Review on Ginseng and its Potential Active Substance G-Rg2 Against Age-Related Diseases: Traditional Efficacy and Mechanism.

ETHNOPHARMACOLOGICAL RELEVANCE: According to the Shen Nong Herbal Classic, Ginseng (Panax ginseng C.A. Meyer) is documented to possess life-prolonging effects and is extensively utilized in traditional Chinese medicine for the treatment of various ailments such as qi deficiency, temper deficiency, insomnia, and forgetfulness. Ginseng is commonly employed for replenishing qi and nourishing blood, fortifying the body and augmenting immunity; it has demonstrated efficacy in alleviating fatigue, enhancing memory, and retarding aging. Furthermore, it exhibits a notable ameliorative impact on age-related conditions including cardiovascular diseases and neurodegenerative disorders. One of its active constituents - ginsenoside Rg2 (G-Rg2) - exhibits potential therapeutic efficacy in addressing these ailments. AIM OF THE REVIEW: The aim of this review is to explore the traditional efficacy of ginseng in anti-aging diseases and the modern pharmacological mechanism of its potential active substance G-Rg2, in order to provide strong theoretical support for further elucidating the mechanism of its anti-aging effect. METHODS: This review provides a comprehensive analysis of the traditional efficacy of ginseng and the potential mechanisms underlying the anti-age-related disease properties of G-Rg2, based on an extensive literature review up to March 12, 2024, from PubMed, Web of Science, Scopus, Cochrane, and Google Scholar databases. Potential anti-aging mechanisms of G-Rg2 were predicted using network pharmacology and molecular docking analysis techniques. RESULTS: In traditional Chinese medicine theory, ginseng has been shown to improve aging-related diseases with a variety of effects, including tonifying qi, strengthening the spleen and stomach, nourishing yin, regulating yin and yang, as well as calming the mind. Its potential active ingredient G-Rg2 has demonstrated significant therapeutic potential in age-related diseases, especially central nervous system and cardiovascular diseases. G-Rg2 exhibited a variety of pharmacological activities, including anti-apoptotic, anti-inflammatory and antioxidant effects. Meanwhile, the network pharmacological analyses and molecular docking results were consistent with the existing literature review, further validating the potential efficacy of G-Rg2 as an anti-aging agent. CONCLUSION: The review firstly explores the ameliorative effects of ginseng on a wide range of age-related diseases based on TCM theories. Secondly, the article focuses on the remarkable significance and value demonstrated by G-Rg2 in age-related cardiovascular and neurodegenerative diseases. Consequently, G-Rg2 has broad prospects for development in intervening in aging and treating age-related health problems.

Platelet-Derived Growth Factor C Facilitates Malignant Behavior of Pancreatic Ductal Adenocarcinoma by Regulating SREBP1 Mediated Lipid Metabolism.

Lipid metabolism reprogramming stands as a fundamental hallmark of cancer cells. Unraveling the core regulators of lipid biosynthesis holds the potential to find promising therapeutic targets in pancreatic ductal adenocarcinoma (PDAC). Here, it is demonstrated that platelet-derived growth factor C (PDGFC) orchestrated lipid metabolism, thereby facilitated the malignant progression of PDAC. Expression of PDGFC is upregulated in PDAC cohorts and is corelated with a poor prognosis. Aberrantly high expression of PDGFC promoted proliferation and metastasis of PDAC both in vitro and in vivo. Mechanistically, PDGFC accelerated the malignant progression of PDAC by upregulating fatty acid accumulation through sterol regulatory element-binding protein 1 (SREBP1), a key transcription factor in lipid metabolism. Remarkably, Betulin, an inhibitor of SREBP1, demonstrated the capability to inhibit proliferation and metastasis of PDAC cell lines, along with attenuating the process of liver metastasis in vivo. Overall, the study underscores the pivotal role of PDGFC-mediated lipid metabolism in PDAC progression, suggesting PDGFC as a potential biomarker for PDAC metastasis. Targeting PDGFC-induced lipid metabolism emerges as a promising therapeutic strategy for metastatic PDAC, with the potential to improve clinical outcomes.

Optimized personalized management approach for moderate/severe OHSS: development and prospective validation of an OHSS risk assessment index.

STUDY QUESTION: Can a simplified ovarian hyperstimulation syndrome (OHSS) risk assessment index be developed and validated with sufficient discrimination of moderate/severe OHSS from those without OHSS? SUMMARY ANSWER: This easy-to-use OHSS risk assessment index shows good discriminative power and high calibration accuracy in internal and external validation cohorts. WHAT IS KNOWN ALREADY: An early alert and risk stratification is critical to prevent the occurrence of OHSS. We have previously developed a multi-stage smartphone app-based prediction model to evaluate the risk of OHSS, but app use might not be so convenient in many primary institutions. A simplified OHSS risk assessment index has been required. STUDY DESIGN, SIZE, DURATION: This training and internal validation of an OHSS risk assessment index used retrospective cohort data from January 2016 to December 2020. External validation was performed with a prospective cohort database from January 2021 to May 2022. There were 15 066 cycles in the training cohort, 6502 cycles in the internal validation cohort, and 8097 cycles in the external validation cohort. PARTICIPANTS/MATERIALS, SETTING, METHODS: This study was performed in the reproductive medicine center of a tertiary hospital. Infertile women who underwent ovarian stimulation were included. Data were extracted from the local database with detailed medical records. A multi-stage risk assessment index was constructed at multiple stages. The first stage was before the initiation of ovarian stimulation, the second was before the ovulation trigger, the third was after oocyte retrieval, and the last stage was on the embryo transfer day if fresh embryo transfer was scheduled. MAIN RESULTS AND THE ROLE OF CHANCE: We established a simplified multi-stage risk assessment index for moderate/severe OHSS, the performance of which was further evaluated with discrimination and calibration abilities in training and internal and external validation cohorts. The discrimination abilities of the OHSS risk assessment index were determined with C-statistics. C-statistics in training (Stages 1-4: 0.631, 0.692, 0.751, 0.788, respectively) and internal (Stages 1-4: 0.626, 0.642, 0.755, 0.771, respectively) and external validation (Stages 1-4: 0.668, 0.670, 0.754, 0.773, respectively) cohorts were all increased from Stage 1 to 3 with similar trends, and were comparable between Stages 3 and 4. Calibration plots showed high agreement between observed and predicted cases in all three cohorts. Incidences of OHSS based on diverse risk stratification (negligible risk, low risk, medium risk, and high risk) were 0%, 0.6%, 2.7%, and 8.3% in the training cohort, 0%, 0.6%, 3.3%, and 8.5% in the internal validation cohort, and 0.1%, 1.1%, 4.1%, and 7.2% in the external validation cohort. LIMITATIONS, REASONS FOR CAUTION: The influence from clinical interventions including cryopreservation of all embryos cannot be eliminated and thus certain risk factors like estrogen level on trigger day might be assigned with a lower risk score. Another weakness of the study is that several preventive treatments, for instance oral aspirin and letrozole, were not recorded and evaluated in the model. Despite the robust reliability of OHSS assessment index, this tool cannot be used directly for clinical decision-making or as a diagnostic tool. Its value lies in its capacity to evaluate the prognosis of various interventions and to facilitate clinician-patient communication. The combination of this tool and further symptoms and examinations should be all taken into consideration for accurate and personalized management of OHSS. WIDER IMPLICATIONS OF THE FINDINGS: The OHSS risk assessment index can be implemented to facilitate personalized counseling and management of OHSS. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by National Key R&D Program of China (2022YFC2702504), Medical Research Fund Guangdong Provincial (A2024003), and Xinjiang Support Rural Science and Technology (Special Correspondent) Program in Guangdong Province (KTPYJ 2023014). All authors had nothing to disclose. TRIAL REGISTRATION NUMBER: N/A.

Hsa_circ_0000520 suppresses vasculogenic mimicry formation and metastasis in bladder cancer through Lin28a/PTEN/PI3K signaling.

BACKGROUND: Vasculogenic mimicry (VM) is a potential cause of resistance to antiangiogenic therapy and is closely related to the malignant progression of tumors. It has been shown that noncoding RNAs play an important role in the formation of VM in malignant tumors. However, the role of circRNAs in VM of bladder cancer and the regulatory mechanisms are unclear. METHODS: Firstly, hsa_circ_0000520 was identified to have circular character by Sanger sequencing and Rnase R assays. Secondly, the potential clinical value of hsa_circ_0000520 was explored by quantitative real-time polymerase chain reaction (qRT-PCR) and fluorescence in situ hybridization (FISH) of clinical specimens. Thirdly, the role of hsa_circ_0000520 in bladder cancer invasion, migration, and VM formation was examined by in vivo and in vitro experiments. Finally, the regulatory mechanisms of hsa_circ_0000520 in the malignant progression of bladder cancer were elucidated by RNA binding protein immunoprecipitation (RIP), RNA pulldown, co-immunoprecipitation (co-IP), qRT-PCR, Western blot (WB), and fluorescence co-localization. RESULTS: Hsa_circ_0000520 was characterized as a circular RNA and was lowly expressed in bladder cancer compared with the paracancer. Bladder cancer patients with high expression of hsa_circ_0000520 had better survival prognosis. Functionally, hsa_circ_0000520 inhibited bladder cancer invasion, migration, and VM formation. Mechanistically, hsa_circ_0000520 acted as a scaffold to promote binding of UBE2V1/UBC13 to Lin28a, further promoting the ubiquitous degradation of Lin28a, improving PTEN mRNA stability, and inhibiting the phosphorylation of the PI3K/AKT pathway. The formation of hsa_circ_0000520 in bladder cancer was regulated by RNA binding protein QKI. CONCLUSIONS: Hsa_circ_0000520 inhibits metastasis and VM formation in bladder cancer and is a potential target for bladder cancer diagnosis and treatment.

Integrated analysis of facial microbiome and skin physio-optical properties unveils cutotype-dependent aging effects.

BACKGROUND: Our facial skin hosts millions of microorganisms, primarily bacteria, crucial for skin health by maintaining the physical barrier, modulating immune response, and metabolizing bioactive materials. Aging significantly influences the composition and function of the facial microbiome, impacting skin immunity, hydration, and inflammation, highlighting potential avenues for interventions targeting aging-related facial microbes amidst changes in skin physiological properties. RESULTS: We conducted a multi-center and deep sequencing survey to investigate the intricate interplay of aging, skin physio-optical conditions, and facial microbiome. Leveraging a newly-generated dataset of 2737 species-level metagenome-assembled genomes (MAGs), our integrative analysis highlighted aging as the primary driver, influencing both facial microbiome composition and key skin characteristics, including moisture, sebum production, gloss, pH, elasticity, and sensitivity. Further mediation analysis revealed that skin characteristics significantly impacted the microbiome, mostly as a mediator of aging. Utilizing this dataset, we uncovered two consistent cutotypes across sampling cities and identified aging-related microbial MAGs. Additionally, a Facial Aging Index (FAI) was formulated based on the microbiome, uncovering the cutotype-dependent effects of unhealthy lifestyles on skin aging. Finally, we distinguished aging related microbial pathways influenced by lifestyles with cutotype-dependent effect. CONCLUSIONS: Together, our findings emphasize aging's central role in facial microbiome dynamics, and support personalized skin microbiome interventions by targeting lifestyle, skin properties, and aging-related microbial factors. Video Abstract.

Turning to immunosuppressive tumors: Deciphering the immunosenescence-related microenvironment and prognostic characteristics in pancreatic cancer, in which GLUT1 contributes to gemcitabine resistance.

Increasing evidence indicates that the remodeling of immune microenvironment heterogeneity influences pancreatic cancer development, as well as sensitivity to chemotherapy and immunotherapy. However, a gap remains in the exploration of the immunosenescence microenvironment in pancreatic cancer. In this study, we identified two immunosenescence-associated isoforms (IMSP1 and IMSP2), with consequential differences in prognosis and immune cell infiltration. We constructed the MLIRS score, a hazard score system with robust prognostic performance (area under the curve, AUC = 0.91), based on multiple machine learning algorithms (101 cross-validation methods). Patients in the high MLIRS score group had worse prognosis (P < 0.0001) and lower abundance of immune cell infiltration. Conversely, the low MLIRS score group showed better sensitivity to chemotherapy and immunotherapy. Additionally, our MLIRS system outperformed 68 other published signatures. We identified the immunosenescence microenvironmental windsock GLUT1 with certain co-expression properties with immunosenescence markers. We further demonstrated its positive modulation ability of proliferation, migration, and gemcitabine resistance in pancreatic cancer cells. To conclude, our study focused on training of composite machine learning algorithms in multiple datasets to develop a robust machine learning modeling system based on immunosenescence and to identify an immunosenescence-related microenvironment windsock, providing direction and guidance for clinical prediction and application.

Lesion region inpainting: an approach for pseudo-healthy image synthesis in intracranial infection imaging.

The synthesis of pseudo-healthy images, involving the generation of healthy counterparts for pathological images, is crucial for data augmentation, clinical disease diagnosis, and understanding pathology-induced changes. Recently, Generative Adversarial Networks (GANs) have shown substantial promise in this domain. However, the heterogeneity of intracranial infection symptoms caused by various infections complicates the model's ability to accurately differentiate between pathological and healthy regions, leading to the loss of critical information in healthy areas and impairing the precise preservation of the subject's identity. Moreover, for images with extensive lesion areas, the pseudo-healthy images generated by these methods often lack distinct organ and tissue structures. To address these challenges, we propose a three-stage method (localization, inpainting, synthesis) that achieves nearly perfect preservation of the subject's identity through precise pseudo-healthy synthesis of the lesion region and its surroundings. The process begins with a Segmentor, which identifies the lesion areas and differentiates them from healthy regions. Subsequently, a Vague-Filler fills the lesion areas to construct a healthy outline, thereby preventing structural loss in cases of extensive lesions. Finally, leveraging this healthy outline, a Generative Adversarial Network integrated with a contextual residual attention module generates a more realistic and clearer image. Our method was validated through extensive experiments across different modalities within the BraTS2021 dataset, achieving a healthiness score of 0.957. The visual quality of the generated images markedly exceeded those produced by competing methods, with enhanced capabilities in repairing large lesion areas. Further testing on the COVID-19-20 dataset showed that our model could effectively partially reconstruct images of other organs.

Proteus syndrome with progressive paralysis of the unilateral lower limb: A rare case report and literature review.

Objective: Proteus syndrome, a rare disorder with an incidence of one in a million, is characterized by connective tissue nevi, asymmetric limb overgrowth, and abnormal subcutaneous adipose tissue distribution. Limited awareness of this condition often hinders accurate clinical diagnosis. We report a case of Proteus syndrome with concurrent progressive paralysis in the unilateral lower limb, aiming to enhance understanding of the disease and its associated complications. Methods: The patient, an 11-year-old male, has been conclusively diagnosed with Proteus Syndrome. This diagnosis was established by analyzing clinical manifestations, imaging studies, and laboratory tests. In addition, a literature review was conducted to systematically elucidate the etiology, diagnosis, treatment, and prognosis of this condition. Results: According to the clinical manifestations, we confirmed a case of Proteus syndrome. This example exhibits the general characteristics of patients with severe hemihypertrophy of the bilateral lower limbs, anomalies in hypodermic and adipose distribution, and unilateral lower limb progressive paralysis. Pathological biopsy confirmed the right chest wall mass as a lipoma. Notably, the patient experiences lower limb movement disorders caused by intraspinal disease. At the same time, the gene sequencing results of this Proteus syndrome patient showed mutations in the IDUS gene and SPECC1L gene, which have not been reported before. Conclusion: We diagnosed Proteus Syndrome with lower limb sensorimotor abnormalities, which may be caused by mutations in the IDUS gene or SPECC1L gene. This is the first report of these kinds of gene mutations in association with Proteus Syndrome.

The Correlation between Epicardial Adipose Tissue Thickness Measured by Echocardiography and P-Wave Dispersion and Atrial Fibrillation.

Background: Recent studies have indicated a close relationship between the thickness of epicardial adipose tissue (EAT) and the occurrence as well as persistence of atrial fibrillation (AF). However, the pathogenesis of this association is still in the exploratory stage. The aim of this study is to explore the correlation EAT, as measured by echocardiography, and P-wave dispersion (Pd) in the context of atrial fibrillation. Additionally, the study seeks to analyze the utility of EAT at different anatomical sites in identifying individuals who are predisposed to atrial fibrillation. Methods: A total of 136 subjects were enrolled and categorized into groups based on the guidelines: paroxysmal atrial fibrillation group (PAF group), persistent atrial fibrillation group (AF group), and non-atrial fibrillation group. Comprehensive clinical data, including general information and medications that could impact the occurrence of atrial fibrillation, were gathered for all patients. Echocardiography was employed to measure the maximum EAT thickness near the apex of the heart on the anterior right ventricular wall and near the base of the right ventricle for each participant. Pd values were computed for each patient based on standard 12-lead synchronous electrocardiogram (ECG). The study involved comparing the disparity in EAT thickness between the two specified sites across the three groups. Additionally, correlation analyses were performed to assess the relationship between EAT thickness at the two sites and Pd. Regression analysis was applied to explore potential risk factors for atrial fibrillation. The diagnostic value of EAT at each site in predicting atrial fibrillation was evaluated using Receiver Operating Characteristic curve (ROC) analysis. Results: EAT thickness of the anterior wall near the apex of the heart and near the base of the right ventricle were significantly positively correlated with Pd (p < 0.05), EAT thickness near the base and left atrial diameter were independent risk factors for atrial fibrillation (OR = 13.673, 95% CI 2.819~66.316, p = 0.001; OR = 2.294, 95% CI 1.020~5.156, p = 0.045). ROC analysis showed that the area under the curve of EAT thickness near the heart base was 0.723, and the best threshold for predicting the occurrence of AF was 1.05 cm. Conclusions: The echocardiography-measured epicardial adipose tissue thickness, particularly in proximity to the heart base, exhibits a significant correlation with Pd. Notably, EAT thickness near the heart base demonstrates superior predictive capability for atrial fibrillation compared to thickness near the apex.

Pharmacological Mechanism of Chinese Medicine in Systemic Lupus Erythematosus: A Narrative Review.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder affecting multiple systems, characterized by the development of harmful autoantibodies and immune complexes that lead to damage in organs and tissues. Chinese medicine (CM) plays a role in mitigating complications, enhancing treatment effectiveness, and reducing toxicity of concurrent medications, and ensuring a safe pregnancy. However, CM mainly solves the disease comprehensively through multi-target and multi-channel regulation process, therefore, its treatment mechanism is often complicated, involving many molecular links. This review introduces the research progress of pathogenesis of SLE from the aspects of genetics, epigenetics, innate immunity and acquired immunity, and then discusses the molecular mechanism and target of single Chinese herbal medicine and prescription that are commonly used and effective in clinic to treat SLE.

Efficacy and safety of vonoprazan and high dose amoxicillin dual therapy in eradicating Helicobacter pylori: A systematic review and meta-analysis.

BACKGROUND: Vonoprazan, the new acid suppressive drug, provides more choices for eradicating H. pylori. Therefore, whether vonoprazan and high dose amoxicillin dual therapy is more effective and safer requires a systematic analysis. MATERIALS AND METHODS: A comprehensive search of the literature from PubMed, Embase, Cochrane Library, Web of Science database, up to May 16, 2024. Trails evaluating H. pylori eradicating rates, adverse events, and compliance of VHA dual therapy compared with other therapies were included. RevMan 5.4 was used for statistical analysis. RESULTS: 11 RCTs and 2 retrospective clinical studies with 4570 samples were included. The VHA dual therapy has superior H. pylori eradicating rates (ITT: 86.0% vs 80.7%, OR=1.36, 95% CI 1.07-1.73, P=0.01; PP: 90.6% vs 85.7%, OR=1.42, 95% CI 1.07-1.88, P=0.02), fewer adverse events(15.4% vs 27.7%, OR=0.49, 95%CI 0.35-0.68, P<0.0001), and similar compliance (94.6% vs 93.2%, OR=1.27, 95% CI 0.98-1.64, P=0.07) in comparison to other guideline therapies. According to subgroup analysis with PP data, VHA is more effective than P-BQT (93.5% vs 89.3%, OR=1.76, 95% CI 1.03-3.00, P=0.04). In addition, the eradicating rates of 10-day and 14-day VHA were 92% (95% CI 0.91-0.94) and 93% (95% CI 0.90-0.97) respectively, with the 7-day VHA 65% (95% CI 0.55-0.75). CONCLUSION: VHA dual therapy, for 10 or 14 days showed superior efficacy and safety comparing with therapies recommended by the guidelines, should be prioritized for adoption.

Bonding Behavior and Quality of Pressureless Ag Sintering on (111)-Oriented Nanotwinned Cu Substrate in Ambient Air.

(111)-oriented nanotwinned Cu ((111)nt-Cu) has shown its high surface diffusion rate and better oxidation resistance over common polycrystalline Cu (C-Cu). The application of (111)nt-Cu as an interface metallization layer in Ag-sintered technology under the role of oxygen was investigated in this work, and its connecting behavior was further clarified by comparing it with C-Cu. As the sintering temperature decreasing from 300 to 200 °C, the shear strength on the (111)nt-Cu substrate was still greater than 55 MPa after sintering for 10 min. The fracture surface correspondingly changed from the interface of Ag/die to mixed fracture mode, involving the interface of the Ag/Cu substrate and Ag/die. The existence of copper oxide provided a tight connection between Ag and the (111)nt-Cu substrate at all of the studied temperatures. Although lots of small dispersed voids were seen at the interface between copper oxide and (111)nt-Cu at 300 °C, these impurity-induced voids would not necessarily be a failure position and could be improved by adjusting the sintering temperature and time; for example, 200 °C/10 min or heating to 300 °C, and then start cooling at the same time. The microstructure of Ag-Cu joint on (111)nt-Cu behaved better than that on C-Cu. The thinner copper oxide layer and the higher connection ratio of the interface between copper oxide and Ag were still found on the (111)nt-Cu connection's structure. The poor connection between copper oxide and Ag on C-Cu easily became the failure interface. By controlling the thickness of copper oxide and the content of impurity-induced voids, the use of (111)nt-Cu in advanced-packaging could be improved to a new level.

Network pharmacology-based study on the mechanism of action of Trollius chinensis capsule in the treatment of upper respiratory tract infection.

BACKGROUND: Upper respiratory tract infection (URTI), one of the most common respiratory diseases, has a high annual incidence. Trollius chinensis capsule has been used to treat URTI in China. However, the underlying-mechanisms remain unclear. METHODS: Network pharmacology was used to explore the potential mechanism of action of Trollius chinensis capsule in URTI treatment. The active compounds in Trollius chinensis were obtained from the TCMSP, SymMap, and ETCM databases. The TCMSP, PubChem, and SwissTargetPrediction databases were used to predict potential targets of Trollius chinensis. URTI-associated targets were gathered from GeneCards and DisGeNET databases. The key targets and signaling pathways associated with URTI were selected by network topology, GO, and KEGG pathway enrichment analysis. Molecular docking was used to verify the binding activity between active compounds and key targets. RESULTS: Quercetin, pectolinarigenin, beta-sitosterol, acacetin and cirsimaritin are major active compounds in Trollius chinensis capsule. Eighty one candidate therapeutic targets were confirmed to be involved in protection of Trollius chinensis capsule against URTI. Among them, 7 key targets (TP53, IL6, AKT1, CASP3, CXCL8, MMP9, and EGFR) were verified to have good binding affinities to the main active compounds. Furthermore, enrichment analyses suggested that inflammatory response, virus infection and oxidative stress related biological processes and pathways were possibly the potential mechanism. CONCLUSION: Overall, the present study clarified that quercetin, pectolinarigenin, beta-sitosterol, acacetin and cirsimaritin are proved to be the main effective compounds of Trollius chinensis capsule treating URTI, possibly by acting on the targets of IL6, AKT1, CASP3, CXCL8, MMP9 and EGFR to play anti-infectious, anti-viral, and anti-oxidative effects. This study provides a new understanding of the active compounds and mechanisms of Trollius chinensis capsule in URTI treatment from the perspective of network pharmacology.

From immune dysregulation to organ dysfunction: understanding the enigma of Sepsis.

Sepsis is a syndrome precipitated by immune dysregulation in response to infection, and represents a pivotal factor in global mortality attributed to diseases. The recent consensus delineates sepsis as a perilous state of organ dysfunction arising from the host's maladaptive reaction to infection. It masks the complexity and breadth of the immune mechanisms involved in sepsis, which is characterized by simultaneous hyperinflammation and immunosuppression. Sepsis is highly correlated with the dysregulation of immune response, which is mainly mediated by various immune cells and their interactions. This syndrome can lead to a plethora of complications, encompassing systemic inflammatory response, metabolic disturbances, infectious shock, MODS, and DIC. Furthermore, more research studies have been conducted on sepsis in the past few years. The pathological characteristics of sepsis have been improved or treated by targeting signaling pathways like NF-B, JAK-STAT, PI3K-Akt, and p38-MAPK. Combined drug therapy is better than single drug therapy for sepsis. This article will review the latest progress in the pathogenesis and treatment of sepsis.

New drug combination regimen based on pharmacokinetic characteristics-Erdafitinib combined with sertraline or duloxetine.

The aim of this study is to investigate novel strategies for reducing adverse reactions caused by erdafitinib through a drug combination based on its pharmacokinetic characteristics. The spectrum and characterizations of drugs that can inhibit the metabolism of erdafitinib are examined both in vitro and in vivo. The efficacy of combination regimens are then evaluated using subcutaneous xenograft tumor models. The results demonstrated that sertraline and duloxetine, out of more than 100 screened drugs, inhibited the metabolism of erdafitinib through mixed and non-competitive inhibition, respectively. This inhibition primarily occurred via the CYP2C9 and CYP2D6 pathways. The primary alleles of CYP2C9 and CYP2D6 not only determine the metabolic characteristics of erdafitinib but also influence the strength of drug-drug interactions. Co-administration of sertraline or duloxetine with erdafitinib in rats and mice resulted in nearly a three-fold increase in the blood exposure of erdafitinib and its major metabolite M6. When sertraline or duloxetine was combined with 1/3 of the erdafitinib dosage, the anti-proliferative and pro-apoptotic effects on SNU-16 xenografts were comparable to those of the original full dose of erdafitinib. However, the combination regimen significantly mitigated hyperphosphatemia, retinal damage, intestinal villus damage, and gut microbiome dysbiosis. This study utilized pharmacokinetic methods to propose a new formulation of erdafitinib combined with sertraline or duloxetine. The findings suggest that this combination has potential for clinical co-administration based on a database analysis, thereby providing a novel strategy for anti-tumor treatment with fibroblast growth factor receptor (FGFR) inhibitors.

Sevoflurane anesthesia during late gestation induces cognitive disorder in rat offspring via the TLR4/BDNF/TrkB/CREB pathway.

Sevoflurane (Sevo) is widely used for general anesthesia during pregnancy. Emerging evidence indicates that maternal Sevo exposure can trigger developmental neurotoxicity in the offspring. Nonetheless, the underlying mechanisms need further investigation. Pregnant Sprague-Dawley rats on gestational day 18 were exposed to 3.5% Sevo to induce the rat model of neurotoxicity. TAK-242, a TLR4 inhibitor, was administrated to inhibit the signaling transduction. Hippocampal tissues of rat offspring were harvested for immunohistochemical staining, TUNEL staining, Western blotting, ELISA, and measurement of oxidative stress-related markers. Serum samples were collected to evaluate lipid metabolism-associated factors. Morris water maze was implemented to test the cognitive function of offspring rats. Rat hippocampal neurons were isolated to elucidate the effect of TAK-242 on the BDNF/TrkB/CREB signaling in vitro. The results showed that maternal Sevo exposure during the third trimester induced neuroinflammation, lipid metabolism disturbance, and oxidative stress, and impaired the spatial learning and memory of rat offspring. Sevo upregulated TLR4 and impeded BDNF/TrkB/CREB signaling transduction in the hippocampus of rat offspring; TAK-242 administration reversed these effects. In conclusion, Sevo anesthesia during late gestation impairs the learning and memory ability of rat offspring possibly by promoting neuroinflammation and disturbing lipid metabolism via the TLR4/BDNF/TrkB/CREB pathway.

Embryonic Genome Activation (EGA) Occurred at 1-Cell Stage of Embryonic Development in the Mud Crab, Scylla paramamosain, Revealed by RNA-Seq.

As a prerequisite for the success of embryo development, embryonic genome activation (EGA) is an important biological event in which zygotic gene products in the embryo are activated to replace maternal-derived transcripts. Although EGA has been extensively studied in a large number of vertebrates and invertebrates, there is a lack of information regarding this event in crustacean crab. In this study, the timing of EGA was confirmed by examining a transcriptomic dataset of early embryonic development, including mature oocytes and embryos through six early developmental stages, and signaling pathways associated with EGA were identified in the mud crab, S. paramamosain. The comprehensive transcriptomic data identified a total of 53,915 transcripts from these sequencing samples. Notable transcriptomic change was evident at the 1-cell stage, indicated by a 36% transcript number shift and a reduction in transcript fragment length, compared to those present in the mature oocytes. Concurrently, a substantial increase in the expression of newly transcribed transcripts was observed, with gene counts reaching 3485 at the 1-cell stage, indicative of the onset of EGA. GO functional enrichment revealed key biological processes initiated at the 1-cell stage, such as protein complex formation, protein metabolism, and various biosynthetic processes. KEGG analysis identified several critical signaling pathways activated during EGA, including the "cell cycle," "spliceosome," "RNA degradation", and "RNA polymerase", pathways. Furthermore, transcription factor families, including zinc finger, T-box, Nrf1, and Tub were predominantly enriched at the 1-cell stage, suggesting their pivotal roles in regulating embryonic development through the targeting of specific DNA sequences during the EGA process. This groundbreaking study not only addresses a significant knowledge gap regarding the developmental biology of S. paramamosain, especially for the understanding of the mechanism underlying EGA, but also provides scientific data crucial for the research on the individual synchronization of seed breeding within S. paramamosain aquaculture. Additionally, it serves as a reference basis for the study of early embryonic development in other crustacean species.

The Effectiveness of Artificial Intelligence-based Pedicle Screw Trajectory Planning in Patients With Different Levels of Bone Mineral Density.

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: To evaluate the effectiveness of pedicle screw trajectory planning based on artificial intelligence (AI) software in patients with different levels of bone mineral density (BMD). SUMMARY OF BACKGROUND DATA: AI-based pedicle screw trajectory planning has potential to improve pullout force (POF) of screws. However, there is currently no literature investigating the efficacy of AI-based pedicle screw trajectory planning in patients with different levels of BMD. METHODS: The patients were divided into 5 groups (group A-E) according to their BMD. The AI software utilizes lumbar spine CT data to perform screw trajectory planning and simulate AO screw trajectories for bilateral L3-5 vertebral bodies. Both screw trajectories were subdivided into unicortical and bicortical modes. The AI software automatically calculating the POF and pullout risk of every screw trajectory. The POF and risk of screw pullout for AI-planned screw trajectories and AO standard trajectories were compared and analyzed. RESULTS: Forty-three patients were included. For the screw sizes, AI-planned screws were greater in diameter and length than those of AO screws (P<0.05). In groups B-E, the AI unicortical trajectories had a POF of over 200N higher than that of AO unicortical trajectories. POF was higher in all groups for the AI bicortical screw trajectories compared with the AO bicortical screw trajectories (P<0.05). AI unicortical trajectories in groups B-E had a lower risk of screw pullout compared with that of AO unicortical trajectories (P<0.05). CONCLUSIONS: AI unicortical screw trajectory planning for lumbar surgery in patients with BMD of 40-120 mg/cm3 can significantly improve screw POF and reduce the risk of screw pullout.

Deep brain stimulation and pallidotomy in primary Meige syndrome: a prospective cohort study.

BACKGROUND: Primary Meige syndrome (PMS) is a rare form of dystonia, and comparative analysis of globus pallidus internal deep brain stimulation (GPi-DBS), subthalamic nucleus deep brain stimulation (STN-DBS), and pallidotomy has been lacking. This study aims to compare the efficacy, safety, and psychiatric features of GPi-DBS, STN-DBS, and pallidotomy in patients with PMS. METHODS: This prospective cohort study was divided into three groups: GPi-DBS, STN-DBS, and pallidotomy. Clinical assessments, including motor and non-motor domains, were evaluated at baseline and at 1 year and 3 years after neurostimulation/surgery. RESULTS: Ninety-eight patients were recruited: 46 patients received GPi-DBS, 34 received STN-DBS, and 18 underwent pallidotomy. In the GPi-DBS group, the movement score of the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) improved from a mean (SE) of 13.8 (1.0) before surgery to 5.0 (0.7) (95% CI, -10.5 to -7.1; P < 0.001) at 3 years. Similarly, in the STN-DBS group, the mean (SE) score improved from 13.2 (0.8) to 3.5 (0.5) (95% CI, -10.3 to -8.1; P < 0.001) at 3 years, and in the pallidotomy group, it improved from 14.9 (1.3) to 6.0 (1.1) (95% CI, -11.3 to -6.5; P < 0.001) at 3 years. They were comparable therapeutic approaches for PMS that can improve motor function and quality of life without non-motor side effects. CONCLUSIONS: DBS and pallidotomy are safe and effective treatments for PMS, and an in-depth exploration of non-motor symptoms may be a new entry point for gaining a comprehensive understanding of the pathophysiology.