Sepsis,a systemic inflammatory disorder triggered by infection,is characterized by a complex pathophysiological mechanism that gives rise to high mortality rates and treatment bottlenecks.Short-Chain Fatty Acids(SCFAs),as the core metabolites of the intestinal flora,exhibit potential in organ protection during sepsis via a multi-target regulatory mechanism.In the realm of immunomodulation,SCFAs achieve a balance between pro-inflammatory and anti-inflammatory responses by activating G protein-coupled receptors,inhibiting the activation of NLRP3 inflammasomes,and suppressing the cascade reaction of pro-inflammatory factors.At the metabolic regu-lation level,SCFAs optimize mitochondrial function,mitigate the hypercatabolic state associated with sepsis,and relieve organ energy failure.Furthermore,SCFAs exert an organ-protective effect in multiple ways.They enhance the integrity of the intestinal barrier,inhibit pathogen translocation,and impede the systemic spread of inflammation through the synergistic mechanisms of the intestinal-organ axis.Animal and preclinical studies have demonstrated that exogenous supplementation of SCFAs or dietary fiber intervention may interact with the intestinal flora,offering a novel strategy for sepsis treatment.In this review,we systematically summarize the multi-target regulatory network of SCFAs in sepsis and the research progress regarding their organ-protective effects in sepsis.Additionally,we propose therapeutic strategies targeting microbial metabolites,thereby providing a new perspective for overcoming the limitations of traditional anti-infection and immunomodulation.

Sepsis,a systemic inflammatory disorder triggered by infection,is characterized by a complex pathophysiological mechanism that gives rise to high mortality rates and treatment bottlenecks.Short-Chain Fatty Acids(SCFAs),as the core metabolites of the intestinal flora,exhibit potential in organ protection during sepsis via a multi-target regulatory mechanism.In the realm of immunomodulation,SCFAs achieve a balance between pro-inflammatory and anti-inflammatory responses by activating G protein-coupled receptors,inhibiting the activation of NLRP3 inflammasomes,and suppressing the cascade reaction of pro-inflammatory factors.At the metabolic regu-lation level,SCFAs optimize mitochondrial function,mitigate the hypercatabolic state associated with sepsis,and relieve organ energy failure.Furthermore,SCFAs exert an organ-protective effect in multiple ways.They enhance the integrity of the intestinal barrier,inhibit pathogen translocation,and impede the systemic spread of inflammation through the synergistic mechanisms of the intestinal-organ axis.Animal and preclinical studies have demonstrated that exogenous supplementation of SCFAs or dietary fiber intervention may interact with the intestinal flora,offering a novel strategy for sepsis treatment.In this review,we systematically summarize the multi-target regulatory network of SCFAs in sepsis and the research progress regarding their organ-protective effects in sepsis.Additionally,we propose therapeutic strategies targeting microbial metabolites,thereby providing a new perspective for overcoming the limitations of traditional anti-infection and immunomodulation.

Objective:To evaluate the mechanism of short-chain fatty acids (SCFAs) reducing cognitive dysfunction in septic mice through transcriptomic analysis.Methods:Sixty SPF healthy adult male C57BL/6 mice, aged 8-12 weeks, weighing 20-25 g, were divided into 3 groups ( n=20 each) using a random number table method: sham operation group (Sham group), sepsis group (SEP group), and SCFAs+ sepsis group (SCFAs+ SEP group). Cecal ligation and puncture (CLP)was used to simulate a sepsis model in anesthetized animals. In SCFAs+ SEP group, 67.5 mmol/L acetate, 40 mmol/L butyrate, and 25.9 mmol/L propionate were added to drinking water starting from 14 days before CLP until 14 days after CLP. Y maze tests were conducted on days 4, 7 and 14 after surgery, with the number of mice in the Y maze test being the number of surviving mice on that day. On day 14 after surgery, 4 mice were selected in SEP group and SCFAs+ SEP group and sacrificed after anesthesia, and brain tissues were obtained to perform transcriptome sequencing, and enrichment analysis was performed using GO database and KEGG database. Finally, 5 mice were randomly sacrificed in each group, and brain tissues were collected and Western blot analysis was performed to verify the sequencing results. Results:Compared with Sham group, the number of times they entered the novel arm on days 4, 7 and 14 after surgery were significantly reduced, and the time spent in the novel arm was shortened in SEP group ( P<0.05). Compared with SEP group, the number of times they entered the novel arm on days 4, 7 and 14 after surgery was significantly increased, and the time spent in the novel arm was prolonged in SCFAs+ SEP group ( P<0.05). The results of transcriptomic analysis showed that 438 significantly differentially expressed genes were identified in SCFAs+ SEP group, of which the expression of 175 genes was up-regulated and the expression of 263 genes was down-regulated compared with SEP group. The expression of gamma-aminobutyric acid receptor rho-2 (GABRR2) in the brain tissues was significantly up-regulated in SEP group as compared with Sham group ( P<0.05). Compared with SEP group, the expression of GABRR2 in the brain tissue was significantly down-regulated in SCFAs+ SEP group ( P<0.05). There was no significant difference in the expression of GABRR2 in brain tissues between Sham group and SCFAs+ SEP group ( P>0.05). Conclusions:SCFAs may reduce cognitive dysfunction by down-regulating the expression of GABRR2 in septic mice.

Objective:To evaluate the role of autophagy in electroacupuncture (EA)-induced improvement in sepsis-associated encephalopathy (SAE) in mice.Methods:A total of 135 healthy adult male mice, aged 8-12 weeks, weighing 22-25 g, were used in this study. Ten mice were randomly selected to prepare caecal slurry after anesthesia. The remaining 125 mice were divided into 5 groups ( n=25 each) using a random number table method: sham operation group (group Sham), SAE group, SAE+ EA group (group EA), SEA+ EA+ autophagy agonist rapamycin group (group SAE+ EA+ R), and SAE+ EA+ autophagy inhibitor 3-methyladenine group (group SAE+ EA+ MA). SAE was induced by intraperitoneal injection of cecal slurry 200 μl. Bilateral Zusanli (ST36) acupoints were stimulated at 2, 24, 48 and 72 h after surgery in group SAE+ EA, group SAE+ EA+ R and group SAE+ EA+ MA. Autophagy agonist rapamycin 10 mg/kg and autophagy inhibitor 3-methyladenine 15 mg/kg were intraperitoneally injected at 30 min before EA in SAE+ EA+ R group and SAE+ EA+ MA group, respectively. The survival of mice was recorded at 7 days after developing the model. Ten mice were selected from each group at 8-12 days after developing the model, and the learning and memory ability was assessed by Morris water maze test. Five mice from each group were sacrificed after anesthesia, brains were removed, and hippocampal tissues were obtained for determination of contents of interleukin-1beta (IL-1β), IL-18 and tumor necrosis factor-α (TNF-α) (by enzyme-linked immunosorbent assay) and expression of p62, autophagy-related protein 16 like protein 1 (ATG16L1), and nucleotide like receptor protein 3 (NLRP3) (by Western blot). Results:Compared with Sham group, the survival rate at 7 days after developing the model was significantly decreased in the other 4 groups ( P<0.01). There was no significant difference in the survival rate at 7 days after developing the model among SAE group, SAE+ EA group, SAE+ EA+ R group and SAE+ EA+ MA group ( P>0.05). Compared with Sham group, the activity time at the target quadrant was significantly shortened, the escape latency was prolonged, the number of crossing the original platform was reduced, the contents of TNF-α, IL-1β and IL-18 were increased, the expression of ATG16L1 was down-regulated, and the expression of p62 and NLRP3 was up-regulated in SAE group ( P<0.05). Compared with SAE group, the escape latency was significantly shortened, the activity time at the target quadrant was prolonged, the number of crossing the original platform was increased, the contents of TNF-α, IL-1β and IL-18 were decreased, the expression of ATG16L1 was up-regulated, and the expression of p62 and NLRP3 was down-regulated in SAE+ EA group ( P<0.05). Compared with SAE+ EA group, no significant change was found in the parameters of Morris water maze test ( P>0.05), the contents of TNF-α, IL-1β and IL-18 were significantly decreased, the expression of ATG16L1 was up-regulated, and the expression of NLRP3 and P62 was down-regulated in SAE+ EA+ R group, and the expression of ATG16L1 was significantly down-regulated, and the expression of p62 and NLRP3 was up-regulated in SAE+ EA+ MA group ( P<0.05). Conclusions:The mechanism by which EA improves SAE is related to promotion of autophagy in hippocampal neurons, inhibition of NLRP3 inflammasome activation, and alleviation of neuroinflammatory responses in mice.

Objective:To construct and validate a prediction model for the risk of intermediate cesarean delivery for primiparous women with failed vaginal trial of labor.Methods:Clinical data of 6 128 pregnant women who gave birth in the Affiliated Hospital of Jining Medical College from January 2019 to December 2020 were collected. The puerpera was randomly divided into train set ( n=4 290) and validation set ( n=1 838). The factors influencing the conversion to cesarean section in primiparous women with failed vaginal trial of labor were analyzed with univariate and binary multivariate logistic regression, and a risk prediction model was established based on the influencing factors. The predictive power of the model was assessed by receiver operating characteristic (ROC) curve and the Hosmer-Lemeshow goodness-of-fit test in train set and validation set. Results:Among 6 128 pregnant women 1 042 cases failed in vaginal trial of labor and were transferred to cesarean section. Univariate analysis showed age, occupation, gestational weight gain, days of gestation, body temperature before delivery, fetal heart condition at delivery, fetal abdominal circumference, Bishop score, premature rupture of membranes, gestational illness, mode of induction of labor, labor analgesia, and fetal orientation were significantly associated with converting to cesarean delivery (all P<0.05). The multivariate binary logistic regression analysis showed that the age, gestational weight gain, body temperature, gestational co-morbidities, days of gestation, premature rupture of membranes, amniotic fluid contamination, induction of labor, and abnormal occipital position were independent risk factors for intermediate cesarean delivery ( OR=1.03-8.06, all P<0.05); while height, occupation, Bishop score, and labor analgesia were protective factors for intermediate cesarean delivery ( OR=0.17-0.96, all P<0.05). A risk prediction model was constructed based on the risk factors and protective factors. In train set, the area under the ROC curve(AUC) of the model was 0.902 (95% CI: 0.89-0.92, P<0.001), with the best cutoff value of 0.138, the sensitivity and specificity were 0.837 and 0.825, respectively; and the Hosmer-Lemeshow goodness-of-fit test showed P=0.192. In validation set the AUC of the model was 0.917 (95% CI: 0.90-0.93, P<0.001), and the sensitivity and specificity were 0.826 and 0.851, respectively; the total correct rate of the model was 87.21% (1 603/1 838). Conclusion:The risk prediction model of failed vaginal trial of labor in primiparous women for intermediate cesarean delivery constructed in this study has good clinical prediction efficacy and high correctness rate.

Objective:To investigate cases of delayed lactation initiation in women with transvaginal delivery and the influencing factors, in order to provide a basis for effective control of delayed lactation initiation and promotion of breastfeeding.Methods:Inpatients who were admitted to the obstetric ward of Affiliated Hospital of Jining Medical College from November 6, 2020 to January 16, 2021 were selected for the study using convenience sampling method and investigated by general information questionnaire and Chindbirth Experience Questionnaire (CEQ). Binary Logistic regression analysis was used to determine the factors influencing delayed lactation initiation.Results:The incidence of delayed lactation initiation in 622 women with transvaginal delivery was 38.75% (241/622). Binary Logistic regression analysis showed that age 20-35 years, full-term delivery, labor and delivery, use of labor analgesia, and good experience of transvaginal delivery were protective factors for delayed lactation initiation ( OR values were 0.012 to 0.868, all P<0.05); age >35 years, excessive weight gain during pregnancy, presence of pregnancy complications, use of induction of labor during delivery, long labor process, and damage to perineal skin after delivery were risk factors for delayed lactation initiation ( OR values were 1.097 to 13.235, all P<0.05). Conclusions:The high incidence of delayed lactation initiation in women with transvaginal delivery is influenced by a number of factors, which reminds the clinic that lactation in women after transvaginal delivery also needs to be taken into account, with priority assessment and prevention for those who are elderly (age≥35 years), primiparous, have other diseases during pregnancy, have gained too much weight during pregnancy, have preterm delivery, have a long duration of labor, have not received labor analgesia, have had a single or combined induction of labor, have had an episiotomy or perineal laceration during labor, and have a poor transvaginal delivery experience.

Objective:To evaluate the role of NIMA-related kinase 7 (NEK7)/Nod-like receptor family pyrin domain-containing protein 3 (NLRP3) signaling pathway in sepsis-associated encephalopathy in mice.Methods:A total of 150 healthy adult male C57BL/6 mice, aged 8-12 weeks, weighing 20-25 g, were divided into 5 groups ( n=30 each) by a random number table method: sham operation group (Sham group), sepsis group (CLP group), sepsis+ NLRP3 inhibitor MCC950 group (CLP+ MCC950 group), sepsis+ NEK7 siRNA group (CLP+ NEK7 siRNA group), and sepsis+ NC siRNA group (CLP+ NC siRNA group). Sepsis was induced by classic cecal ligation and puncture (CLP) in anesthetized animals.MCC950 10 mg/kg was intraperitoneally injected for 3 consecutive days after operation in CLP+ MCC950 group, while the equal volume of normal saline was given instead in Sham group.Immediately after operation and on 3rd day after operation, NEK7 siRNA 3 nmol/20 g was injected into the ventricle in CLP+ NEK7 siRNA group, and the equal dose of NC siRNA was injected into the ventricle instead in Sham group.The survival of mice was recorded on 4th postoperative day.On 4th and 7th days after operation, 10 mice in each group were selected for Y maze space recognition experiment.On 7th day after operation, 5 mice in each group were randomly sacrificed and hippocampal tissues were taken for determination of the contents of interleukin-1beta (IL-1β), interleukin-18 (IL-18) and tumor necrosis factor-alpha (TNF-α) (by enzyme-linked immunosorbent assay), and 6 mice in each group were sacrificed and hippocampal tissues were taken for determination of the expression of NEK7, NLRP3, cleaved-caspase-1 and apoptosis-associated speck-like protein containing a caspase-1 recruitment domain (ASC) (by Western blot). Results:The survival rates were 100%, 50%, 73%, 60% and 53% in Sham, CLP, CLP+ MCC950, CLP+ NEK7 siRNA, and CLP+ NC siRNA groups, respectively, on day 4 after surgery.Compared with Sham group, the frequency of entries into novel arm was significantly reduced, and the time spent in the novel arm was shortened at 4th and 7th days after operation, and the contents of IL-1β, IL-18 and TNF-α in hippocampus were increased, and the expression of NEK7, NLRP3, cleaved-caspase-1 and ASC was up-regulated at 7th day after operation in CLP group ( P<0.05). Compared with CLP group, the frequency of entries into novel arm was significantly increased, and the time spent in the novel arm was prolonged at 4th and 7th days after operation, and the contents of IL-1β, IL-18 and TNF-α in hippocampus were decreased at 7th day after operation in CLP+ MCC950 and CLP+ NEK7 siRNA groups, the expression of NLRP3, cleaved-caspase-1 and ASC was significantly down-regulated at 7th day after operation in CLP+ MCC950 group, the expression of NEK7, NLRP3, cleaved-caspase-1 and ASC was significantly down-regulated in CLP+ NEK7 siRNA group ( P<0.05), and no significant change was found in the parameters mentioned above in CLP+ NC siRNA group ( P>0.05). Conclusions:NEK7/NLRP3 signaling pathway is involved in SAE in mice, and the underlying mechanism may be related to promotion of inflammatory responses.

Cognitive impairment seriously affects the quality of life of patients. Clinically, it is common in cerebral ischemia, sepsis and postoperative. Its etiology includes abnormal expression of regulatory molecules in the brain, ischemic injury of brain tissue and abnormal expression of genes and proteins in brain tissues. However, there is no effective treatment at present. Electroacupuncture has a certain effect on cognitive impairment. Its mechanism mainly includes inhibiting oxidative stress response, enhancing synaptic plasticity, inhibiting neuroinflammation, regulating glial cell activity, regulating excitatory amino acids, and improving glucose metabolism.

Objective:To evaluate the efficacy of continuous infusion of lidocaine via urinary catheter for postoperative analgesia in patients undergoing urological surgery.Methods:Forty male American Society of Anesthesiologists physical status Ⅱ or Ⅲ patients, aged 65-75 yr, with body mass index of 18-25 kg/m 2, scheduled for elective percutaneous nephrolithotomy, were divided into 2 groups ( n=20 each) using a random number table method: continuous infusion of lidocaine through urinary catheter group (group L) and patient controlled intravenous analgesia (PCIA) group (group PCIA). All the patients underwent total intravenous anesthesia, and a matched type of sterile urethral irrigation catheter was inserted after the operation.In group L, 0.5% lidocaine was continuously infused at a rate of 5 ml/h via the urinary catheter, while the equal volume of 0.9% normal saline was continuously infused via the urinary catheter, and PCIA was connected in group PCIA.PCIA solution contained sufentanil 125 μg (diluted to 250 ml in normal saline), and the PCA pump was set up with a 5 ml bolus dose, a 15 min lockout interval and background infusion at a rate of 5 ml/h.When visual analogue score was>4, sufentanil 0.05 μg/kg was injected intravenously as rescue analgesic.The development and severity of catheter-related bladder discomfort (CRBD) were recorded immediately at the end of the operation (T 1), and at 6 h (T 2), 24 h (T 3) and 48 h (T 4) after the operation, respectively.Riker sedation-agitation scale (SAS) score was recorded at T 1, 2, and QoR-9 scale was recorded at T 3, 4.The concentrations of serum cortisol (Cor), norepinephrine (NE), epinephrine (E) and blood glucose (Glu) were measured by enzyme linked immunosorbent assay.First off-bed time, exhaust time, length of hospital stay after surgery, and the requirement for rescue analgesia and adverse reactions (nausea and vomiting, respiratory depression, hypotension, skin itching) within 48 h after the operation were recorded. Results:Compared with group PCIA, the incidence of CRBD and the severity were significantly decreased at T 1-4, SAS score was decreased at T 1, 2, QoR-9 score was increased at T 3, 4, Cor, NE, E and Glu concentrations were decreased at T 1-4, the incidence of postoperative rescue analgesia was decreased, first off-bed time, exhaust time and length of hospital stay after surgery was shortened, and the incidence of postoperative nausea and vomiting, respiratory depression, hypotension, skin itching was decreased in group L ( P<0.05). Conclusion:Continuous infusion of lidocaine through the urinary catheter can provide good postoperative analgesia, reduce postoperative stress response and adverse reactions, and facilitate early postoperative recovery in patients undergoing urological surgery.

Objective:To evaluate the effect of electroacupuncture (EA) on pyroptosis of hippocampal neurons in mice with sepsis-associated encephalopathy (SAE).Methods:Ninety male C57BL/6 mice, aged 8-12 weeks, weighing 22-25 g, were divided into 3 groups ( n=30 each) by a random number table method: sham operation group (Sham group), SAE group and EA treatment group (EA group). Sepsis model was established by cecal ligation and puncture in anesthetized animals.Bilateral acupoints Zusanli (ST36) were stimulated at 2, 24, 48 and 72 h after surgery in group EA.The survival was observed on day 7 after surgery.Cognitive function was assessed by Morris water maze.Then the animals were sacrificed, and hippocampal tissues were obtained for determination of the expression of nucleotide-binding oligomerization domain-like receptor protein 1 (NLRP1), cysteine-containing aspartate-specific protease 1 (caspase-1), and Gasdermin D (GSDMD) in hippocampal neurons (by Western blot) and content of activated caspase-1 (by enzyme-linked immunosorbent assay). Results:Compared with group Sham, the survival rate was significantly decreased, postoperative escape latency was prolonged, the activity time spent in the target quadrant was shortened, the number of crossing the original platform was decreased, the expression of NLRP1, caspase-1 and GSDMD was up-regulated, and the content of activated caspase-1 was increased in group SAE ( P<0.05). Compared with group SAE, the survival rate was significantly increased, postoperative escape latency was shortened, the activity time spent in the target quadrant was prolonged, the number of crossing the original platform was increased, the expression of NLRP1, caspase-1 and GSDMD was down-regulated, and the content of activated caspase-1 was decreased in group EA ( P<0.05). Conclusion:The mechanism by which EA reduces SAE may be related to inhibiting pyrolysis in hippocampal neurons of mice.