SHH induces macrophage oxidative phosphorylation and efferocytosis to promote scar formation.

Excessive scar formation such as hypertrophic scars and keloids, resulting from trauma or surgical procedures, present a widespread concern for causing disfigurement, discomfort, and functional limitations. Macrophages play pivotal roles in maintaining tissue homeostasis, orchestrating tissue development, repair, and immune responses, and its transition of function and phenotype plays a critical role in regulating the balance between inflammation and tissue regeneration, which is central to cutaneous scar formation. Recent evidence suggests the involvement of Sonic Hedgehog (SHH) in the induction of anti-inflammatory M2-like macrophage phenotypes within tumor microenvironments. In our study, we observed increased SHH expression in human hypertrophic scars, prompting an investigation into its influence on macrophage polarization, efferocytosis, and cutaneous scar formation. Our findings reveal that SHH can enhance oxidative phosphorylation (OXPHOS) in macrophages, augment macrophage efferocytosis, and promote M2 polarization, finally contributing to the progression of cutaneous scar formation. Notably, targeting SHH signaling with vismodegib exhibited promising potential in mitigating scar formation by reversing the effects of enhanced OXPHOS and M2 polarization in macrophages. In conclusion, this study underscores the critical roles of macrophage metabolism, particularly OXPHOS, efferocytosis and SHH signaling in cutaneous scar formation. Understanding these mechanisms provides new avenues for potential interventions and scar prevention strategies.

Hemoadsorption and Coagulation Systemic Rebalance in Patients Undergoing Nonelective Cardiac Surgery and Treated with Antithrombotics.

INTRODUCTION: Insufficient withdrawal duration of antithrombotics leads to excessive bleeding after major surgery. We hypothesize that intraoperative hemoadsorption (HA) can reduce postoperative allogeneic transfusion requirements and excessive bleeding events (EBE), without an increase in ischemic/thromboembolic events (ITE) in patients who have taken antithrombotics and undergone nonelective cardiac surgery. METHODS: A total of 460 patients admitted to our hospital from 2018 to 2022 were included in this study and divided into two groups: HA and non-HA. Because of the risk of bias due to differences in antithrombotic type, withdrawal duration, or basic coagulation function, propensity score matching was used for analyses. RESULTS: Out of 154 cases in the HA group, 144 pairs were successfully matched. No HA safety events such as hemolysis, hypotension, or device failure occurred. After matching, the two groups were found to be comparable in preoperative antithrombotic type, withdrawal duration, platelets and coagulation function, and demographic and perioperative characteristics. Although the HA group did not have a reduced incidence of EBE, this group exhibited significant decreases in the transfusion rate and volume, the incidence of ITE, acute kidney injury, and central nervous system injury. CONCLUSIONS: For patients who have undergone nonelective cardiac surgery and taken antithrombotics, HA can simply and safely rebalance the postoperative coagulation system and have associations with reduced transfusion and postoperative ITE.

Direct adenylation from 5'-OH-terminated oligonucleotides by a fusion enzyme containing Pfu RNA ligase and T4 polynucleotide kinase.

5'-Adenylated oligonucleotides (AppOligos) are widely used for single-stranded DNA/RNA ligation in next-generation sequencing (NGS) applications such as microRNA (miRNA) profiling. The ligation between an AppOligo adapter and target molecules (such as miRNA) no longer requires ATP, thereby minimizing potential self-ligations and simplifying library preparation procedures. AppOligos can be produced by chemical synthesis or enzymatic modification. However, adenylation via chemical synthesis is inefficient and expensive, while enzymatic modification requires pre-phosphorylated substrate and additional purification. Here we cloned and characterized the Pfu RNA ligase encoded by the PF0353 gene in the hyperthermophilic archaea Pyrococcus furiosus. We further engineered fusion enzymes containing both Pfu RNA ligase and T4 polynucleotide kinase. One fusion enzyme, 8H-AP, was thermostable and can directly catalyze 5'-OH-terminated DNA substrates to adenylated products. The newly discovered Pfu RNA ligase and the engineered fusion enzyme may be useful tools for applications using AppOligos.

Impact of resampling interpolation FIR filter in the practical Kramers-Kronig receiver.

The practical Kramers-Kronig (KK) receiver has been a competitive receiving technique in the data-center, medium reach, and even long-haul metropolitan networks. Nevertheless, an extra digital resampling operation is required at both ends of the KK field reconstruction algorithm due to the spectrum broadening caused by adopting the nonlinear function. Generally, the digital resampling function can be implemented by using linear interpolation (LI-ITP), the Lagrange cubic interpolation (LC-ITP), the spline cubic interpolation (SC-ITP), time-domain anti-aliasing finite impulse response (FIR) filter method (TD-FRM) scheme, and fast Fourier transform (FFT)-based scheme. However, the performance and the computational complexity analysis of different resampling interpolation schemes in the KK receiver have not been thoroughly investigated yet. Different from the interpolation schemes of conventional coherent detection, the interpolation function of the KK system is followed by the nonlinear operation, which will broaden the spectrum significantly. Due to the frequency-domain transfer function of different interpolation schemes, the broadened spectrum will have a potential spectrum aliasing, which will cause serious inter-symbol interference (ISI) and further impair the KK phase retrieval performance. We experimentally investigate the performance of different interpolation schemes under different digital up-sampling rates (i.e. the computational complexity) as well as the cut-off frequency, the tap number of the anti-aliasing filter, and the shape factor of the TD-FRM scheme in a 112-Gbit/s SSB DD 16-QAM system over 1920-km Raman amplification (RFA)-based standard single-mode fiber (SSMF). The experimental results involve that the TD-FRM scheme outperforms other interpolation schemes and the complexity is reduced by at least 49.6%. In fiber transmission results, take 20% soft decision-forward error correction (SD-FEC) of 2×10-2 as the threshold, the LI-ITP and LC-ITP schemes only reach 720-km while others can reach up to 1440-km.

Coexistence of 1 Tbps classical optical communication and quantum key distribution over a 100.96 km few-mode fiber.

The integration of quantum key distribution (QKD) and classical optical communication has attracted widespread attention. In this Letter, we experimentally demonstrate a real-time co-propagation of 1 Tbps for 10 classical channels with one discrete-variable QKD channel in the weakly coupled few-mode fiber (FMF). Based on the selection of optimal device parameters and wavelength assignment of classical channels, as well as the optimization of equipment performance, a secure key rate of as high as 2.7 kbps of coexistence transmission of QKD and classical optical communication can be achieved using a 100.96 km weakly coupled FMF. Therefore, this study is a step toward realizing long-distance quantum-classical coexistence transmission.

Prognostic potential of serum mesencephalic astrocyte-derived neurotrophic factor in acute intracerebral hemorrhage: a prospective observational study.

OBJECTIVE: Mesencephalic astrocyte-derived neurotrophic factor (MANF) expressions are dramatically up-regulated in injured brain tissues, thereby conferring neurological protective effects. We intended to determine significance of serum MANF as a prognostic biomarker of intracerebral hemorrhage (ICH). METHODS: In this prospective, observational study done from February 2018 to July 2021, 124 patients with new-onset primary supratentorial ICH were consecutively enrolled. Also, a group of 124 healthy individuals constituted controls. Their serum MANF levels were detected using the Enzyme-Linked Immunosorbent Assay. National Institutes of Health Stroke Scale (NIHSS) and hematoma volume were designated as the two severity indicators. Early neurologic deterioration (END) was referred to as an increase of 4 or greater points in NIHSS scores or death at post-stroke 24 h. Post-stroke 90-day modified Rankin scale (mRS) scores of 3-6 was considered as a poor prognosis. Serum MANF levels were analyzed using multivariate analysis with respect to its association with stroke severity and prognosis. RESULTS: Patients, in comparison to controls, displayed markedly elevated serum MANF levels (median, 24.7 versus 2.7 ng/ml; P < 0.001), and serum MANF levels were independently correlated with NIHSS scores (beta, 3.912; 95% confidence interval (CI), 1.623-6.200; VIF = 2.394; t = 3.385; P = 0.002), hematoma volumes (beta, 1.688; 95% CI, 0.764-2.612; VIF = 2.661; t = 3.617; P = 0.001) and mRS scores (beta, 0.018; 95% CI, 0.013-0.023; VIF = 1.984; t = 2.047; P = 0.043). Serum MANF levels significantly predicted END and poor 90-day prognosis with areas under receiver operating characteristic curve at 0.752 and 0.787 respectively. END and prognostic predictive abilities were similar between serum MANF levels and NIHSS scores plus hematoma volumes (all P > 0.05). Combination of serum MANF levels with NIHSS scores and hematoma volumes had significantly higher prognostic capability than each of them (both P < 0.05). Serum MANF levels above 52.5 ng/ml and 62.0 ng/ml distinguished development of END and poor prognosis respectively with median-high sensitivity and specificity values. Using multivariate analysis, serum MANF levels > 52.5 ng/ml predicted END with odds ratio (OR) value of 2.713 (95% CI, 1.004-7.330; P = 0.042) and > 62.0 ng/ml predicted a poor prognosis with OR value of 3.848 (95% CI, 1.193-12.417; P = 0.024). Using restricted cubic spline, there was a linear correlation between serum MANF levels and poor prognosis or END risk (both P > 0.05). Nomograms were well established to predict END and a poor 90-day prognosis. Under calibration curve, such combination models were comparatively stable (using Hosmer & Lemeshow test, both P > 0.05). CONCLUSION: Increased serum MANF levels after ICH, in independent correlation with disease severity, independently distinguished risks of END and 90-day poor prognosis. Therefore, serum MANF may be a potential prognostic biomarker of ICH.

Immune cell profiles of patients with interstitial cystitis/bladder pain syndrome.

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a disorder characterized by bladder pain upon filling which severely affects quality of life. Clinical presentation can vary. Local inflammatory events typify the clinical presentation of IC/BPS patients with Hunner lesions (IC/BPS-HL). It has previously been proposed that B cells are more prevalent in HL, but understanding their exact role in this environment requires a more complete immunological profile of HL. We characterized immunological dysfunction specifically in HL using immunohistochemistry. We detected significantly more plasma cells (50× increase, p < 0.0001), B cells (28× increase, p < 0.0001), T cells (3× increase, p < 0.0001), monocytes/macrophages (6× increase, p < 0.0001), granulocytes (4× increase, p < 0.0001), and natural killer cells (2× increase, p = 0.0249) in IC/BPS patients with HL than in unaffected controls (UC). Patients with IC/BPS-HL also had significantly elevated urinary levels of IL-6 (p = 0.0054), TNF-α (p = 0.0064) and IL-13 (p = 0.0304) compared to patients with IC/BPS without HL (IC/BPS-NHL). In contrast, IL-12p70 levels were significantly lower in the patients with HL than in those without these lesions (p = 0.0422). Different cytokines were elevated in the urine of IC/BPS patients with and without HL, indicating that different disease processes are active in IC/BPS patients with and without HL. Elevated levels of CD138+, CD20+, and CD3+ cells in HL are consistent B and T-cell involvement in disease processes within HL.

Paravertebral Block versus Thoracic Epidural Analgesia for Postthoracotomy Pain Relief: A Meta-Analysis of Randomized Trials.

OBJECTIVE: Paravertebral block (PVB) and thoracic epidural analgesia (TEA) are commonly used for postthoracotomy pain management. The purpose of this research is to evaluate the effects of TEA versus PVB for postthoracotomy pain relief. METHODS: A systematic literature search was conducted in PubMed, EMBASE, Web of Science, and the Cochrane Library (last performed on August 2020) to identify randomized controlled trials comparing PVB and TEA for thoracotomy. The rest and dynamic visual analog scale (VAS) scores, rescue analgesic consumption, the incidences of side effects were pooled. RESULTS: Sixteen trials involving 1,000 patients were included in this meta-analysis. The pooled results showed that the rest and dynamic VAS at 12, 24, and rest VAS at 48 hours were similar between PVB and TEA groups. The rescue analgesic consumption (weighted mean differences: 3.81; 95% confidence interval [CI]: 0.982-6.638, p < 0.01) and the incidence of rescue analgesia (relative risk [RR]: 1.963; 95% CI: 1.336-2.884, p < 0.01) were less in TEA group. However, the incidence of hypotension (RR: 0.228; 95% CI: 0.137-0.380, p < 0.001), urinary retention (RR: 0.392; 95% CI: 0.198-0.776, p < 0.01), and vomiting (RR: 0.665; 95% CI: 0.451-0.981, p < 0.05) was less in PVB group. CONCLUSION: For thoracotomy, PVB may provide no superior analgesia compared with TEA but PVB can reduce side effects. Thus, individualized treatment is recommended. Further study is still necessary to determine which concentration of local anesthetics can be used for PVB and can provide equal analgesic efficiency to TEA.

SIRT5 stabilizes mitochondrial glutaminase and supports breast cancer tumorigenesis.

The mitochondrial enzyme glutaminase (GLS) is frequently up-regulated during tumorigenesis and is being evaluated as a target for cancer therapy. GLS catalyzes the hydrolysis of glutamine to glutamate, which then supplies diverse metabolic pathways with carbon and/or nitrogen. Here, we report that SIRT5, a mitochondrial NAD+-dependent lysine deacylase, plays a key role in stabilizing GLS. In transformed cells, SIRT5 regulates glutamine metabolism by desuccinylating GLS and thereby protecting it from ubiquitin-mediated degradation. Moreover, we show that SIRT5 is up-regulated during cellular transformation and supports proliferation and tumorigenesis. Elevated SIRT5 expression in human breast tumors correlates with poor patient prognosis. These findings reveal a mechanism for increasing GLS expression in cancer cells and establish a role for SIRT5 in metabolic reprogramming and mammary tumorigenesis.

Clinical characteristics, treatment and outcomes of acute postpartum inflammatory sacroiliitis: a retrospective study.

PURPOSE: We performed this research to report the clinical characteristics and clinical therapeutic strategies of acute postpartum inflammatory sacroiliitis. METHODS: We retrospectively analyzed the data of patients diagnosed with acute postpartum inflammatory sacroiliitis from 2014 to 2020. All their clinical details including clinical symptoms and signs, laboratory tests, radiologic examination, diagnosis and treatment process and clinical outcomes were obtained and analyzed in this retrospective analysis. RESULTS: Eleven patients diagnosed with acute postpartum inflammatory sacroiliitis complain of low back pain. Magnetic resonance imaging (MRI) is useful in diagnosing acute postpartum inflammatory sacroiliitis. The systemic non-steroidal anti-inflammatory drugs (NSAIDs) administration, sacroiliac joint injection, and physical therapy effectively alleviated the pain with symptoms disappearing, and the abnormal signal reduced in MRI. CONCLUSION: Acute postpartum inflammatory sacroiliitis is an uncommon disease with atypical symptoms. MRI examination may be the best diagnostic method. General NSAIDs and sacroiliac joint injections of local anesthetic plus corticosteroid under the guidance of fluoroscopy or ultrasound can achieve safe and effective treatment. This retrospective study was approved by the Committee on the Ethics of our hospital (No. 202101023). TRIAL REGISTRY: Trial registration was performed in the Chinese Clinical Trial Registry ( http://www.chictr.org.cn , No. ChiCTR2100045656).

Application of retrograde cerebral perfusion in aortic root replacement combined with right half aortic arch replacement. / é€†è¡Œè„‘çŒæ³¨åœ¨ä¸»åŠ¨è„‰æ ¹éƒ¨å’Œå³åŠå¼“ç½®æ¢æ‰‹æœ¯ä¸­çš„åº”ç”¨.

OBJECTIVES: After cardiac surgery involving the aortic arch, the incidence of neurological complications remains high, therefore it is very important to take measures to protect brain. This study is to investigate the safety and effectiveness of deep hypothermic circulatory arrest and retrograde cerebral perfusion for aortic root combined with right half aortic arch replacement. METHODS: Clinical data of 31 patients, who underwent aortic root and right half aortic arch replacement with deep hypothermic circulatory arrest and retrograde cerebral perfusion in Xiangya Hospital, Central South University, were retrospectively analyzed. This cohort included 23 aortic aneurysms and 8 aortic dissections. Aortic root replacement was conducted in 26 patients by Bentall procedures, and 5 patients by David procedures. Time of deep hypothermic circulatory arrest and retrograde cerebral perfusion in surgery was (21.9±5.2) min. The in-hospital mortality, postoperative neurological dysfunction and other major adverse complications were observed and recorded. RESULTS: No in-hospital death and permanent neurological dysfunction occurred. Two patients had transient neurological dysfunction and 2 patients with aortic dissection requiring long-time ventilation due to hypoxemia, 1 patient underwent resternotomy. During 6-36 months of follow-up, all patients recovered satisfactorily. CONCLUSIONS: Deep hypothermic circulatory arrest and retrograde cerebral perfusion can be safely and effectively applied in aortic root and right half aortic arch replacement, and which can simplify the surgical procedures and be worth of clinical promotion.

Del Nido versus HTK cardioplegia for myocardial protection during adult complex valve surgery: a retrospective study.

BACKGROUND: Histidine-tryptophan-ketoglutarate (HTK) and del Nido (DN) cardioplegia are intracellular-type and extracellular-type solution respectively, both can provide a long period of myocardial protection with single-dose infusion, but studies comparing the two are rare for adult cardiac surgery. This study aims to evaluate whether DN is suitable for cardioplegia in complex and high-risk valve surgery with long-term cardiac ischemia when compared with HTK. METHODS: The perioperative records of adult patients infused with DN/HTK as a cardioplegic solution who underwent complex valve surgery with an expected myocardial ischaemic duration longer than 90 min between Oct 2018 and Oct 2019 were analysed retrospectively. RESULTS: Of the 160 patients who received DN/HTK and underwent complex valve surgery, we propensity matched 73 pairs. Both groups achieved satisfactory cardiac arrest effects, and no significant difference was found in their cTnI and CK-MB levels within 12 to 72 h postoperatively. The DN group had a higher rate of return to spontaneous rhythm (0.88 v 0.52, P < 0.001), a lower frequency of postoperative severe arrythmias (12% v 26%, P = 0.036), a higher postoperative stroke volume (65 v 59 ml, P = 0.011) and a higher cardiac output (6.0 v 4.9 L/min, P = 0.007) as evaluated by echocardiography, fewer transfusions and shorter ICU stays (both P < 0.05). The two groups had similar inotrope usage and similar incidences of low cardiac output, morbidities and mortality. Subgroup analysis showed that when the aortic clamping time was greater than 120 min, the advantages of DN were weakened. CONCLUSIONS: DN can be safely applied to complex valve surgery, and it has a similar myocardial protection effect as HTK. Further prospective studies are required to verify these retrospective findings. Trial registration retrospectively registered.

The Programmed Cell Death Ligand-1/Programmed Cell Death-1 Pathway Mediates Pregnancy-Induced Analgesia via Regulating Spinal Inflammatory Cytokines.

BACKGROUND: The maternal pain threshold gradually increases during pregnancy, especially in late pregnancy. A series of mechanisms underlying pregnancy-induced analgesia have been reported. However, these mechanisms are still not completely clear, and the underlying molecular mechanisms need further investigation. We examined the relationship between the antinociceptive effect and the expression level of programmed cell death ligand-1 (PD-L1) during pregnancy and further observed the changes in pain thresholds and expression levels of cytokines in late-pregnant mice before and after blockade of PD-L1 or programmed cell death-1 (PD-1). METHODS: Part 1: Female mice were assigned to 3 groups (nonpregnant, late-pregnant, and postpartum). Part 2: Late-pregnant mice were assigned to 3 treatment groups (control [phosphate buffer solution], RMP1-14 [mouse anti-PD-1 antibody], and soluble PD-1 [sPD-1]). Behavioral testing (mechanical and thermal) and tissue (serum and spinal cord) analysis were performed on all groups. PD-L1, interleukin (IL)-10, tumor necrosis factor-α (TNF-α), and IL-6 expression levels in tissue were examined via reverse transcription-polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), and Western blot analysis. RESULTS: The mechanical and thermal pain thresholds were significantly increased in late pregnancy and decreased after delivery. PD-L1 expression was also elevated in late pregnancy and decreased after delivery. In addition, in the late stage of gestation, the maternal inflammatory microenvironment was dominated by anti-inflammatory factors. After administration of RMP1-14 or sPD-1, the pain thresholds of late-pregnant mice were significantly reduced. In late-pregnant mice, the high level of IL-10 was obviously reduced, and the low levels of TNF-α and IL-6 were elevated. CONCLUSIONS: The PD-L1/PD-1 pathway mediates pregnancy-induced analgesia, partially via the regulation of cytokines.

Treatment of thoracoabdominal aortic aneurysm by prosthetic vessel replacement under left heart bypass. / å·¦å¿ƒè½¬æµä¸‹äººå·¥è¡€ç®¡ç½®æ¢æœ¯æ²»ç–—èƒ¸è ¹ä¸»åŠ¨è„‰ç˜¤.

OBJECTIVES: Thoracoabdominal aortic aneurysm (TAAA) prosthetic vessel replacement is one of the most complex operations in the field of cardiovascular surgery. The key to success of this operation is to prevent and avoid ischemia of important organs while repairing TAAA. This study aims to summarize and analyze the effect of prosthetic vessel replacement under left heart bypass in the treatment of TAAA. METHODS: Data of 15 patients with TAAA who underwent prosthetic vessel replacement under left heart bypass in Xiangya Hospital of Central South University were retrospectively analyzed. According to Crawford classification, there were 2 cases of type I, 8 cases of type II, 3 cases of type III, and 2 cases of type V. There were 14 cases of selective operation and 1 case of emergency operation. All operations were performed under left heart bypass, and cerebrospinal fluid drainage was performed before operation. Left heart bypass was established by intubation of left inferior pulmonary vein and distal abdominal aorta or left femoral artery. The thoracoabdominal aorta was replaced segment by segment. After aortic dissection, the kidneys were perfused with cold crystalloid renal protective solution, and the celiac trunk and superior mesenteric artery were perfused with warm blood. RESULTS: One patient with TAAA after aortic dissection of type A died. During the operation, straight blood vessels were used to repair TAAA, and the celiac artery branches were trimmed into island shape and anastomosed with prosthetic vessels. After the operation, massive bleeding occurred at the anastomotic stoma, then anaphylactic reaction occurred during massive blood transfusion, resulting in death. One patient suffered from paraplegia due to ischemic injury of spinal cord. The other patients recovered well and were discharged. The postoperative ventilation time was (16.5±13.8) h and the postoperative hospital stay was (10±4) d. The amount of red blood cell transfusion was (13±9) U. The patients were followed up for 2 months to 2 years, and the recovery was satisfactory. CONCLUSIONS: The effect of prosthetic vessel replacement under left heart bypass in the treatment of TAAA is good, which is worthy of clinical promotion.

A systematic evaluation of stool DNA preparation protocols for colorectal cancer screening via analysis of DNA methylation biomarkers.

Objectives: Colorectal cancer (CRC) screening using stool samples is now in routine use where tumor DNA methylation analysis for leading markers such as NDRG4 and SDC2 is an integral part of the test. However, processing stool samples for reproducible and efficient extraction of human genomic DNA remains a bottleneck for further research into better biomarkers and assays. Methods: We systematically evaluated several factors involved in the processing of stool samples and extraction of DNA. These factors include: stool processing (solid and homogenized samples), preparation of DNA from supernatant and pellets, and DNA extraction with column and magnetic beads-based methods. Furthermore, SDC2 and NDRG4 methylation levels were used to evaluate the clinical performance of the optimal protocol. Results: The yield of total and human genomic DNA (hgDNA) was not reproducible when solid stool scraping is used, possibly due to sampling variations. More reproducible results were obtained from homogenized stool samples. Magnetic beads-based DNA extraction using the supernatant from the homogenized stool was chosen for further analysis due to better reproducibility, higher hgDNA yield, lower non-hgDNA background, and the potential for automation. With this protocol, a combination of SDC2 and NDRG4 methylation signals with a linear regression model achieved a sensitivity and specificity of 81.82 and 93.75%, respectively. Conclusions: Through the systematic evaluation of different stool processing and DNA extraction methods, we established a reproducible protocol for analyzing tumor DNA methylation markers in stool samples for colorectal cancer screening.

Detection techniques of carboxylesterase activity: An update review.

Mammalian carboxylesterases (CESs) are essential members of serine esterase hydrolase superfamily, which are widely distributed in many tissues including liver, intestine, lung and kidney. CESs play an important role in the metabolism of various xenobiotics including ester drugs and environmental toxicants, and also participate in lipid homeostasis, so the development of CESs activity detection techniques are of great significance for drug discovery and biomedical research. With the rapid development of separated and detection technologies such as chromatography, capillary electrophoresis, fluorescent probe-based detection technology, bioluminescent sensor and colorimetric sensor in recent decade, the research of physiological functions of CESs have make huge breakthrough. This review summarizes the development and application of CESs activity detection techniques, as well as comparatively analyzes the characteristics of various detection techniques. The information and knowledge represented here will help the researchers carry out various biochemical studies for understanding activation mechanism and role of CESs in drug metabolism.

Efficacy of caudal vs intravenous administration of α2 adrenoceptor agonists to prolong analgesia in pediatric caudal block: A systematic review and meta-analysis.

BACKGROUND: α2 adrenoceptor agonists have been proposed as adjuncts to prolong analgesia in pediatric caudal block. The aim of this meta-analysis was to compare the analgesic efficacy of caudal vs intravenous α2 adrenoceptor agonists during pediatric caudal block. METHODS: A systematic search, data extraction, bias risk assessment, and pooled data analysis were performed following the PRISMA guidelines. All randomized controlled trials comparing caudal with intravenous α2 adrenoceptor agonists in pediatric caudal block were included. Relative risk and weighted mean differences (the corresponding 95% confidence intervals) were calculated for dichotomous and continuous data, respectively. Trial sequential analyses were performed to evaluate the credibility of the meta-analysis. RESULTS: A total of 244 patients in five trials were identified. Compared with the intravenous group (9.56 ± 4.23 hours), the time to the first rescue analgesia was prolonged in the caudal α2 adrenoceptor agonists group (12.72 ± 5.99 hours) by a weighted mean difference of 2.98 hours [95% confidence interval: 0.59-5.36 hours; P = .01]. The number of children requiring rescue analgesia in the caudal group (64, 66.67%) was lower than that in the intravenous group (80, 81.63%) [relative risk = 0.82; 95% confidence interval: 0.69-0.97; P = .02]. These findings were also verified by trial sequential analysis. There were no significant differences in the side effects. CONCLUSION: Caudal α2 adrenoceptor agonists as adjuncts to local anesthetic during pediatric caudal block are more effective than intravenous injection. However, the results were affected by small sample size and significant heterogeneity.

A Red Emissive Fluorescent Turn-on Sensor for the Rapid Detection of Selenocysteine and Its Application in Living Cells Imaging.

The content of selenocysteine in cells has an important effect on a variety of human diseases, and the detection of selenocysteine by fluorescent sensors in vivo has shown many advantages. In order to further develop fast-reaction-time, good-selectivity, and high-sensitivity long-wavelength selenocysteine fluorescent sensors, we designed and synthesized the compound YZ-A4 as a turn-on fluorescent sensor to detect the content of selenocysteine. The quantitative detection range of the sensor YZ-A4 to selenocysteine was from 0 to 32 µM, and the detection limit was as low as 11.2 nM. The sensor displayed a rapid turn-on response, good selectivity, and high sensitivity to selenocysteine. Finally, we have demonstrated that YZ-A4 could be used for fluorescence imaging of selenocysteine in living cells.

A FRET-ICT Dual-Modulated Ratiometric Fluorescence Sensor for Monitoring and Bio-Imaging of Cellular Selenocysteine.

Since the fluctuation of cellular selenocysteine (Sec) concentration plays an all-important role in the development of numerous human disorders, the real-time fluorescence detection of Sec in living systems has attracted plenty of interest during the past decade. In order to obtain a faster and more sensitive small organic molecule fluorescence sensor for the Sec detection, a new ratiometric fluorescence sensor Q7 was designed based on the fluorescence resonance energy transfer (FRET) strategy with coumarin fluorophore as energy donor and 4-hydroxy naphthalimide fluorophore (with 2,4-dinitrobenzene sulfonate as fluorescence signal quencher and Sec-selective recognition site) as an energy acceptor. The sensor Q7 exhibited only a blue fluorescence signal, and displayed two well distinguished emission bands (blue and green) in the presence of Sec with ∆λ of 68 nm. Moreover, concentrations ranging of quantitative detection of Sec of Q7 was from 0 to 45 µM (limit of detection = 6.9 nM), with rapid ratiometric response, high sensitivity and selectivity capability. Impressively, the results of the living cell imaging test demonstrated Q7 has the potentiality of being an ideal sensor for real-time Sec detection in biosystems.

Characterization of the interactions of potent allosteric inhibitors with glutaminase C, a key enzyme in cancer cell glutamine metabolism.

Altered glycolytic flux in cancer cells (the "Warburg effect") causes their proliferation to rely upon elevated glutamine metabolism ("glutamine addiction"). This requirement is met by the overexpression of glutaminase C (GAC), which catalyzes the first step in glutamine metabolism and therefore represents a potential therapeutic target. The small molecule CB-839 was reported to be more potent than other allosteric GAC inhibitors, including the parent compound bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl (BPTES), and is in clinical trials. Recently, we described the synthesis of BPTES analogs having distinct saturated heterocyclic cores as a replacement for the flexible chain moiety, with improved microsomal stability relative to CB-839 and BPTES. Here, we show that one of these new compounds, UPGL00004, like CB-839, more potently inhibits the enzymatic activity of GAC, compared with BPTES. We also compare the abilities of UPGL00004, CB-839, and BPTES to directly bind to recombinant GAC and demonstrate that UPGL00004 has a similar binding affinity as CB-839 for GAC. We also show that UPGL00004 potently inhibits the growth of triple-negative breast cancer cells, as well as tumor growth when combined with the anti-vascular endothelial growth factor antibody bevacizumab. Finally, we compare the X-ray crystal structures for UPGL00004 and CB-839 bound to GAC, verifying that UPGL00004 occupies the same binding site as CB-839 or BPTES and that all three inhibitors regulate the enzymatic activity of GAC via a similar allosteric mechanism. These results provide insights regarding the potency of these inhibitors that will be useful in designing novel small-molecules that target a key enzyme in cancer cell metabolism.