperature and sunshine duration on them were analyzed. The results showed that before flowering, positive correlations existed among the first day of phenological phases, and after flowering, the correlations among the first day of phenological phases were mostly less. A significant positive correlation was observed between earlier bud flower swelling and the days of dormant period. and growth period, and a significant negative correlation existed between later bud flower swelling and the days of dormant period and growth period. Before fruit maturation, there was negative correlation between temperature and the interval days of phenological period, and after fruit maturation, the correlations were mostly positive. But the correlation between sunshine duration and the interval days of phenological period was positive before and after fruit maturation. The interval days from fruit maturation to the beginning date of leaf colour change had evident response to the average maximum temperature, and the interval days from the emergence of inflorescence to the ending data of flowering, and from the beginning date of leaf colour change to the ending date of leaf fall, had obvious response to sunshine duration. When the dormant period exceeded 30 days and the average daily temperature met the rang from -3.0 to -7.5 °C, A. communis would get into the flower swelling period after another 17-28 d. There were one-to-one correspondences between flower swelling, the beginning date of flowering, the beginning date of leaf colour change, the ending date of leaf fall, and the first pentad average temperature greater than or equal to 4 °C and pentad average maximum temperature greater than or equal to 12 °C, pentad average temperature greater than or equal to 14 °C and pentad average maximum temperature greater than or equal to 22 °C in spring, the first pentad temperature less than or equal to 10 °C and pentad average maximum temperature less than or equal to 18 °C in autumn the first pentad average temperature less than or equal to 1.9 °C in winter, respectively. By using partial least squares regression analysis, the first day of flowering forecast model of A. communis was established with good prediction.