Multiparametric magnetic resonance imaging-based assessment of the effect of adenomyosis on determining the depth of myometrial invasion in endometrial cancer.

Background: Accurate preoperative diagnosis of endometrial cancer (EC) with deep myometrial invasion (DMI) is critical to deciding whether to perform lymphadenectomy. However, the presence of adenomyosis makes distinguishing DMI from superficial myometrial invasion (SMI) on magnetic resonance imaging (MRI) challenging. We aimed to evaluate the accuracy of multiparametric MRI (mpMRI) in diagnosing DMI in EC coexisting with adenomyosis (EC-A) compared with EC without coexisting adenomyosis and to evaluate the effect of different adenomyosis subtypes on myometrial invasion (MI) depth in EC. Methods: Patients with histologically confirmed International Federation of Gynecology and Obstetrics (FIGO) stage I EC who underwent preoperative MRI were consecutively included in this 2-center retrospective study. Institution 1 was searched from January 2017 to November 2022 and institution 2 was searched from June 2017 to March 2021. Patients were divided into 2 groups: group A, patients with EC-A; group B, EC patients without coexisting adenomyosis, matched 1:2 according to age ±5 years and tumor grade. A senior radiologist assessed the MRI adenomyosis classification in group A. Then, 2 radiologists (R1/R2) independently interpreted T2-weighted imaging (T2WI), diffusion-weighted imaging (DWI), T1-weighted contrast-enhanced (T1CE), and a combination of all images (mpMRI) respectively, and then assessed MI depth. Accuracy, sensitivity, specificity, and the areas under the receiver operating curve (AUC) were calculated. The chi-square test was used to compare the accuracy of diagnosing DMI. Interobserver agreement was evaluated using the Kappa test. Results: A total of 70 cases in group A and 140 cases in group B were included. The accuracy, sensitivity, and specificity of consensus were 94.3% [95% confidence interval (CI): 88.9-99.7%] vs. 92.1% (95% CI: 87.7-96.6%), 60.0% (95% CI: 17-92.7%) vs. 86.7% (95% CI: 68.4-95.6%), and 96.9% (95% CI: 88.4-95.5%) vs. 93.6% (95% CI: 86.8-97.2%) (group A vs. group B, respectively). There was no significant difference in the diagnostic accuracy of DMI on each sequence between the groups (Reviewer 1/Reviewer 2): PT2WI=0.14/0.17, PDWI=0.50/0.33, PT1CE=0.90/0.18, PmpMRI=0.50/0.37. The AUC for T2WI, DWI, T1CE, and mpMRI (Reviewer 1/Reviewer 2), respectively, were 0.54 (95% CI: 0.42-0.66)/0.78 (95% CI: 0.67-0.87), 0.63 (95% CI: 0.50-0.74)/0.77 (95% CI: 0.65-0.86), 0.69 (95% CI: 0.57-0.80)/0.79 (95% CI: 0.68-0.88), and 0.91 (95% CI: 0.82-0.97)/0.89 (95% CI: 0.79-0.95) (group A) and 0.83 (95% CI: 0.76-0.89)/0.85 (95% CI: 0.78-0.90), 0.83 (95% CI: 0.76-0.89)/0.86 (95% CI: 0.79-0.91), 0.88 (95% CI: 0.82-0.93)/0.86 (95% CI: 0.80-0.92), and 0.91 (95% CI: 0.85-0.95)/0.87 (95% CI: 0.80-0.92) (group B). Interobserver agreement was highest with mpMRI [κ=0.387/0.695 (case/control)]. The consensus results of MRI categorization of adenomyosis revealed no significant difference in the accuracy of diagnosing DMI by adenomyosis subtype (Pspatial relationship>0.99, Paffected area=0.52, Paffected pattern=0.58, Paffected size>0.99). Conclusions: The presence of adenomyosis or adenomyosis subtype had no significant effect on the interpretation of the depth of MI. T1CE can increase the contrast between adenomyosis and cancer foci; therefore, the information provided by T1CE should be valued.

Evaluation of the effect of intraoperative tropisetron on postoperative rebound pain after brachial plexus block: a randomized controlled trial.

Introduction: Postoperative rebound pain after peripheral nerve block increases patient suffering and delays recovery after surgery. Objectives: We tested whether the 5HT-3 receptor antagonist and α7nAChR agonist tropisetron could prevent postoperative rebound pain. Methods: A total of 115 patients were randomized to receive 5-mg/5-mL tropisetron or the same volume of normal saline. Pain intensity was measured with the numerical rating scale of pain (NRS). Rebound pain was defined as a change from mild pain (NRS ≤ 3) measured in the postanesthesia care unit to severe pain (NRS ≥ 7) within 24 hours after peripheral nerve blockade. Logistic regression was used to identify relevant factors associated with postoperative rebound pain. Results: Tropisetron did not affect the NRS score or the incidence of rebound pain after peripheral nerve block. Logistic regression revealed that preoperative pain, bone surgery, and length of incision were risk factors for postoperative rebound pain, and patient-controlled analgesia was protective against postoperative rebound pain. Conclusion: Tropisetron does not affect the incidence of rebound pain after peripheral nerve block. Patients at high risk of postoperative rebound pain should be identified for appropriate management. Registration site: www.chictr.org.cn (ChiCTR2300069994).

A sponge-like nanofiber melatonin-loaded scaffold accelerates vascularized bone regeneration via improving mitochondrial energy metabolism.

Electrospun nanofibers have been widely employed in bone tissue engineering for their ability to mimic the micro to nanometer scale network of the native bone extracellular matrix. However, the dense fibrous structure and limited mechanical support of these nanofibers pose challenges for the treatment of critical size bone defects. In this study, we propose a facile approach for creating a three-dimensional scaffold using interconnected electrospun nanofibers containing melatonin (Scaffold@MT). The hypothesis posited that the sponge-like Scaffold@MT could potentially enhance bone regeneration and angiogenesis by modulating mitochondrial energy metabolism. Melatonin-loaded gelatin and poly-lactic-acid nanofibers were fabricated using electrospinning, then fragmented into shorter fibers. The sponge-like Scaffold@MT was created through a process involving homogenization, low-temperature lyophilization, and chemical cross-linking, while maintaining the microstructure of the continuous nanofibers. The incorporation of short nanofibers led to a low release of melatonin and increased Young's modulus of the scaffold. Scaffold@MT demonstrated positive biocompatibility by promoting a 14.2 % increase in cell proliferation. In comparison to the control group, Scaffold@MT significantly enhanced matrix mineralization by 3.2-fold and upregulated the gene expression of osteoblast-specific markers, thereby facilitating osteogenic differentiation of bone marrow mesenchymal stem cells (BMMSCs). Significantly, Scaffold@MT led to a marked enhancement in the mitochondrial energy function of BMMSCs, evidenced by elevated adenosine triphosphate (ATP) production, mitochondrial membrane potential, and protein expression of respiratory chain factors. Furthermore, Scaffold@MT promoted the migration of human umbilical vein endothelial cells (HUVECs) and increased tube formation by 1.3 times compared to the control group, accompanied by an increase in vascular endothelial growth factor (VEGFA) expression. The results of in vivo experiments indicate that the implantation of Scaffold@MT significantly improved vascularized bone regeneration in a distal femur defect in rats. Micro-computed tomography analysis conducted 8 weeks post-surgery revealed that Scaffold@MT led to optimal development of new bone microarchitecture. Histological and immunohistochemical analyses demonstrated that Scaffold@MT facilitated bone matrix deposition and new blood vessel formation at the defect site. Overall, the utilization of melatonin-loaded nanofiber sponges exhibits significant promise as a scaffold that promotes bone growth and angiogenesis, making it a viable option for the repair of critical-sized bone defects.

Evaluation of Renal Microhemodynamics Heterogeneity in Different Strains and Sexes of Mice.

Addressing the existing gaps in our understanding of sex- and strain-dependent disparities in renal microhemodynamics, this study conducts an investigation into the variations in renal function and related biological oscillators. Utilizing the genetically diverse mouse models BALB/c, C57BL/6, and KM, which serve as established proxies for the study of renal pathophysiology, we implemented laser Doppler flowmetry conjoined with wavelet transform analyses to interrogate the dynamic renal microcirculation. Creatinine, urea, uric acid, glucose, and cystatin C, were quantified to investigate potential divergences attributable to sex and genetic lineage. Our findings reveal marked sexual dimorphism in metabolite concentrations, as well as strain-specific variances, particularly in creatinine and cystatin C levels. Through the combination of Mantel tests and Pearson's correlation coefficients, we delineated the associations between renal functional metrics and microhemodynamics, uncovering interactions in female BALB/c mice for creatinine and uric acid, and in male C57BL/6 mice for cystatin C. Histopathological examination confirmed an augmented microvascular density in females and elucidating variations in the expression of estrogen receptor ß amongst the strains. These data collectively highlight the influence of both sex and genetic constitution on renal microcirculation, providing an understanding that may inform the etiological exploration of renal ailments.

Symptom cluster among cancer survivors from a nationally representative survey: a network analysis.

PURPOSE: To identify the symptom cluster among cancer survivors and examine their subgroup differences via network analysis based on nationally representative data. METHODS: This cross-sectional study included 2966 survivors participating in the 2020 National Health Interview Survey (NHIS). Participants self-reported the presence of 14 symptoms capturing four clusters (physical, somatic, sleep, and psychologic problems). Network analysis models were used to reveal the relationships between symptoms and those interactions. Network comparison tests were applied to compare subgroups. RESULTS: The core symptoms of the symptom cluster were fatigue (Bet = 33, Clo = 0.0067, Str = 0.9397), pain (Bet = 11, Clo = 0.0060, Str = 0.9226), wake up well rested (Bet = 25, Clo = 0.0057, Str = 0.8491), and anxiety (Bet = 5, Clo = 0.0043, Str = 0.9697) among cancer survivors. The core symptoms, network structure, and global strength were invariant between time since diagnoses (< 2 years vs. ≥ 2 years) or between numbers of cancers (1 vs. ≥ 2), yet varied between the comorbidity group and non-comorbidity group (≥ 1 vs. 0). CONCLUSIONS: Fatigue would be a potential target for alleviating other symptoms through a negative feedback loop of other related symptoms of cancer survivors. In particular, cancer survivors with other chronic diseases should be the focus of attention and strengthen targeted intervention.

Targeted inhibition of transforming growth factor-ß type I receptor by AZ12601011 improves paraquat poisoning-induced multiple organ fibrosis.

Paraquat (PQ) causes fatal poisoning that leads to systemic multiple organ fibrosis, and transforming growth factor (TGF)-ß1 plays a critical role in this process. In this study, we aimed to investigate the effects of AZ12601011 (a small molecular inhibitor of TGFßRI) on PQ-induced multiple organ fibrosis. We established a mouse model of PQ in vivo and used PQ-treated lung epithelial cell (A549) and renal tubular epithelial cells (TECs) in vitro. Haematoxylin-eosin and Masson staining revealed that AZ12601011 ameliorated pulmonary, hepatic, and renal fibrosis, consistent with the decrease in the levels of fibrotic indicators, alpha-smooth muscle actin (α-SMA) and collagen-1, in the lungs and kidneys of PQ-treated mice. In vitro data showed that AZ12601011 suppressed the induction of α-SMA and collagen-1 in PQ-treated A549 cells and TECs. In addition, AZ12601011 inhibited the release of inflammatory factors, interleukin (IL)-1ß, IL-6, and tumour necrosis factor-α. Mechanistically, TGF-ß and TGFßRI levels were significantly upregulated in the lungs and kidneys of PQ-treated mice. Cellular thermal shift assay and western blotting revealed that AZ12601011 directly bound with TGFßRI and blocked the activation of Smad3 downstream. In conclusion, our findings revealed that AZ12601011 attenuated PQ-induced multiple organ fibrosis by blocking the TGF-ß/Smad3 signalling pathway, suggesting its potential for PQ poisoning treatment.

Discovery of novel diaryl substituted isoquinolin-1(2H)-one derivatives as hypoxia-inducible factor-1 signaling inhibitors for the treatment of rheumatoid arthritis.

Since synovial hypoxic microenvironment significantly promotes the pathological progress of rheumatoid arthritis (RA), hypoxia-inducible factor 1 (HIF-1) has been emerged as a promising target for the development of novel therapeutic agents for RA treatment. In this study, we designed and synthesized a series of diaryl substituted isoquinolin-1(2H)-one derivatives as HIF-1 signaling inhibitors using scaffold-hopping strategy. By modifying the substituents on N-atom and 6-position of isoquinolin-1-one, we discovered compound 17q with the most potent activities against HIF-1 (IC50 = 0.55 µM) in a hypoxia-reactive element (HRE) luciferase reporter assay. Further pharmacological studies revealed that 17q concentration-dependently blocked hypoxia-induced HIF-1α protein accumulation, reduced inflammation response, inhibited cellular invasiveness and promoted VHL-dependent HIF-1α degradation in human RA synovial cell line. Moreover, 17q improved the pathological injury of ankle joints, decreased angiogenesis and attenuated inflammation response in the adjuvant-induced arthritis (AIA) rat model, indicating the promising therapeutic potential of compound 17q as an effective HIF-1 inhibitor for RA therapy.

Comparison of metabolic syndrome prevalence and characteristics using five different definitions in China: a population-based retrospective study.

Background: Metabolic syndrome (MetS) is on the rise in developing countries and is characterized by a series of indications of metabolic disturbance. However, the prevalence of MetS varies under different definitions. The study aimed to compare five definitions of MetS in the China adult population, to explore their prevalence, characteristics and agreement. Methods: The data for the retrospective study came from the China Health and Retirement Longitudinal Study (CHARLS), consisting of 9,588 participants (≥45). MetS definitions from International Diabetes Federation (IDF) (2006), National Cholesterol Education Program Adult Treatment Panel III (ATPIII) (2005), National Cholesterol Education Program Adult Treatment Panel III (ATPIII) (2001), Chinese Diabetes society (CDS) (2004) and the World Health Organization (WHO) (1999). We used binary and multivariable logistic analysis to explore factors connected with MetS. Results: The five definitions of MetS led to different prevalence of MetS:34.52% by IDF (2006), 38.63% by ATP (2005), 25.94% by ATP (2001), 26.31% by CDS (2004), 21.57% by WHO (1999). According to the definition of IDF (2006) (22.32% vs. 45.06%), ATPIII (2005) definition (27.99% vs. 47.82%), ATPIII (2001) definition (15.37% vs. 35.07%), CDS (2004) definition (19.96% vs. 31.80%), and WHO (1999) definition (17.44% vs. 25.14%), the prevalence of MetS in men was low but in women was high. The agreement between the five definitions for men was good except for the IDF (2006) definition and ATPIII (2001) definition (kappa = 0.51), with kappa values from 0.64 to 0.85. For women, the agreement between the five definitions was good ranging from 0.67 to 0.95, however, except for the definition of CDS (2004) and the definition of IDF (2006) (kappa = 0.44), the definition of WHO (1999) and the definition of IDF (2006) (kappa = 0.55), and the definition of WHO (1999) and the definition of ATPIII (2005) (kappa = 0.54). Binary logistic analysis indicated that although the impact and relevance varied by sex and definition, age, education, marital status, current residence, current smoking, alcohol using, taking activities and number of chronic diseases were factors connected to MetS. Conclusion: the prevalence and characteristics of the five definitions of MetS are different in the Chinese population. Therefore, it is vital to use the same definition for a country to diagnose MetS. On the other side, a lower prevalence in men than in women and the consistency of five MetS definitions are good in men but relatively poor in women.

Ranolazine for improving coronary microvascular function in patients with nonobstructive coronary artery disease: a systematic review and meta-analysis with a trial sequential analysis of randomized controlled trials.

Background: Microvascular dysfunction in patients with nonobstructive coronary artery disease is increasingly being recognized as an important health issue. This systematic review and meta-analysis evaluated the effectiveness of ranolazine, an antianginal agent, in improving coronary microvascular function. Methods: We conducted a comprehensive literature search of the Cochrane Library, PubMed, Embase, China National Knowledge Infrastructure, the Chinese BioMedical Literature Database, and gray literature databases until September 30, 2023. The included studies were randomized controlled trials (RCTs) published in the English or Chinese languages that screened for eligibility using two independent investigators. Risk of bias was evaluated with the Cochrane Collaboration tool. Subgroup and sensitivity analyses were used to identify sources of heterogeneity. Meta-analysis was performed using RevMan version 5.4 (Cochrane) and Stata version 16.0 (StataCorp). Results: From 1,470 citations, 8 RCTs involving 379 participants were included in this analysis. Our findings showed that ranolazine increased coronary flow reserve (CFR) over an 8 to 12-week follow-up period [standardized mean difference =1.16; 95% confidence interval (CI): 0.4-1.89; P=0.002]. Ranolazine increased the global myocardial perfusion reserve index (MPRI) [weighted mean difference (WMD) =0.18; 95% CI: 0.07-0.29; P=0.002] and the midsubendocardial MPRI (WMD =0.10; 95% CI: 0.02-0.19; P=0.02). Moreover, ranolazine improved 3 of the 5 Seattle Angina Questionnaire scores, namely, physical functioning (WMD =4.89; 95% CI: 0.14 to 9.64; P=0.04), angina stability (WMD =17.31; 95% CI: 7.13-27.49; P=0.0009), and quality of life (WMD =10.11; 95% CI: 3.57-16.65; P=0.0003). Trial sequential analysis showed that the meta-analysis of angina stability and quality of life scores had a sufficient sample size and statistical power. Conclusions: Our analysis suggests that ranolazine is associated with improvements in CFR, myocardial perfusion, and the Seattle Angina Questionnaire scores in patients with nonobstructive coronary artery disease. However, further large-scale RCTs with long-term follow-up are recommended to validate these findings and provide a more comprehensive understanding of the effects of ranolazine on coronary microvascular function.

Effect of deep learning image reconstruction with high-definition standard scan mode on image quality of coronary stents and arteries.

Background: The high-definition standard (HD-standard) scan mode has been proven to display stents better than the standard (STND) scan mode but with more image noise. Deep learning image reconstruction (DLIR) is capable of reducing image noise. This study examined the impact of HD-standard scan mode with DLIR algorithms on stent and coronary artery image quality in coronary computed tomography angiography (CCTA) via a comparison with conventional STND scan mode and adaptive statistical iterative reconstruction-Veo (ASIR-V) algorithms. Methods: The data of 121 patients who underwent HD-standard mode scans (group A: N=47, with coronary stent) or STND mode scans (group B: N=74, without coronary stent) were retrospectively collected. All images were reconstructed with ASIR-V at a level of 50% (ASIR-V50%) and a level of 80% (ASIR-V80%) and with DLIR at medium (DLIR-M) and high (DLIR-H) levels. The noise, signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), artifact index (AI), and in-stent diameter were measured as objective evaluation parameters. Subjective assessment involved a 5-point scale for overall image quality, image noise, stent appearance, stent artifacts, vascular sharpness, and diagnostic confidence. Diagnostic confidence was evaluated based on the presence or absence of significant stenosis (≥50% lumen reduction). Both subjective and objective evaluations were conducted by two radiologists independently, with kappa and intraclass correlation statistics being used to test the interobserver agreement. Results: There were 76 evaluable stents in group A, and the DLIR-H algorithm significantly outperformed other algorithms, demonstrating the lowest noise (41.6±7.1/41.3±7.2) and AI (32.4±8.9/31.2±10.1), the highest SNR (14.6±3.5/15.0±3.5) and CNR (13.6±3.8/13.9±3.8), and the largest in-stent diameter (2.18±0.61/2.19±0.61) in representing true stent diameter (all P values <0.01), as well as the highest score in each subjective evaluation parameter. In group B, a total of 296 coronary arteries were evaluated, and the DLIR-H algorithm provided the best objective image quality, with statistically superior noise, SNR, and CNR compared with the other algorithms (all P values <0.05). Moreover, the HD-standard mode scan with DLIR provided better image quality and a lower radiation dose than did the STND mode scan with ASIR-V (P<0.01). Conclusions: HD-standard scan mode with DLIR-H improves image quality of both stents and coronary arteries on CCTA under a lower radiation dose.

Activation of NRF2 by celastrol increases antioxidant functions and prevents the progression of osteoarthritis in mice.

Excessive oxidative stress impairs cartilage matrix metabolism balance, significantly contributing to osteoarthritis (OA) development. Celastrol (CSL), a drug derived from Tripterygium wilfordii, has recognized applications in the treatment of cancer and immune system disorders, yet its antioxidative stress mechanisms in OA remain underexplored. This study aimed to substantiate CSL's chondroprotective effects and unravel its underlying mechanisms. We investigated CSL's impact on chondrocytes under both normal and inflammatory conditions. In vitro, CSL mitigated interleukin (IL)-1ß-induced activation of proteinases and promoted cartilage extracellular matrix (ECM) synthesis. In vivo, intra-articular injection of CSL ameliorated cartilage degeneration and mitigated subchondral bone lesions in OA mice. Mechanistically, it was found that inhibiting nuclear factor erythroid 2-related factor 2 (NRF2) abrogated CSL-mediated antioxidative functions and exacerbated the progression of OA. This study is the first to elucidate the role of CSL in the treatment of OA through the activation of NRF2, offering a novel therapeutic avenue for arthritis therapy.

Self-amplified activatable nanoprodrugs for enhanced chemodynamic/chemo combination therapy.

Chemodynamic therapy (CDT) has gained increasing attention by virtue of its high tumor specificity and low side effect. However, the low concentration of hydrogen peroxide (H2O2) in the tumor site suppresses the therapeutic efficacy of CDT. To improve the efficacy, introducing other kind of therapeutic modality is a feasible choice. Herein, we develop a self-amplified activatable nanomedicine (PCPTH NP) for chemodynamic/chemo combination therapy. PCPTH NP is composed of a H2O2-activatable amphiphilic prodrug PEG-PCPT and hemin. Upon addition of H2O2, the oxalate linkers within PCPTH NP are cleaved, which makes the simultaneous release of CPT and hemin. The released CPT can not only kill cancer cells but also upregulate the intracellular reactive oxygen species (ROS) level. The elevated ROS level may accelerate the release of drugs and enhance the CDT efficacy. PCPTH NP shows a H2O2concentration dependent release profile, and can effectively catalyze H2O2into hydroxyl radical (·OH) under acidic condition. Compared with PCPT NP without hemin, PCPTH NP has better anticancer efficacy bothin vitroandin vivowith high biosafety. Thus, our study provides an effective approach to improve the CDT efficacy with high tumor specificity.

Genome-wide identification and integrated analysis of TCP genes controlling ginsenoside biosynthesis in Panax ginseng.

Panax ginseng is an important medicinal plant, and ginsenosides are the main bioactive molecules of ginseng. The TCP (TBI, CYC, PCF) family is a group of transcription factors (TFs) that play an important role in plant growth and development, hormone signalling and synthesis of secondary metabolites. In our study, 78 PgTCP transcripts were identified from the established ginseng transcriptome database. A phylogenetic tree analysis showed that the 67 PgTCP transcripts with complete open reading frames were classified into three subfamilies, including CIN, PCF, and CYC/TB1. Protein structure analysis showed that PgTCP genes had bHLH structures. Chromosomal localization analysis showed that 63 PgTCP genes were localized on 17 of the 24 chromosomes of the Chinese ginseng genome. Expression pattern analysis showed that PgTCP genes differed among different lineages and were spatiotemporally specific. Coexpression network analysis indicated that PgTCP genes were coexpressed and involved in plant activities or metabolic regulation in ginseng. The expression levels of PgTCP genes from class I (PCF) were significantly downregulated, while the expression levels of PgTCP genes from class II (CIN and CYC/TB1) were upregulated, suggesting that TCP genes may be involved in the regulation of secondary metabolism in ginseng. As the PgTCP26-02 gene was found to be related to ginsenoside synthesis, its predicted protein structure and expression pattern were further analysed. Our results provide new insights into the origin, differentiation, evolution and function of the PgTCP gene family in ginseng, as well as the regulation of plant secondary metabolism.

Anti-babesial activity of a series of 6,7-dimethoxyquinazoline-2,4-diamines (DMQDAs).

Diminazene aceturate (DA), imidocarb dipropionate (ID), atovaquone (ATO), azithromycin (AZI), clindamycin, and quinine have been used to treat animal and human babesiosis for many years, despite their negative effects and rising indications of resistance. Thus, finding anti-babesial compounds that can either treat the infection or lower the dose of drugs given has been a primary objective. Quinazolines are one of the most important nitrogen heterocycles, with a wide range of pharmacological activities including analgesic, anti-inflammatory, sedative-hypnotic, anti-histaminic, anti-cancer, and anti-protozoan properties. The present study investigated the anti-babesial activities of twenty 6,7-dimethoxyquinazoline-2,4-diamines on Babesia spp. One candidate, 6,7-dimethoxy-N4-ethylisopropyl-N2-ethyl(pyridin-4-yl)quinazoline-2,4-diamine (SHG02), showed potent inhibition on Babesia gibsoni in vitro, as well as on B. microti and B. rodhaini in mice. Our findings indicate that the candidate compound SHG02 is promising for further development of anti-babesial drugs and provides a new structure to be explored for developing anti-Babesia therapeutics.

Dynamic interactions between E-cadherin and Ankyrin-G mediate epithelial cell polarity maintenance.

E-cadherin is an essential cell‒cell adhesion protein that mediates canonical cadherin-catenin complex formation in epithelial lateral membranes. Ankyrin-G (AnkG), a scaffold protein linking membrane proteins to the spectrin-based cytoskeleton, coordinates with E-cadherin to maintain epithelial cell polarity. However, the molecular mechanisms governing this complex formation and its relationships with the cadherin-catenin complex remain elusive. Here, we report that AnkG employs a promiscuous manner to encapsulate three discrete sites of E-cadherin by the same region, a dynamic mechanism that is distinct from the canonical 1:1 molar ratio previously described for other AnkG or E-cadherin-mediated complexes. Moreover, we demonstrate that AnkG-binding-deficient E-cadherin exhibited defective accumulation at the lateral membranes and show that disruption of interactions resulted in cell polarity malfunction. Finally, we demonstrate that E-cadherin is capable of simultaneously anchoring to AnkG and ß-catenin, providing mechanistic insights into the functional orchestration of the ankyrin-spectrin complex with the cadherin-catenin complex. Collectively, our results show that complex formation between E-cadherin and AnkG is dynamic, which enables the maintenance of epithelial cell polarity by ensuring faithful targeting of the adhesion molecule-scaffold protein complex, thus providing molecular mechanisms for essential E-cadherin-mediated complex assembly at cell‒cell junctions.

Multiomics studies with co-transformation reveal microRNAs via miRNA-TF-mRNA network participating in wood formation in Hevea brasiliensis.

Introduction: MicroRNAs (miRNAs) are small endogenous non-coding RNAs that play an important role in wood formation in plants. However, the significance of the link between miRNAs and their target transcripts in wood formation remains unclear in rubber tree (Hevea brasiliensis). Methods: In this study, we induced the formation of reaction wood by artificially bending rubber trees for 300 days and performed small RNA sequencing and transcriptome deep sequencing (RNA-seq) to describe the complement of miRNAs and their targets contributing to this process. Results and discussion: We identified 5, 11, and 2 differentially abundant miRNAs in normal wood (NW) compared to tension wood (TW), in NW relative to opposite wood (OW), and between TW and OW, respectively. We also identified 12 novel miRNAs and 39 potential miRNA-mRNA pairs with different accumulation patterns in NW, TW, and OW. We noticed that many miRNAs targeted transcription factor genes, which were enriched in KEGG pathways associated with phenylpropanoid biosynthesis, phenylalanine metabolism, and pyruvate metabolism. Thus, miRNA-TF-mRNA network involved in wood formation via tension wood model were constructed. We validated the differential accumulation of miRNAs and their targets by RT-qPCR analysis and overexpressed miRNA in Nicotiana benthamiana with its potential target gene. These results will provide a reference for a deep exploration of growth and development in rubber tree.

Therapeutic effect of YiQi HuoXue BuShen decoction combined with Western medicine on hypertensive nephropathy: a meta-analysis.

OBJECTIVE: To comprehensively evaluate therapeutic effect of YiQi HuoXue BuShen decoction combined with Western medicine on hypertensive nephropathy. METHODS: The CNKI, WanFang, VIP, Chinese Biomedical Database (CBM), PubMed, Embase and Cochrane Library databases were searched to collect the randomized controlled trials (RCTs) of YiQi HuoXue BuShen decoction combined with Western medicine on hypertensive nephropathy, which were published as of March 10, 2023. Then, these articles were screened to extract and evaluate the data. Revman 5.3 was applied for data analysis. RESULTS: Eight RCTs involving 732 patients were included after screening. Comparing with Western medicine, YiQi HuoXue BuShen decoction combined with Western medicine enhanced the clinical effect [OR = 3.48, 95% CI: 2.12~5.73, P < 0.00001]; reduced 24-hour urine protein content [OR = -0.60, 95% CI: -0.92~-0.28, P = 0.0003], serum creatinine (Scr) [OR = -39.11, 95% CI: -44.72~-33.51, P < 0.00001], blood urea nitrogen (BUN) [OR = -2.51, 95% CI: -4.06~-0.95, P = 0.002], cystatin C (Cys-C) [OR = -0.30, 95% CI: -0.36~-0.25, P < 0.00001], Urine ß2-microglobulin [OR = -0.42, 95% CI: -0.87~-0.02, P = 0.06]; and enhanced creatinine clear rate (Ccr) [OR = 3.24, 95% CI: 1.85~4.64, P < 0.00001]. In addition, the combination treatment didn't increase the incidence of adverse reaction compared with western medicine [OR = 1.55, 95% CI: 0.61~3.95, P > 0.05]. CONCLUSIONS: The combination of Yiqi Huoxue Bushen decoction and western medicine can effectively improve the clinical symptoms and renal function of patients with hypertensive nephropathy and provide more theoretical basis for clinical application.

Novel insights into STAT3 in renal diseases.

Signal transducer and activator of transcription 3 (STAT3) is a cell-signal transcription factor that has attracted considerable attention in recent years. The stimulation of cytokines and growth factors can result in the transcription of a wide range of genes that are crucial for several cellular biological processes involved in pro- and anti-inflammatory responses. STAT3 has attracted considerable interest as a result of a recent upsurge in study because of their role in directing the innate immune response and sustaining inflammatory pathways, which is a key feature in the pathogenesis of many diseases, including renal disorders. Several pathological conditions which may involve STAT3 include diabetic nephropathy, acute kidney injury, lupus nephritis, polycystic kidney disease, and renal cell carcinoma. STAT3 is expressed in various renal tissues under these pathological conditions. To better understand the role of STAT3 in the kidney and provide a theoretical foundation for STAT3-targeted therapy for renal disorders, this review covers the current work on the activities of STAT3 and its mechanisms in the pathophysiological processes of various types of renal diseases.

Meta-analysis of the clinical effect of Kanglaite injection-assisted gemcitabine plus cisplatin regimen on non-small cell lung cancer.

OBJECTIVE: To systematically evaluate the clinical effect of Kanglaite (KLT) injection-assisted gemcitabine plus cisplatin (GP) regimen on non-small cell lung cancer (NSCLC). METHODS: The CNKI, WanFang, VIP, Chinese Biomedical Database, PubMed, Embase and Cochrane Library databases were searched to collect the randomized controlled trials (RCTs), which evaluated the clinical effect of KLT combined with GP chemotherapy on NSCLC, published as of February 15, 2023. These articles were screened, extracted and evaluated. Revman 5.3 and STATA 17 were used for analysis, where the odds ratio (OR) was used as the statistic for the binary variables, and the mean difference (MD) was used as the statistic for the continuous variables. RESULTS: After selection, this meta-analysis included 27 RCTs and 2,579 patients. Comparing with GP chemotherapy, KLT combined with GP regimen enhanced the total response rate (OR=1.76, 95% CI: 1.49-2.06, P<0.00001), improved the Karnofsky (KPS) score (OR=2.03, 95% CI: 1.55-2.66, P<0.00001), decreased the adverse reactions, including gastrointestinal reactions (OR=0.41, 95% CI: 0.33-0.51, P<0.00001), leucopenia (OR=0.45, 95% CI: 0.35-0.58, P<0.00001), anemia (OR=0.47, 95% CI: 0.32-0.67, P<0.0001) and liver function damage (OR=0.52, 95% CI: 0.38-0.73, P<0.0001), as well as elevated immune level, including CD3+ (MD=8.51, 95% CI: 7.63-9.39, P<0.00001), CD4+ (MD=5.68, 95% CI: 5.08-6.27, P<0.00001) and CD4+/CD8+ (MD=0.41, 95% CI: 0.38-0.44, P<0.00001). CONCLUSIONS: Current evidence shows that the combination regimen of KLT with GP has shown promising results in increasing the response rate, improving the KPS score, enhancing the immune level, and reducing the incidence of adverse reactions in NSCLC patients. However, this conclusion needs to be further verified due to limitations such as the limited number of articles included in this paper and the variability in research methodology and quality among the included studies.

Clinical and Radiographic Comparison of Oblique Lateral Lumbar Interbody Fusion and Minimally Invasive Transforaminal Lumbar Interbody Fusion in Patients with L4/5 grade-1 Degenerative Spondylolisthesis.

OBJECTIVES: To compare the clinical and radiographic outcomes of oblique lateral lumbar interbody fusion and minimally invasive transforaminal lumbar interbody fusion in patients with grade-1 L4/5 degenerative spondylolisthesis. METHODS: Based on the inclusion and exclusion criteria, the comparative analysis included consecutive patients with grade-1 degenerative spondylolisthesis who underwent oblique LIF (OLIF, n = 36) or minimally invasive transforaminal LIF (MI-TLIF, n = 45) at the Department of Spine Surgery, Beijing Jishuitan Hospital from January 2016 to August 2017. Patient satisfaction Japanese Orthopaedic Association score, visual analog scale (VAS) scores for back and leg pain, Oswestry disability index (ODI), radiographic outcomes including anterior/posterior disc heights (ADH/PDH), foraminal height (FH), foraminal width (FW), cage subsidence, cage retropulsion, and fusion rate were assessed during a 2-year follow-up. Continuous data are presented as mean ± standard deviation and were compared between groups using the independent sample t-test. Categorical data are presented as n (%) and were compared between groups using the Pearson chi-squared test or Fisher's exact test. Repetitive measurement and analysis of variance was employed in the analysis of ODI, back pain VAS score, and leg pain VAS score. Statistical significance was defined as p < 0.05. RESULTS: The OLIF and MI-TLIF groups comprised 36 patients (age, 52.1 ± 7.2 years; 27 women) and 45 patients (age, 48.4 ± 14.4 years; 24 women), respectively. Satisfaction rates at 2 years post procedure exceeded 90% in both groups. The OLIF group had less intraoperative blood loss (140 ± 36 vs 233 ± 62 mL), lower back pain VAS score (2.42 ± 0.81 vs 3.38 ± 0.47), and ODI score (20.47 ± 2.53 vs 27.31 ± 3.71) at 3 months follow-up (with trends toward lower values at 2 years follow-up), but higher leg pain VAS scores at all postoperative time points than the MI-TLIF group (all p < 0.001). ADH, PDH, FD, and FW improved in both groups post-surgery. At the 2 year follow-up, the OLIF group had a higher rate of Bridwell grade-I fusion (100% vs 88.9%, p = 0.046) and lower incidences of cage subsidence (8.33% vs 46.67%, p < 0.001) and retropulsion (0% vs 6.67%, p = 0.046) than the MI-TLIF group. CONCLUSIONS: In patients with grade-I spondylolisthesis, OLIF was associated with lower blood loss and greater improvements in VAS for back pain and ODI and radiologic outcomes than MI-TLIF. The OLIF is more suitable for these patients with low back pain as the main symptoms are accompanied by mild or no leg symptoms before operation.