Effect of different surgical techniques on postoperative wound infection in patients with uterine prolapse: A meta-analysis.

The assumption is that a number of controlled trials have been conducted to assess the impact of uterus retaining or hysterectomy on wound and haemorrhage, but there is no indication as to which method would be more beneficial for wound healing. This research is intended to provide a comprehensive overview of the availability of wound healing in case studies of both operative methods. From inception to October 2023, four databases were reviewed. The odds ratio (OR) and the mean difference (MD) for both groups were computed with a random effect model, as well as the corresponding 95% confidence intervals. A total of five studies were carried out in the overall design and enrolled 16 972 patients. No statistical significance was found in the rate of postoperative wound infection among the two treatments (OR,1.46; 95% CI,0.66,3.22 p = 0.35); The rates of bleeding after surgery did not differ significantly from one procedure to another (OR,1.41; 95% CI,0.91,2.17 p = 0.12); two studies demonstrated no statistical significance for the rate of incisional hernia after surgery (OR,2.58; 95% CI,0.37,18.05 p = 0.34). Our findings indicate that there is a similar risk between uterine preservation and hysterectomies for the incidence of wound infection, haemorrhage and protrusion of incision.

Research on atrial fibrillation mechanisms and prediction of therapeutic prospects: focus on the autonomic nervous system upstream pathways.

Atrial fibrillation (AF) is the most common clinical arrhythmia disorder. It can easily lead to complications such as thromboembolism, palpitations, dizziness, angina, heart failure, and stroke. The disability and mortality rates associated with AF are extremely high, significantly affecting the quality of life and work of patients. With the deepening of research into the brain-heart connection, the link between AF and stroke has become increasingly evident. AF is now categorized as either Known Atrial Fibrillation (KAF) or Atrial Fibrillation Detected After Stroke (AFDAS), with stroke as the baseline. This article, through a literature review, briefly summarizes the current pathogenesis of KAF and AFDAS, as well as the status of their clinical pharmacological and non-pharmacological treatments. It has been found that the existing treatments for KAF and AFDAS have limited efficacy and are often associated with significant adverse reactions and a risk of recurrence. Moreover, most drugs and treatment methods tend to focus on a single mechanism pathway. For example, drugs targeting ion channels primarily modulate ion channels and have relatively limited impact on other pathways. This limitation underscores the need to break away from the "one disease, one target, one drug/measurement" dogma for the development of innovative treatments, promoting both drug and non-drug therapies and significantly improving the quality of clinical treatment. With the increasing refinement of the overall mechanisms of KAF and AFDAS, a deeper exploration of physiological pathology, and comprehensive research on the brain-heart relationship, it is imperative to shift from long-term symptom management to more precise and optimized treatment methods that are effective for almost all patients. We anticipate that drugs or non-drug therapies targeting the central nervous system and upstream pathways can guide the simultaneous treatment of multiple downstream pathways in AF, thereby becoming a new breakthrough in AF treatment research.

One-Step Platform for Maduramicin and Salinomycin Detection Based on Bispecific Monoclonal Antibody and Interpretation of Molecular Recognition Mechanism.

Maduramicin (MAD) and salinomycin (SAL) are the widely used poly(ether ionophore) antibiotics to control coccidiosis in animals. Due to their strong cytotoxicity, strict control over their dosage and residue in animal food is necessary. To improve the detection efficiency of the existing single-residue detection methods, a tetraploid tumor hybrid system was constructed using drug mutagenesis, and the bispecific monoclonal antibody (BsMAb) against MAD and SAL was obtained by hybridization-hybridoma technology. By optimizing the optimal working concentration of the tracer and antibody, a multiresidue fluorescence polarization immunoassay method based on BsMAb was successfully established. The whole detection process takes 10 min, and the LOD values of MAD and SAL were 4.71 and 3.49 ng·g-1, respectively. IC50 values were 6.45 and 6.24 ng·mL-1, respectively. There was no cross-reactivity with other polyether ionophore antibiotics. Finally, a breakthrough in detection was achieved: bispecific monoclonal antibody prepared by the hybridization-hybridoma technology was used to detect maduramicin and salinomycin.

Research Progress on the Mechanisms of Central Post-Stroke Pain: A Review.

Central Post-Stroke Pain (CPSP) is a primary sequelae of stroke that can develop in the body part corresponding to the cerebrovascular lesion after stroke, most typically after ischemic stroke but also after hemorrhagic stroke. The pathogenesis of CPSP is currently unknown, and research into its mechanism is ongoing. To summarize current research on the CPSP mechanism and provide guidance for future studies. Use "central post-stroke pain," "stroke AND thalamic pain," "stroke AND neuropathic pain," "post-stroke thalamic pain" as the search term. The search was conducted in the PubMed and China National Knowledge Infrastructure databases, summarizing and classifying the retrieved mechanism studies. The mechanistic studies on CPSP are extensive, and we categorized the included mechanistic studies and summarized them in terms of relevant pathway studies, relevant signals and receptors, relevant neural tissues, and described endoplasmic reticulum stress and other relevant studies, as well as summarized the mechanisms of acupuncture treatment. Studies have shown that the pathogenesis of CPSP involves the entire spinal-thalamo-cortical pathway and that multiple substances in the nervous system are involved in the formation and development of CPSP. Among them, the relevant receptors and signals are the hotspot of research, and the discovery and exploration of different receptors and signals have provided a wide range of therapeutic ideas for CPSP. As a very effective treatment, acupuncture is less studied regarding the analgesic mechanism of CPSP, and further experimental studies are still needed.

Development of a detection method for 10 non-steroidal anti-inflammatory drugs residues in four swine tissues by ultra-performance liquid chromatography with tandem mass spectrometry.

The ultra-performance liquid chromatography with tandem mass spectrometry (UPLC-MS/MS) detection method was developed for the residues of 10 NSAIDs (salicylic acid, acetylsalicylic acid, acetaminophen, diclofenac, tolfenamic acid, antipyrine, flunixin meglumine, aminophenazone, meloxicam, metamizole sodium) in swine muscle, liver, kidney, and fat. Swine tissue samples were extracted by phosphorylated acetonitrile with the addition of an appropriate amount of internal standard working solution, defatted with acetonitrile-saturated n-hexane, and purified by Hydrophile-Lipophile Balance (HLB) solid-phase extraction column, then separated by UPLC BEH shield RP18 column with 0.1% formic acid in water/0.1% formic acid in acetonitrile with gradient elution, which was detected in the multiple reaction monitoring (MRM) modes. The correlation coefficient of the standard curve equation is greater than 0.99, and the coefficient of variation within and between batches is less than 14.4%. We evaluated the analytical method using two green assessment tools. The method established in this study met the requirements of NSAID residue analysis and provides analytical tools for determining and confirming NSAIDs in swine tissue samples. This is the first report on the simultaneous determination of 10 NSAIDs in four swine tissues by the UPLC-MS/MS method and accurate quantification using deuterated internal standards.

Detection of salinomycin and lasalocid in chicken liver by icELISA based on functional bispecific single-chain antibody (scDb) and interpretation of molecular recognition mechanism.

Salinomycin (SAL) and lasalocid (LAS) are widely used as ionophore antibiotics for coccidiosis control. However, their common use as feed additives has led to the occurrence of feed cross-contamination, which has toxic effects on non-target animals. There have been few reports on multiple-residue detection for SAL and LAS in recent years. In this study, two single-chain antibody fragments (scFvs) capable of specifically recognizing SAL and LAS were constructed. Using LAS-scFv and SAL-scFv as parent antibodies, a complete bispecific single-chain diabody (scDb) against both LAS and SAL was built using splicing by overlap extension polymerase chain reaction (SOE-PCR). In addition, the key amino acid sites and interaction energy of antibody variable regions for small-molecule recognition were preliminarily studied by homology modeling and molecular docking. Finally, IC50 values of 12.9 and 8.6 ng/mL, with a linear range of 6.9-24.0 and 4.7-16.0 ng/mL, were obtained for LAS-scFv and SAL-scFv, respectively. An indirect competitive enzyme-linked immunosorbent assay (icELISA) method was established using scDb to obtain an IC50 of 3.5 ng/mL for LAS and 4.1 ng/mL for SAL, which showed better sensitivity and specificity than those of the parent scFv antibodies. The recoveries of LAS and SAL in chicken liver were 89.2-92.7%(CV<4.7%) and 88.6-90.2% (CV<6.8%)), respectively.

Analysis of the application of "psycho-cardiology" model in nursing care of acute stroke patients with depression.

OBJECTIVE: To evaluate the effect of "psycho-cardiology" model in nursing care of acute stroke patients with depression. METHODS: Seventy-eight acute stroke patients with depression were selected for this prospective study, and they were divided into two groups according to the random number table method. The control group (n=39) were given usual care, and the study group (n=39) were given nursing intervention of "psycho-cardiology" model in addition to usual care. The changes of mental state (Hamilton Depression Scale, HAMD; Hamilton Anxiety Scale, HAMA), the neurological function (National Institute of Health Stroke scale, NIHSS), and the cognitive function (Mini-Mental State Examination, MMSE), the prognostic indicator (Fugl-Meyer Assessment, FMA; Barthel Index, BI) were compared between the two groups before and after the intervention. The incidence of complications and nursing satisfaction were also compared between the two groups. RESULTS: After nursing, the scores of HAMA and HAMD in the study group were significantly lower than those in the control group (P<0.05). The NIHSS score of the study group was significantly lower than that of the control group (P<0.05). The score of MMSE in the study group was significantly higher than that of the control group (P<0.05). The scores of FMA and BI in the study group were significantly higher than those of the control group (P<0.05). There was no significant difference in the incidence of complications between the two groups (P>0.05). The nursing satisfaction of the study group was significantly higher than that of the control group (P<0.05). CONCLUSION: Nursing intervention of "psycho-cardiology" model for acute stroke patients with depression can effectively alleviate the mental stress of patients, improve neurological function and cognitive function, reduce the occurrence of complications, improve prognosis and nursing satisfaction.

Enterobacter cloacae infection of the shoulder in a 52-year-old woman without apparent predisposing risk factor: a case report and literature review.

BACKGROUND: Enterobacter cloacae (E. cloacae) is one of the commensal flora in the human intestinal tract and a prevalent nosocomial pathogen, which rarely causes infectious osteoarthritis in immunocompetent patients without recent trauma or surgery. Here, we report the first case of septic monoarthritis of the shoulder caused by E. cloacae in an immunocompetent patient. CASE PRESENTATION: A 52-year-old female with a 6-year history of right shoulder pain was referred to our emergency department due to fever, acute severe shoulder pain, and swelling. Blood test showed elevated inflammatory markers. The patient denied any recent invasive surgical procedure and trauma. She was misdiagnosed with a frozen shoulder, and the anti-inflammatory painkiller celecoxib for symptomatic treatment was ineffective. Magnetic resonance imaging (MRI) showed a shoulder joint abscess and supraspinatus tendon tear. The joint aspirate culture showed E. cloacae. After late diagnosis, she was treated with levofloxacin and underwent surgical debridement and irrigation. Her follow-up data revealed that she did not suffer from shoulder swelling and severe pain. CONCLUSION: This is a rare case of E. cloacae infected arthritis of the shoulder in an immunocompetent patient with a rotator cuff tear, indicating that even if the symptoms and age of the patients match the characteristics of frozen shoulder, the possibility of septic arthritis should be considered in the presence of fever and increasing inflammatory markers. The cases of our literature review suggest that the patients subjected to invasive procedure may develop a subsequent E. cloacae osteoarticular infection, regardless of being asymptomatic after the procedure.

Discovery of 3-Quinazolin-4(3H)-on-3-yl-2,N-dimethylpropanamides as Orally Active and Selective PI3Kα Inhibitors.

Phosphoinositide 3-kinases (PI3Ks) mediate a series of events related to cell growth, proliferation, survival, and differentiation. Overexpression of PI3Ks can lead to the dysregulation of cell homeostasis and cause tumorigenesis. In this study, rationally designed compounds were investigated as PI3Kα-selective inhibitors. Our efforts culminated in the discovery of a series of quinazolin-4(3H)-one derivatives with 2-substituted-N-methylpropanamide substitutions as PI3Kα-selective inhibitors. The best compound, 10, has PI3Kα enzymatic and cellular IC50 values of 1.8 and 12.1 nM, respectively. It exhibits biochemical selectivities for PI3Kα over PI3Kß/δ/γ of 150/7.72/7.67-fold and cellular selectivities of 115/15.1/>826-fold, respectively. Compound 10 is 59% orally bioavailable with a dose-normalized AUC of 3090 nM. These effects translated into in vivo conditions, as 10 significantly time- and dose-dependently inhibited phosphorylation of Akt in BT-474 subcutaneous xenograft mice and inhibited tumor growth.

Recent advances in the structure-based and ligand-based design of IKKß inhibitors as anti-inflammation and anti-cancer agents.

NF-κB is a significant transcription factor that regulates the expression of various pro-survival genes. IKK is a crucial protein kinase that activates NF-κB translocating from cytoplasm to nucleus for DNA binding. It is composed of three subunits, IKKα, IKKß, IKKγ (NEMO), where IKKα and IKKß are catalytic subunits, and IKKγ is the regulatory subunit. Many diseases, such as Hodgkin's disease, Hepatitis-associated hepatocellular carcinoma, colorectal cancer, prostate cancer, rheumatoid arthritis and inflammatory bowel disease, are related to IKK and NF-κB. So far, various IKK inhibitors targeting the ATP binding site have been identified through high throughput screening, rational design or in silico methods, however, only three of them (CHS-828, EB-1627 and IMD-1041) have been under clinical studies, indicating the strategy for the design of IKK inhibitors need to be reinspected. Besides ATP-competitive inhibitors, several other inhibitors have also been disclosed recently, which provide novel concepts to the discovery of IKK inhibitors. In this review, we focus on two parts: 1) the chemotypes and binding patterns of the traditional ATP-competitive IKK inhibitors; 2) novel strategies for the identification of non-ATP-competitive IKK inhibitors as NF-κB modulators. Through these discussions we hope to present inspirations for the development of new IKK inhibitors.

Insights into targeting NEMO for pharmacological regulation.

NF-κB essential modulator (NEMO), the non-catalytic regulatory subunit of the IκB kinase (IKK) complex, is essential for the canonical NF-κB activation pathway. It has been identified as a molecular platform for assembling the IKK complex and recruiting upstream IKK activators. However, the exact mechanism for regulating IKK activity has still remained elusive. This review describes structural and functional characteristics of NEMO protein, covers the feasible polyubiquitin-mediated NEMO-dependent IKK complex activation mechanism, and briefly summarizes some proteins that bind to NEMO for enhancing or suppressing IKK complex activity. Furthermore, it also discusses several bioactive compounds that disrupt the protein-protein interactions (PPI) involving NEMO, as these PPI may act as alternative routes to develop novel pharmacological agents for inflammation and cancer therapy.

Insight into the intermolecular recognition mechanism between Keap1 and IKKß combining homology modelling, protein-protein docking, molecular dynamics simulations and virtual alanine mutation.

Degradation of certain proteins through the ubiquitin-proteasome pathway is a common strategy taken by the key modulators responsible for stress responses. Kelch-like ECH-associated protein-1(Keap1), a substrate adaptor component of the Cullin3 (Cul3)-based ubiquitin E3 ligase complex, mediates the ubiquitination of two key modulators, NF-E2-related factor 2 (Nrf2) and IκB kinase ß (IKKß), which are involved in the redox control of gene transcription. However, compared to the Keap1-Nrf2 protein-protein interaction (PPI), the intermolecular recognition mechanism of Keap1 and IKKß has been poorly investigated. In order to explore the binding pattern between Keap1 and IKKß, the PPI model of Keap1 and IKKß was investigated. The structure of human IKKß was constructed by means of the homology modeling method and using reported crystal structure of Xenopus laevis IKKß as the template. A protein-protein docking method was applied to develop the Keap1-IKKß complex model. After the refinement and visual analysis of docked proteins, the chosen pose was further optimized through molecular dynamics simulations. The resulting structure was utilized to conduct the virtual alanine mutation for the exploration of hot-spots significant for the intermolecular interaction. Overall, our results provided structural insights into the PPI model of Keap1-IKKß and suggest that the substrate specificity of Keap1 depend on the interaction with the key tyrosines, namely Tyr525, Tyr574 and Tyr334. The study presented in the current project may be useful to design molecules that selectively modulate Keap1. The selective recognition mechanism of Keap1 with IKKß or Nrf2 will be helpful to further know the crosstalk between NF-κB and Nrf2 signaling.

Discovery and design of tricyclic scaffolds as protein kinase CK2 (CK2) inhibitors through a combination of shape-based virtual screening and structure-based molecular modification.

Protein kinase CK2 (CK2), a ubiquitous serine/threonine protein kinase for hundreds of endogenous substrates, serves as an attractive anticancer target. One of its most potent inhibitors, CX-4945, has entered a phase I clinical trial. Herein we present an integrated workflow combining shape-based virtual screening for the identification of novel CK2 inhibitors. A shape-based model derived from CX-4945 was built, and the subsequent virtual screening led to the identification of several novel scaffolds with high shape similarity to that of CX-4945. Among them two tricyclic scaffolds named [1,2,4]triazolo[4,3-c]quinazolin and [1,2,4]triazolo[4,3-a]quinoxalin attracted us the most. Combining strictly chemical similarity analysis, a second-round shape-based screening was performed based on the two tricyclic scaffolds, leading to 28 derivatives. These compounds not only targeted CK2 with potent and dose-dependent activities but also showed acceptable antiproliferative effects against a series of cancer cell lines. Our workflow supplies a high efficient strategy in the identification of novel CK2 inhibitors. Compounds reported here can serve as ideal leads for further modifications.

Synthesis and bioevaluation of a series of α-pyrone derivatives as potent activators of Nrf2/ARE pathway (part I).

When exposed to electrophiles, human colorectal cancer cells (HCT116) counteract oxidative stress through activating NF-E2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway. To identify new activators, luciferase reporter gene assay was used to screen in-house database of our laboratory, leading to a novel α-pyrone compound 1 as a hit. 2 with 2-fluoro phenyl group exhibited the strongest ARE inductive activity in the first round structure-activity relationship (SAR) study. Biological studies showed the compound induced nuclear translocation of Nrf2 preceded by phosphorylation of ERK1/2. The data encouraged us to use 2 as lead and 20 derivatives were synthesized to discuss a more detailed SAR, leading to a more potent compound 9, which can be the starting compound for further modification.

Novel IKKß inhibitors discovery based on the co-crystal structure by using binding-conformation-based and ligand-based method.

IκB kinase ß (IKKß), an attractive anti-inflammation and anti-cancer target, plays a crucial role in the activation of NF-κB signalling pathway. To identify novel IKKß inhibitors, we combined structure-based and ligand-based methods based on the co-crystal structure of IKKß. According to the chemical similarity, 162 reported IKKß inhibitors were divided into five classes. For each class, a 3D pharmacophore model was established based on the binding conformations of the compounds. The validated models were further used in virtual screening. Twelve drugable compounds were retained for biological test, resulting in two novel inhibitors with IC50 values lower than 10 µM. Compared to other models, our method considers the crystal structure of IKKß for the first time.