Unified Multi-modal Diagnostic Framework with Reconstruction Pre-training and Heterogeneity-combat Tuning.

Medical multi-modal pre-training has revealed promise in computer-aided diagnosis by leveraging large-scale unlabeled datasets. However, existing methods based on masked autoencoders mainly rely on data-level reconstruction tasks, but lack high-level semantic information. Furthermore, two significant heterogeneity challenges hinder the transfer of pre-trained knowledge to downstream tasks, i.e., the distribution heterogeneity between pre-training data and downstream data, and the modality heterogeneity within downstream data. To address these challenges, we propose a Unified Medical Multi-modal Diagnostic (UMD) framework with tailored pre-training and downstream tuning strategies. Specifically, to enhance the representation abilities of vision and language encoders, we propose the Multi-level Reconstruction Pre-training (MR-Pretrain) strategy, including a feature-level and data-level reconstruction, which guides models to capture the semantic information from masked inputs of different modalities. Moreover, to tackle two kinds of heterogeneities during the downstream tuning, we present the heterogeneity-combat downstream tuning strategy, which consists of a Task-oriented Distribution Calibration (TD-Calib) and a Gradient-guided Modality Coordination (GM-Coord). In particular, TD-Calib fine-tunes the pre-trained model regarding the distribution of downstream datasets, and GM-Coord adjusts the gradient weights according to the dynamic optimization status of different modalities. Extensive experiments on five public medical datasets demonstrate the effectiveness of our UMD framework, which remarkably outperforms existing approaches on three kinds of downstream tasks.

The value of SINO robot combined with Angio Render technology-assisted stereo-electroencephalography electrode implantation for the treatment of drug-resistant epilepsy.

BACKGROUND AND OBJECTIVE: Stereo-electroencephalography (SEEG) electrodes are implanted using a variety of stereotactic technologies to treat refractory epilepsy. The value of SINO-robot for SEEG electrode implantation is rarely reported. The aim of the current study was to assess the value of SINO-robot in conjunction with Angio Render technology, in SEEG electrode implantation. We also assess its efficacy by examining factors such as localization error, operation time, and complications. METHODS: Between June 2018 and October 2020, we retrospectively reviewed 58 patients who underwent SEEG implantation to resect or ablate their epileptogenic zone (EZ) while minimizing the risk of hemorrhage. SINO-robot combined with Angio Render technology-assisted SEEG electrode implantation was used to visualize each patient' blood vessel in a 3D plane. The 3D view functionality was used to increase the safety and accuracy of the implantation, and reducing the risk of hemorrhage by avoiding said blood vessel. RESULTS: In this study, 634 SEEG electrodes were implanted in 58 patients. The mean 10.92(range 5- 18) leads per patient. The mean entry point localization error (EPLE) was 0.94 ± 0.23 mm (range: 0.39- 1.63 mm), and the mean target point localization error (TPLE) was 1.49 ± 0.37 mm (range: 0.80-2.78 mm). The mean operating time per lead (MOTPL) was 6. 18 ± 1.80 min (range: 3.02- 14.61 min). And the mean depth of electrodes was 56.96± 3.62 mm (range:27.23-124.85 mm). At a follow-up of at least one year, totally 81.57% (47/58) of patients achieved an Engel class I of seizure freedom. There were 2 patients with asymptomatic brain hematomas following SEEG placement, and no late complications or mortality in this cohort. CONCLUSIONS: SINO-robot in conjunction with Angio Render technology assist, in SEEG electrode implantation is safe and accurate in mitigating the risk of intracranial hemorrhage in patients suffering from drug-resistant epilepsy.

Differential diagnosis of Crohn's disease and intestinal tuberculosis based on ATR-FTIR spectroscopy combined with machine learning.

BACKGROUND: Crohn's disease (CD) is often misdiagnosed as intestinal tuberculosis (ITB). However, the treatment and prognosis of these two diseases are dramatically different. Therefore, it is important to develop a method to identify CD and ITB with high accuracy, specificity, and speed. AIM: To develop a method to identify CD and ITB with high accuracy, specificity, and speed. METHODS: A total of 72 paraffin wax-embedded tissue sections were pathologically and clinically diagnosed as CD or ITB. Paraffin wax-embedded tissue sections were attached to a metal coating and measured using attenuated total reflectance fourier transform infrared spectroscopy at mid-infrared wavelengths combined with XGBoost for differential diagnosis. RESULTS: The results showed that the paraffin wax-embedded specimens of CD and ITB were significantly different in their spectral signals at 1074 cm-1 and 1234 cm-1 bands, and the differential diagnosis model based on spectral characteristics combined with machine learning showed accuracy, specificity, and sensitivity of 91.84%, 92.59%, and 90.90%, respectively, for the differential diagnosis of CD and ITB. CONCLUSION: Information on the mid-infrared region can reveal the different histological components of CD and ITB at the molecular level, and spectral analysis combined with machine learning to establish a diagnostic model is expected to become a new method for the differential diagnosis of CD and ITB.

Potent human neutralizing antibodies against Nipah virus derived from two ancestral antibody heavy chains.

Nipah virus (NiV) is a World Health Organization priority pathogen and there are currently no approved drugs for clinical immunotherapy. Through the use of a naïve human phage-displayed Fab library, two neutralizing antibodies (NiV41 and NiV42) targeting the NiV receptor binding protein (RBP) were identified. Following affinity maturation, antibodies derived from NiV41 display cross-reactivity against both NiV and Hendra virus (HeV), whereas the antibody based on NiV42 is only specific to NiV. Results of immunogenetic analysis reveal a correlation between the maturation of antibodies and their antiviral activity. In vivo testing of NiV41 and its mature form (41-6) show protective efficacy against a lethal NiV challenge in hamsters. Furthermore, a 2.88 Å Cryo-EM structure of the tetrameric RBP and antibody complex demonstrates that 41-6 blocks the receptor binding interface. These findings can be beneficial for the development of antiviral drugs and the design of vaccines with broad spectrum against henipaviruses.

Kinetic Resolution of Helicenols via Palladium-Catalyzed Atroposelective C-C Bond Cleavage/Ring-Opening Reaction.

Helicenes represent a class of inherently chiral structures that lack conventional chiral elements, such as stereogenic centers, chiral axes, or plane. The asymmetric synthesis of these helical compounds can be particularly challenging as a result of their pronounced molecular strain. In this study, we report a palladium-catalyzed atroposelective carbon-carbon bond cleavage reaction of helical tertiary alcohols. Because the helical alcohols are configurationally stable, the reaction proceeded through a kinetic resolution pathway, resulting in achieving optically active helicenols alongside the sterically hindered axially chiral products.

Methods, Mechanisms, and Application Prospects for Enhancing Extracellular Vesicle Uptake.

Extracellular vesicles (EVs) are considered to be a new generation of bioinspired nanoscale drug delivery systems due to their low immunogenicity, natural functionality, and excellent biocompatibility. However, limitations such as low uptake efficiency, insufficient production, and inhomogeneous performance undermine their potential. To address these issues, numerous researchers have put forward various methods and applications for enhancing EV uptake in recent decades. In this review, we introduce various methods for the cellular uptake of EVs and summarize recent advances on the methods and mechanisms for enhancing EV uptake. In addition, we provide further understanding regarding enhancing EV uptake and put forward prospects and challenges for the development of EV-based therapy in the future.

Comparing fetal ultrasound biometric measurements to neonatal anthropometry at the extremes of birthweight.

OBJECTIVE: Error in birthweight prediction by sonographic estimated fetal weight (EFW) has clinical implications, such as avoidable cesarean or misclassification of fetal risk in labor. We aimed to evaluate optimal timing of ultrasound and which fetal measurements contribute to error in fetal ultrasound estimations of birth size at the extremes of birthweight. STUDY DESIGN: We compared differences in head circumference (HC), abdominal circumference (AC), femur length (FL), and EFW between ultrasound and corresponding birth measurements within 14 (n=1290) and 7 (n=617) days of birth for small (SGA, <10th percentile), appropriate (AGA, 10th-90th), and large-for-gestational age (LGA, >90th) newborns. RESULTS: Average differences between EFW and birthweight for SGA neonates were: -40.2g (CI -82.1, 1.6) at 14 days vs. 13.6g (CI -52.4, 79.7) at 7 days; for AGA, -122.4g (-139.6, -105.1) at 14 days vs.-27.2g (-50.4, -4.0) at 7 days; and for LGA, -242.8g (-306.5, -179.1) at 14 days vs. -72.1g (-152.0, 7.9) at 7 days. Differences between fetal and neonatal HC were larger at 14 versus 7 days, and similar to patterns for EFW and birthweight, differences were largest for LGA at both intervals. In contrast, differences between fetal and neonatal AC were larger at 7 versus 14 days, suggesting larger error in AC estimation closer to birth. CONCLUSIONS: Using a standardized ultrasound protocol, SGA neonates had ultrasound measurements closer to actual birth measurements compared to AGA or LGA neonates. LGA neonates had the largest differences between fetal and neonatal size, with measurements 14 days from delivery showing 3-4-fold greater differences from birthweight. Differences in EFW and birthweight may not be explained by a single fetal measurement; whether estimation may be improved by incorporation of other knowable factors should be evaluated in future research.

New anti-inflammatory limonoids from the fruits of Melia azedarach.

The phytochemical study of the fruits of Melia azedarach (Meliaceae) led to the isolation and characterisation of two novel natural limonoids1-deoxy- 3, 20-dicinnamoyl-11-methoxy-meliacarpinin (1) and 12ß- O- methyl nimbolinin A (2), along with twelve known limonoids. Its structure was identified by 1D- and 2D-NMR, HR-ESI-MS and comparison with published data. The anti-inflammatory effect of the compounds was measured in vitro in RAW 264.7 cells by evaluating the production of NO stimulated by LPS. Compounds 1, 8 and 14 indicated significant anti-inflammatory effect with inhibition rate of 11.76, 8.45 and 6.59 µM, respectively. Limonoid 1 significantly inhibited the production of NO, TNF-α and IL-1ß in RAW 264.7 cells. Therefore, limonoid derivative may be a promising source of bioactive metabolite for inflammatory diseases.

Observation on the Analgesic Effect of Different Doses of a Combination of Esketamine and Dexmedetomidine Administered for Percutaneous Endoscopic Transforaminal Discectomy: A Randomized, Double-Blind Controlled Trial.

BACKGROUND: Percutaneous endoscopic transforaminal discectomy (PETD) is an effective method for treating lumbar disc herniation, and is typically performed under local anesthesia. However, inadequate analgesia during the procedure remains a concern, prompting the search for a medication that can provide optimal pain control with minimal impact on the respiratory and circulatory systems. OBJECTIVES: The aim of this study was to observe the effects of different doses of esketamine combined with dexmedetomidine on reducing visual analog scale (VAS) scores during surgical interventions. METHODS: One hundred two patients who underwent PETD were randomly divided into a control group (group C: normal saline + dexmedetomidine), an E1 group (0.1 mg kg-1 esketamine + dexmedetomidine), and an E2 group (0.2 mg kg-1 esketamine + dexmedetomidine). The primary outcome was the maximum visual analogue scale (VAS) (score: 0 = no pain and 10 = worst pain) at six time points. The secondary outcomes included the Assessment of Alertness/Sedation Scale (OAA/S) score and mean arterial pressure (BP), heart rate (HR), respiratory rate (RR), and oxygen saturation (SpO2) at 11 time points. The incidence of adverse reactions during and 24 h after the operation and patient satisfaction with the anesthesia were also recorded. RESULTS: Compared with those in group C, the VAS scores of patients in groups E1 and E2 were lower at T6, T7, and T9 (P < 0.05). From T4 to T10, the OAA/S scores of the E1 and E2 groups were both lower than those of group C (P < 0.05), and at the T4-T6 time points, the OAA/S score of the E2 group was lower than that of group E1 (P < 0.05). At T4 and T5, the HR and BP of patients in groups E1 and E2 were greater than those in group C (P < 0.05). Compared with those in group C, the incidences of intraoperative illusion, floating sensation, postoperative dizziness, and hyperalgesia in groups E1 and E2 were significantly greater (P < 0.01). There was no significant difference in patient RR, SpO2, or postoperative satisfaction with anesthesia among the three groups (P > 0.05). CONCLUSION: The combination of esketamine and dexmedetomidine can reduce VAS scores during certain stages of this type of surgery; it has minimal impact on respiration and circulation. However, this approach is associated with increased incidences of postoperative dizziness and psychiatric side effects, which may also affect patients' compliance with surgical instructions from medical staff. Patient satisfaction was not greater with dexmedetomidine combined with esketamine than with dexmedetomidine alone. TRIAL REGISTRATION: http://www.chictr.org.cn . Identifier: ChiCTR2300068206. Date of registration: 10 February 2023.

Multi-omics analysis reveals that linoleic acid metabolism is associated with variations of trained immunity induced by distinct BCG strains.

Trained immunity is one of the mechanisms by which BCG vaccination confers persistent nonspecific protection against diverse diseases. Genomic differences between the different BCG vaccine strains that are in global use could result in variable protection against tuberculosis and therapeutic effects on bladder cancer. In this study, we found that four representative BCG strains (BCG-Russia, BCG-Sweden, BCG-China, and BCG-Pasteur) covering all four genetic clusters differed in their ability to induce trained immunity and nonspecific protection. The trained immunity induced by BCG was associated with the Akt-mTOR-HIF1α axis, glycolysis, and NOD-like receptor signaling pathway. Multi-omics analysis (epigenomics, transcriptomics, and metabolomics) showed that linoleic acid metabolism was correlated with the trained immunity-inducing capacity of different BCG strains. Linoleic acid participated in the induction of trained immunity and could act as adjuvants to enhance BCG-induced trained immunity, revealing a trained immunity-inducing signaling pathway that could be used in the adjuvant development.

High-Flow Nasal Oxygen versus Conventional Nasal Cannula in Preventing Hypoxemia in Elderly Patients Undergoing Gastroscopy with Sedation: A Randomized Controlled Trial.

Background: We aimed to compare the prevention of hypoxemia using High-flow nasal oxygen (HFNO) or regular nasal tubing (CNC) in elderly patients undergoing gastroscopy with sedation. Methods: This study was a prospective, randomized, controlled trial conducted at a single center. We included elective patients aged 65 and above who were undergoing gastroscopy with sedation. In the intervention group (HFNO), we set the oxygen flow rate to 60 liters per minute with an oxygen fraction (FiO2) of 0.6, while in the control group (CNC), it was 6 liters per minute. The primary outcome was the occurrence of hypoxemia (defined as Spo2 < 90%). Results: A total of 125 participants were enrolled (HFNO group: n = 63; CNC group: n = 62). The occurrence of hypoxemia was found to be significantly lower in the HFNO group compared to the CNC group (3.2% vs. 22.6%, p = 0.001). Additionally, a significantly shorter duration of low oxygen levels was observed in the HFNO group [0.0 seconds (0.0-13.0)] compared to the CNC group [0.0 seconds (0.0-124.0), p<0.001]. Moreover, a higher minimum Spo2 value was achieved in the HFNO group [99.0% (98.0-100.0) vs. 96.5% (91.0-99.0), p < 0.001], and a shorter recovery time was recorded [0.5 minutes (0.0-0.5) vs. 0.5 minutes (0.0-1.0), p = 0.016] in comparison to the CNC group. There were no differences in terms of comfort level [0 (0-4) vs. 0 (0-5), p = 0.268] between the two groups. Conclusions: The HFNO system was determined to be a safe and highly effective method for oxygen delivery, leading to a reduction in the occurrence of hypoxemia in elderly patients undergoing gastroscopy with sedation. It is recommended that HFNO be considered as the standard approach for management in this population.

The pathological mechanisms and potential therapeutic drugs for myocardial ischemia reperfusion injury.

BACKGROUND: Cardiovascular disease is the main cause of death and disability, with myocardial ischemia being the predominant type that poses a significant threat to humans. Reperfusion, an essential therapeutic approach, promptly reinstates blood circulation to the ischemic myocardium and stands as the most efficacious clinical method for myocardial preservation. Nevertheless, the restoration of blood flow associated with this process can potentially induce myocardial ischemia-reperfusion injury (MIRI), thereby diminishing the effectiveness of reperfusion and impacting patient prognosis. Therefore, it is of great significance to prevent and treat MIRI. PURPOSE: MIRI is an important factor affecting the prognosis of patients, and there is no specific in-clinic treatment plan. In this review, we have endeavored to summarize its pathological mechanisms and therapeutic drugs to provide more powerful evidence for clinical application. METHODS: A comprehensive literature review was conducted using PubMed, Web of Science, Embase, Medline and Google Scholar with a core focus on the pathological mechanisms and potential therapeutic drugs of MIRI. RESULTS: Accumulated evidence revealed that oxidative stress, calcium overload, mitochondrial dysfunction, energy metabolism disorder, ferroptosis, inflammatory reaction, endoplasmic reticulum stress, pyroptosis and autophagy regulation have been shown to participate in the process, and that the occurrence and development of MIRI are related to plenty of signaling pathways. Currently, a range of chemical drugs, natural products, and traditional Chinese medicine (TCM) preparations have demonstrated the ability to mitigate MIRI by targeting various mechanisms. CONCLUSIONS: At present, most of the research focuses on animal and cell experiments, and the regulatory mechanisms of each signaling pathway are still unclear. The translation of experimental findings into clinical practice remains incomplete, necessitating further exploration through large-scale, multi-center randomized controlled trials. Given the absence of a specific drug for MIRI, the identification of therapeutic agents to reduce myocardial ischemia is of utmost significance. For the future, it is imperative to enhance our understanding of the pathological mechanism underlying MIRI, continuously investigate and develop novel pharmaceutical agents, expedite the clinical translation of these drugs, and foster innovative approaches that integrate TCM with Western medicine. These efforts will facilitate the emergence of fresh perspectives for the clinical management of MIRI.

Total Synthesis of Quebrachamine and Kopsiyunnanine D.

The total syntheses of (±)-quebrachamine and (±)-kopsiyunnanine D are reported. Key transformations include an intermolecular Horner-Wadsworth-Emmons olefination to merge the two fragments convergently and an intramolecular Mitsunobu reaction to introduce the synthetically challenging nine-membered azonane ring efficiently.

Immunogenicity and safety of an ORF7-deficient skin-attenuated and neuro-attenuated live vaccine for varicella: a randomised, double-blind, controlled, phase 2a trial.

BACKGROUND: The Oka varicella vaccine strain remains neurovirulent and can establish lifelong latent infection, raising safety concerns about vaccine-related herpes zoster. In this study, we aimed to evaluate the immunogenicity and safety of a skin-attenuated and neuro-attenuated varicella vaccine candidate (v7D vaccine). METHODS: We did this randomised, double-blind, controlled, phase 2a clinical trial in Jiangsu, China. Healthy children aged 3-12 years with no history of varicella infection or vaccination were enrolled and randomly assigned (1:1:1:1) to receive a single subcutaneous injection of the v7D vaccine at 3·3 log10 plaque forming units (PFU; low-dose v7D group), 3·9 log10 PFU (medium-dose v7D group), and 4·2 log10 PFU (high-dose v7D group), or the positive control varicella vaccine (vOka vaccine group). All the participants, laboratory personnel, and investigators other than the vaccine preparation and management staff were masked to the vaccine allocation. The primary outcome was assessment of the geometric mean titres (GMTs) and seroconversion rates of anti-varicella zoster virus immunoglobulin G (IgG) induced by different dose groups of v7D vaccine at 0, 42, 60, and 90 days after vaccination in the per-protocol set for humoral immune response analysis. Safety was a secondary outcome, focusing on adverse events within 42 days post-vaccination, and serious adverse events within 6 months after vaccination. This study was registered on Chinese Clinical Trial Registry, ChiCTR2000034434. FINDINGS: On Aug 18-21, 2020, 842 eligible volunteers were enrolled and randomly assigned treatment. After three participants withdrew, 839 received a low dose (n=211), middle dose (n=210), or high dose (n=210) of v7D vaccine, or the vOka vaccine (n=208). In the per-protocol set for humoral immune response analysis, the anti-varicella zoster virus IgG antibody response was highest at day 90. At day 90, the seroconversion rates of the low-dose, medium-dose, and high-dose groups of v7D vaccine and the positive control vOka vaccine group were 100·0% (95% CI 95·8-100·0; 87 of 87 participants), 98·9% (93·8-100·0; 87 of 88 participants), 97·8% (92·4-99·7; 91 of 93 participants), and 96·4% (89·8-99·2; 80 of 83 participants), respectively; the GMTs corresponded to values of 30·8 (95% CI 26·2-36·0), 31·3 (26·7-36·6), 28·2 (23·9-33·2), and 38·5 (31·7-46·7). The v7D vaccine, at low dose and medium dose, elicited a humoral immune response similar to that of the vOka vaccine. However, the high-dose v7D vaccine induced a marginally lower GMT compared with the vOka vaccine at day 90 (p=0·027). In the per-protocol set, the three dose groups of the v7D vaccine induced a similar humoral immune response at each timepoint, with no statistically significant differences. The incidence of adverse reactions in the low-dose, medium-dose, and high-dose groups of v7D vaccine was significantly lower than that in the vOka vaccine group (17% [35 of 211 participants], 20% [41 of 210 participants], and 13% [27 of 210 participants] vs 24% [50 of 208 participants], respectively; p=0·025), especially local adverse reactions (10% [22 of 211 participants], 14% [30 of 210 participants] and 9% [18 of 210 participants] vs 18% [38 of 208 participants], respectively; p=0·016). None of the serious adverse events were vaccine related. INTERPRETATION: The three dose groups of the candidate v7D vaccine exhibit similar humoral immunogenicity to the vOka vaccine and are well tolerated. These findings encourage further investigations on two-dose vaccination schedules, efficacy, and the potential safety benefit of v7D vaccine in the future. FUNDING: The National Natural Science Foundation of China, CAMS Innovation Fund for Medical Sciences, the Fundamental Research Funds for the Central Universities, and Beijing Wantai. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

The Role of Hydrogen Bonds in Thermally Responsive Crystallization-Driven Template Autocatalysis.

Autocatalysis has been well recognized to implicate in the emergence of life and is intrinsic to the biomolecular replication. Recently, an efficient template autocatalysis driven by solvent-free crystallization has been reported. Herein, we unveil the role of intermolecular hydrogen (H) bonds formed by amides in crystallization-driven template autocatalysis (CDTA), which involves the autocatalytic activity, template selectivity, and thermal responsiveness. We found that the thermal-induced cis-trans isomerization of amides possibly affects the H-bonding-mediated template ability of products for autocatalytic transformation. As a result, CDTA can be reversibly inhibited and activated by tuning the reaction temperatures. Our work sheds light on the significance of noncovalent H-bonding interactions in artificial self-replicators.

The tibial capsular reflection and septum in posterior compartment are safe and reliable soft-tissue landmark for tibial tunnel drilling in posterior cruciate ligament reconstruction.

PURPOSE: To investigate the validity of using tibial capsular reflection and septum in the posterior compartment as landmark during posterior cruciate ligament (PCL) reconstruction (PCLR). METHODS: Anatomic measurements were obtained for 12 fresh human cadaveric knee specimens to observe the spatial position of the tibial insertion of the PCL in relation to the posterior septum and the capsular reflection in the posterior compartment. Sixty patients who underwent reconstruction of the PCL between 2020 and 2023 were also retrospectively investigated. The tibial tunnel was replaced in all patients using the same method (with reference to the tibial capsular reflection and the posterior septum). The placement of the tibial tunnel was assessed using X-ray fluoroscopy intraoperatively and computed tomography and three-dimensional reconstruction postoperatively. RESULTS: All fibres in the tibial insertion of the PCL in the 12 cadaveric specimens were located in the posteromedial compartment, adjacent to the posterior septum. The inferior border of the PCL insertion is adjacent to the tibial capsular reflection, which is attached at the champagne glass drop-off of the posterior tibia. In our previous cases, none of the patients experienced postoperative or intraoperative complications such as neurovascular injury, and the angle between the pin and the PCL facet was 93.1 ± 3.9° as measured on intraoperative radiographs. The mean distance from the centre of the tibial tunnel outlet to the inferior border of the PCL insertion was 5.6 ± 1.1 mm, and the distance from the centre of the tibial tunnel outlet to the outer border of the PCL insertion as a percentage of the length of the inferior border of PCL insertion was 42.2 ± 6.3%. CONCLUSION: The tibial capsular reflection and septum in the posterior compartment are safe and reliable soft-tissue landmark for tibial tunnel drilling in PCLR. LEVEL OF EVIDENCE: Level Ⅳ.

Mechanisms of Action of Potentilla discolor Bunge in Type 2 Diabetes Mellitus Based on Network Pharmacology and Experimental Verification in Drosophila.

Purpose: Type 2 diabetes mellitus (T2DM) is associated with reduced insulin uptake and glucose metabolic capacity. Potentilla discolor Bunge (PDB) has been used to treat T2DM; however, the fundamental biological mechanisms remain unclear. This study aimed to understand the active ingredients, potential targets, and underlying mechanisms through which PDB treats T2DM. Methods: Components and action targets were predicted using network pharmacology and molecular docking analyses. PDB extracts were prepared and validated through pharmacological intervention in a Cg>InRK1409A diabetes Drosophila model. Network pharmacology and molecular docking analyses were used to identify the key components and core targets of PDB in the treatment of T2DM, which were subsequently verified in animal experiments. Results: Network pharmacology analysis revealed five effective compounds made up of 107 T2DM-related therapeutic targets and seven protein-protein interaction network core molecules. Molecular docking results showed that quercetin has a strong preference for interleukin-1 beta (IL1B), IL6, RAC-alpha serine/threonine-protein kinase 1 (AKT1), and cellular tumor antigen p53; kaempferol exhibited superior binding to tumor necrosis factor and AKT1; ß-sitosterol demonstrated pronounced binding to Caspase-3 (CASP3). High-performance liquid chromatography data quantified quercetin, kaempferol, and ß-sitosterol at proportions of 0.030%, 0.025%, and 0.076%, respectively. The animal experiments revealed that PDB had no effect on the development, viability, or fertility of Drosophila and it ameliorated glycolipid metabolism disorders in the diabetes Cg>InRK1409A fly. Furthermore, PDB improved the body size and weight of Drosophila, suggesting its potential to alleviate insulin resistance. Moreover, PDB improved Akt phosphorylation and suppressed CASP3 activity to improve insulin resistance in Drosophila with T2DM. Conclusion: Our findings suggest that PDB ameliorates diabetes metabolism disorders in the fly model by enhancing Akt activity and suppressing CASP3 expression. This will facilitate the development of key drug targets and a potential therapeutic strategy for the clinical treatment of T2DM and related metabolic diseases.

Berberine chloride suppresses pancreatic adenocarcinoma proliferation and growth by targeting inflammation-related genes: an in silico analysis with in vitro and vivo validation.

PURPOSE: Targeting inflammatory crosstalk between tumors and their microenvironment has emerged as a crucial method for suppressing pancreatic adenocarcinoma (PAAD) progression. Berberine (BBR) is a natural pentacyclic isoquinoline alkaloid known for its anti-inflammatory and antitumor pharmacological effects; however, the mechanism underlying PAAD suppression remains unclear. We aim to investigate the effects of BBR on PAAD progression and their underlying mechanisms. METHODS: The prognostic value of inflammation-related genes in PAAD was assessed using bioinformatics analyses, then the pharmacological effects and potential mechanisms of BBR on PAAD will be investigated in silico, in vitro, and in vivo. RESULTS: Fifty-eight prognostic inflammation-related genes were identified in PAAD, which were shown to have good sensitivity and specificity using a novel inflammation-related gene risk-prognosis prediction model. Among these, four candidate genes (CAPS3, PTGS2, ICAM1, and CXCR4) were predicted as targets of BBR in PAAD in silico. Molecular docking simulations showed that the four key targets docked well with BBR. Further BBR treatment suppressed cell proliferation, colony formation, and induced cell cycle arrest in vitro. Moreover, BBR exhibited a significant tumor-suppressive effect in murine subcutaneous xenografts without macroscopic hepatic and renal toxicities. In addition, BBR downregulated CAPS3, PTGS2, ICAM1, and CXCR4 protein expression. CONCLUSION: This study not only elucidated the prognostic value of inflammation-related genes in PAAD but also demonstrated the potential of BBR to inhibit PAAD by targeting these genes.

KDM4A-AS1 Promotes Cell Proliferation, Migration, and Invasion via the miR-4306/STX6 Axis in Hepatocellular Carcinoma.

As a primary liver malignancy, hepatocellular carcinoma (HCC) is commonly induced by chronic liver disease and cirrhosis. Bioinformatics analysis reveals that long noncoding RNA KDM4A antisense RNA 1 (KDM4A-AS1) may be aberrantly expressed in HCC and its abnormal expression might influence prognosis in patients. We conducted this study to illustrate the functions and mechanism of KDM4A-AS1 in regulating HCC malignant cell behavior. KD-M4A-AS1, microRNA (miR)-4306 and messenger RNA syntaxin 6 (STX6) expression was examined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). HCC cell proliferation, apoptosis, migration, and invasion were measured by colony forming assays, flow cytometry, wound healing and Transwell assays. The interaction between genes was verified by RNA immunoprecipitation and luciferase reporter assays. Western blotting was performed to quantify protein expression of STX6 or apoptotic markers. KDM4A-AS1 was highly expressed in HCC cells and tissues. KDM4A-AS1 knockdown led to enhanced HCC cell apoptosis and suppressed HCC cell proliferation, migration, and invasion. MiR-4306 bound to and negatively regulated STX6. KDM4A-AS1 directly bound to miR-4306 and thus up-regulated STX6. STX6 overexpression reversed the inhibitory influence of KDM4A-AS1 depletion on HCC malignant behavior. KDM4A-AS1 promotes HCC cell migration, invasion, and growth by upregulating STX6 via miR-4306.