Catalytic Asymmetric Transfer Hydrogenation of Acylboronates: BMIDA as the Privileged Directing Group.

Developing a general, highly efficient, and enantioselective catalytic method for the synthesis of chiral alcohols is still a formidable challenge. We report in this article the asymmetric transfer hydrogenation (ATH) of N-methyliminodiacetyl (MIDA) acylboronates as a general substrate-independent entry to enantioenriched secondary alcohols. ATH of acyl-MIDA-boronates with (het)aryl, alkyl, alkynyl, alkenyl, and carbonyl substituents delivers a variety of enantioenriched α-boryl alcohols. The latter are used in a range of stereospecific transformations based on the boron moiety, enabling the synthesis of carbinols with two closely related α-substituents, which cannot be obtained with high enantioselectivities using direct asymmetric hydrogenation methods, such as the (R)-cloperastine intermediate. Computational studies illustrate that the BMIDA group is a privileged enantioselectivity-directing group in Noyori-Ikariya ATH compared to the conventionally used aryl and alkynyl groups due to the favorable CH-O attractive electrostatic interaction between the η6-arene-CH of the catalyst and the σ-bonded oxygen atoms in BMIDA. The work expands the domain of conventional ATH and shows its huge potential in addressing challenges in symmetric synthesis.

Gypenoside L inhibits hepatocellular carcinoma by targeting the SREBP2-HMGCS1 axis and enhancing immune response.

Hepatocellular carcinoma (HCC) is a malignant tumor that occurs in the liver, with a high degree of malignancy and relatively poor prognosis. Gypenoside L has inhibitory effects on liver cancer cells. However, its mechanism of action is still unclear. This study aims to investigate the inhibitory effects of gypenoside L on HCC in vitro and in vivo, and explore its potential mechanisms. The results showed that gypenoside L reduced the cholesterol and triglyceride content in HepG2 and Huh-7 cells, inhibited cell proliferation, invasion and metastasis, arrested cell cycle at G0/G1 phase, promoted cell apoptosis. Mechanistically, it targeted the transcription factor SREPB2 to inhibit the expression of HMGCS1 protein and inhibited the downstream proteins HMGCR and MVK, thereby regulating the mevalonate (MVA) pathway. Overexpression HMGCS1 led to significant alterations in the cholesterol metabolism pathway of HCC, which mediated HCC cell proliferation and conferred resistance to the therapeutic effect of gypenoside L. In vivo, gypenoside L effectively suppressed HCC growth in tumor-bearing mice by reducing cholesterol production, exhibiting favorable safety profiles and minimal toxic side effects. Gypenoside L modulated cholesterol homeostasis, enhanced expression of inflammatory factors by regulating MHC I pathway-related proteins to augment anticancer immune responses. Clinical samples from HCC patients also exhibited high expression levels of MVA pathway-related genes in tumor tissues. These findings highlight gypenoside L as a promising agent for targeting cholesterol metabolism in HCC while emphasizing the effectiveness of regulating the SREBP2-HMGCS1 axis as a therapeutic strategy.

2H-Phosphindole-Enabled Dearomatization and [4+2] Cycloaddition of (Hetero)Arenes.

The heavier main group multiple bonds offer an effective tool for small molecule activation. Transient 2H-phosphinidole working as a reactive phosphadiene system undergoes phospha-Diels-Alder reaction with a wide range of non-activated aromatic carbocycles and heterocycles, including naphthalene, anthracene, phenanthrene, furan, thiophene, pyrrole, pyridine, and benzo-fused heterocycles, affording concise access to a range of polycyclic fused rings feature with phosphorus at the bridgehead. These results demonstrate that non-activated (hetero)arenes are capable of acting as 2π systems in [4+2] cycloaddition with highly reactive 2H-phosphindole complex.

Genetically engineered CXCR4-modified exosomes for delivery of miR-126 mimics to macrophages alleviate periodontitis.

Biofilm-related diseases are a group of diseases that tolerate antimicrobial chemotherapies and therefore are refractory to treatment. Periodontitis, a non-device chronic biofilm disease induced by dental plaque, can serve as an excellent in vivo model to study the important effects of host factors on the biofilm microenvironment. Macrophage activity is one of the key factors that modulate the progression of inflammation-driven destruction in periodontitis; therefore it is an important host immunomodulatory factor. In this study, the reduction of microRNA-126 (miR-126) with the recruitment of macrophages in periodontitis was confirmed in clinical samples, and a strategy for targeted delivery of miR-126 to macrophages was explored. Exosomes overexpressing the C-X-C motif chemokine receptor 4 (CXCR4) loaded with miR-126 (CXCR4-miR126-Exo) was successfully constructed, which reduced off-target delivery to macrophages and regulated macrophages toward the anti-inflammatory phenotype. In vivo local injection of CXCR4-miR126-Exo into sites of periodontitis in rats effectively reduced bone resorption and osteoclastogenesis and inhibited the progression of periodontitis. These results provide new insights for designing novel immunomodulatory factor targeted delivery systems to treat periodontitis and other biofilm-related diseases.

Digital anatomical study and clinical application of the ideal S2 alar-lliac screw trajectory.

BACKGROUND: To investigate the ideal trajectory for the S2AI screw and to clinically validate its safety feasibility. METHODS: The 3D model was reconstructed from CT data of the pelvis of 30 selected adults, and the 3D coordinate system was established with the first sacral superior endplate as the horizontal plane. A set of cutting planes was made at 3 mm intervals in the coronal plane, and the cross-sectional internal tangent circles were divided in the target area. Using the linear fitting function, the axis of 90 mm length was calculated by the least squares method for each inner tangent circle center. The diameter of the axis is gradually increased until the first contact with the cortex, and the cylindrical model is the ideal screw trajectory. The intersection of the axis and the dorsal cortex is the screw placement point, which is located by Horizon Distance (HD) and Vertical Distance (VD); the diameter of the screw trajectory (d) is the diameter of the cylindrical model; the direction of the screw trajectory is determined by Sagittal Angle (SA) and Transverse Angle (TA). The screw trajectory orientation is determined by Sagittal Angle (SA) and Transverse Angle (TA). Based on the ideal screw trajectory, the 3D printed surgical guide and freehand techniques were used to verify its safety feasibility, respectively. RESULTS: The screw placement points [HD (4.7 ± 1.0) mm, VD (19.7 ± 1.9) mm], screw placement directions [SA (31.3°±2.3°), TA (42.4°±2.3°)], and screw dimensions for the ideal screw trajectory of the S2AI were combined for analysis. (L is 90 mm, d is 13.2 ± 1.4 mm). The S2AI screw superiority rate [96.6% (56/58)] and reasonable rate [100%] were higher in the guide group than in the freehand group [90.0% (63/70), 97.1% (68/70)], but the differences were not statistically significant (P > 0.05). Although screws invaded the cortex in both groups, there were no associated adverse events in either group. CONCLUSION: The S2AI screw-based ideal trajectory placement is a safe, feasible and accurate method of screw placement.

FGF8 and BMP2 mediated dynamic regulation of dental mesenchyme proliferation and differentiation via Lhx8/Suv39h1 complex.

The homeobox gene, LIM-homeobox 8 (Lhx8), has previously been identified as an essential transcription factor for dental mesenchymal development. However, how Lhx8 itself is regulated and regulates odontogenesis remains poorly understood. In this study, we employed an RNAscope assay to detect the co-expression pattern of Lhx8 and Suv39h1 in the dental mesenchyme, which coincided with the dynamic expression profiles of the early epithelium signal of Fibroblast Growth Factor 8 (FGF8) and the later mesenchymal signal Bone Morphogenetic Protein 2 (BMP2). Moreover, FGF8 activated Lhx8, whereas BMP2 repressed Lhx8 expression at the transcriptional level. The high expression of Lhx8 in the early dental mesenchyme maintained the cell fate in an undifferentiated status by interacting with Suv39h1, a histone-lysine N-methyltransferase constitutively expressed in the dental mesenchyme. Further in the ex vivo organ culture model, the knockdown of Suv39h1 significantly blocked the function of Lhx8 and FGF8. Mechanistically, Lhx8/Suv39h1 recognized the odontoblast differentiation-related genes and repressed gene expression via methylating H3K9 on their promoters. Taken together, our data here suggest that Lhx8/Suv39h1 complex is inversely regulated by epithelium-mesenchymal signals, balancing the differentiation and proliferation of dental mesenchyme via H3K9 methylation.

Comparative study of 3D printed navigation template-assisted atlantoaxial pedicle screws versus free-hand screws for type II odontoid fractures.

OBJECTIVE: The objective of the study was to compare the safety, efficacy, and accuracy of the pedicle screws with the three-dimensional (3D) printed navigation template to the free-hand screws for type II odontoid fractures. PATIENTS AND METHODS: A total of 60 patients with type II odontoid fractures, treated with either template guiding pedicle screws or free-hand screws, were retrospectively assessed. The guiding group was treated with pedicle screws with the assistance of a virtual reality (VR) software-designed, 3D printed navigation template with two guide tubes. The safety rate and treatment efficacy of the screw placement, as well as the trajectory accuracy, were evaluated by respective measures and compared between two surgical groups. RESULTS: There were reduced surgical time (P < 0.05), blood loss (P < 0.01), and C-arm shots (P < 0.01) with 3D printed template guiding screws. The rates of safe pedicle screws in both C1 and C2 were significantly higher in 3D guiding group (P < 0.01) compared to the free-hand group, and the scores of visual analogue scale (VAS) and impairment scale (ASIA) were improved in guiding group at 1 week post-surgery (P < 0.01 and P < 0.05, respectively). Postoperative CT and image reconstruction showed the 3D guiding group had better horizontal screw accuracy on both sides of C1 (L: P < 0.001, R: P < 0.01) and C2 (L: P < 0.001, R: P < 0.01) than free-hand group. CONCLUSION: The herein screw technique using 3D printed navigation template leads to greater improvement in the screw safety, efficacy, and accuracy, which may be a promising alternative to free-hand surgery for the treatment of odontoid fractures.

Double-trajectory lumbar screw placement guided by a set of 3D-printed surgical guide templates: a cadaver study.

BACKGROUND: To improve the strength of posterior spine fixation in patients with osteoporosis, some scholars have proposed a method of simultaneously inserting traditional pedicle screws and cortical bone trajectory screws into the pedicle. However, due to the difficulty of the operation and few clinical applications, the safety and accuracy of this method are still unclear. The purpose of this study was to investigate the safety and accuracy of double-trajectory lumbar screw placement guided by surgical guide templates. METHODS: Six wet lumbar specimens were selected for computed tomography (CT) scanning, a three-dimensional (3D) model of the lumbar spine was established using computer software, and surgical guide templates for double-trajectory [traditional pedicle trajectory (TPT) and cortical bone trajectory (CBT)] lumbar screw placement at various segments of the lumbar spine were designed and printed using a 3D printer. Screw placement was guided only by the surgical guide template, with no fluoroscopy. Postoperative CT examination was performed to determine whether the screw penetrated the screw path and the location and depth of penetration of the cortex. The preoperative and postoperative sagittal and axial angles of CBT screws or TPT screws were also measured and compared. RESULTS: Four screws were placed in each vertebral body of six lumbar specimens for a total of 120 screws. Screw grades: 99 screws as grade 0, 15 as grade 1, six as grade 2, and zero as grade 3. Thus, grade 0 accounted for 82.5% of the screws. No significant differences in the preoperative and postoperative angles of the screws were found (P > 0.05). CONCLUSIONS: 3D-printed surgical guide templates for double-trajectory screw placement can reduce the difficulty of surgery and the use of intraoperative fluoroscopy. Using such templates is a safe, feasible, and accurate screw placement method.

Clinical Application of 3-Dimensional Printed Navigation Templates in Treating Femoral Head Osteonecrosis With Pedicled Iliac Bone Graft.

OBJECTIVE: The aim of the study was to explore the feasibility and early effect of digital design combined with 3-dimensional (3D) printing technique in the transplantation of vascular pedicled iliac bone flap in the treatment of avascular necrosis of the femoral head. METHODS: The navigation template was designed according to computed tomography scan and printed in 3D printing technique before operation, which was used to guide the localization and clearance of osteonecrosis of the femoral head in vascular pedicled iliac bone flap transplantation. In blank control group, 28 cases (32 hips) of osteonecrosis of the femoral head were treated with vascular pedicled iliac bone flap without the assistance of 3D navigation template from February 2002 to February 2009, including 19 males (21 hips) and 9 females (11 hips), with an average age of 37 years (range, 20-61 years). There were 12 cases of left hip, 16 cases of right hip, and 4 cases of double hip. According to the International Association of Bone Circulation staging, there were 8 hips in stage II B, 9 hips in stage II C, 8 hips in stage III B, and 7 hips in stage III C. In the experimental group, from February 2014 to June 2014, 15 patients (24 hips) with avascular necrosis of the femoral head were treated with vascular pedicled iliac bone flap with the aid of 3D navigation template. There were 11 males (17 hips) and 4 females (7 hips) with an average age of 38 years (range, 18-56 years). There were 2 cases of left hip, 4 cases of right hip, and 9 cases of double hip. According to the International Association of Bone Circulation staging, there were 5 hips in stage II B, 8 hips in stage II C, 6 hips in stage III B, and 5 hips in stage III C. The operation time, bleeding volume, and postoperative Harris score of the experimental group and the control group were statistically analyzed. RESULTS: The incisions in both groups healed in the first stage, and there were no operation-related complications such as deep venous thrombosis and infection of lower extremities. All patients were followed up for 12 to 16 months (with an average of 14 months). On the second day after operation, X-ray and computed tomography showed that the necrotic focus of the femoral head and the surrounding sclerotic bone was completely removed, and the position of the vascular pedicled iliac bone flap was satisfactory and did not penetrate the articular surface. The iliac bone flap and bone graft achieved bony fusion. In the navigation template group, the mean ± SD operation time was 135.38 ± 9.49 minutes, the mean ± SD blood loss was 225.13 ± 13.41 mL, the mean ± SD postoperative Harris score was 89.53 ± 5.83, 12 hips were excellent, 10 hips were good, and 2 hips were moderate, whereas in the group without navigation template, the mean ± SD operation time was 151.00 ± 15.28 minutes, the mean ± SD blood loss was 283.56 ± 30.60 mL, the mean ± SD postoperative Harris score was 83.32 ± 3.75, 15 hips were excellent, 14 hips were good, and 3 hips were fair. By independent sample t test, there were significant differences in average operation time, average blood loss, and postoperative Harris score between the 2 groups (P < 0.05). CONCLUSIONS: Compared with not using navigation template, vascular pedicled iliac bone flap combined with navigation template in the treatment of osteonecrosis of femoral head could locate the area of osteonecrosis of femoral head more accurately, shorten the time of operation, and reduce the amount of bleeding during operation. Postoperative hip joint function recovery was better, and the early effect was satisfactory.

Comparison of the 3D-printed operation guide template technique and the free-hand technique for S2-alar-iliac screw placement.

BACKGROUND: To compare the safety and accuracy of the 3D-printed operation guide template technique and the free-hand technique in the placement of the S2-alar-iliac (S2AI) screw. METHODS: We conducted a retrospective analysis of 47 patients undergoing S2AI screw placement in our hospital, divided into the 3D-printed operation guide template group and the free-hand screw placement group. The duration of single S2AI screw placement was documented in all patients. A postoperative CT scan was performed to assess screw placement effectiveness according to the distance from the screw tip to the breach of the cortical bone wall. RESULTS: In total, 42 screws were placed in the guide template group, with an average screw placement duration of 151.6 ± 44.8 s. Screw placement grading was as follows: 40 screws in grade 0, two in grade 1, and none in grades 2 and 3. This grading resulted in excellent and good rates of 95.2% and 100%, respectively. In total, 52 screws were placed in the free-hand group, with an average screw placement duration of 138.3 ± 45.9 s. Screw placement grading was as follows: 42 screws in grade 0, seven in grade 1, three in grade 2, and none in grade 3. This grading resulted in excellent, good and acceptable rates 80.8%, 94.2% and 100%, respectively. Screw placement duration did not significantly differ between the groups (p > 0.05). The excellent rate of screw placement was greater in the guide template group than in the free-hand group (p < 0.05), but the good and acceptable rates did not significantly differ between the two groups (p > 0.05). CONCLUSION: Both techniques can be applied to S2AI screw placement. The 3D-printed guide technique is superior to the free-hand technique in terms of safety and accuracy.

A novel patient-specific navigational template for anatomical reconstruction of the lateral ankle ligaments.

PURPOSE: We discuss the clinical effects of anatomical reconstruction of the lateral ankle ligaments to treat chronic lateral ankle instability (CAI) by creating fibular channels with a patient-specific navigational template. METHODS: From August 2010 to February 2014, 15 patients presenting with CAI were treated by creating fibular channels with a patient-specific navigational template for anatomical reconstruction of the lateral ankle ligaments. RESULTS: All patients were followed up for nine to 24 months postoperatively (15 months on average); no recurrent CAI was found. Pre- and postoperative American Orthopaedic Foot and Ankle Society (AOFAS) scores for patients in the calcaneofibular ligament (CFL) plus anterior talofibular ligament (ATFL) repair group were 48.3 ± 5.1 and 88.1 ± 6.7) respectively. The difference (average 39.8) showed high statistical significance (P < 0.001). Pre- and postoperative scores in the ATFL group were 50.4 ± 6.2 and 90.3 ± 7.8, respectively. The difference (average 39.9) showed high statistical significance (P < 0.001). Regarding the Good score, 14 patients were rated as "excellent and one as good (good = 100 %). No severe complications were found in the patients in this group. CONCLUSIONS: We studied and successfully built a digital navigation template for creating fibular channels to anatomically reconstruct the lateral ankle ligament. By using the template, fibular channels could be built, and lateral ligaments could be anatomically reconstructed individually, easily and safely, which largely facilitates the treatment of CAI.

The biomechanical effects of bilateral sagittal split ramus osteotomy and bimaxillary osteotomies to the patients with maxillofacial deformities under incisal clenching.

OBJECTIVE: Bilateral sagittal split ramus osteotomy (BSSRO) and bimaxillary osteotomies (BSSRO plus Lefort1 osteotomy) are widely used to solve maxillofacial deformities. The effect of the surgeries on the temporomandibular joint (TMJ) is still not clear. The purpose of this study was to investigate the preoperative and postoperative stress environment of the patients and to compare the biomechanical differences of the two surgeries. METHODS: Ten patients were performed BSSRO and fourteen underwent bimaxillary osteotomies. Eleven asymptomatic subjects were recruited to be the control group. The muscle forces of incisal clenching were applied on the finite element models. And contact was used to simulate the interactions within the TMJs. RESULTS: two kinds of surgeries could not completely eliminate the negative biomechanical distribution within the TMJs. CONCLUSION: Compared to BSSRO only, the bimaxillary osteotomies could better repair the biomechanical environment of the TMJs under incisal clenching. And the TMD symptoms were strongly related to the stress distributions of the TMJs.

The biomechanical effects of bimaxillary osteotomies to the patients with mandibular retraction under incisal clenching.

The purpose of this study is to investigate the biomechanical effect of bimaxillary osteotomies on patients with mandibular retraction. Mandibular retraction, as a typical maxillofacial deformity, and has great adverse effects on TMJ. Bimaxillary osteotomies are widely used to correct symptoms of mandibular retraction. It is necessary to understand the effect of surgery on temporomandibular disc (TMJ). Five patients with mandibular retraction and 10 asymptomatic subjects were involved in this study. Finite element models of preoperative, postoperative and control group were constructed based on the CT data. Nine sets of concentrated forces were used to simulate the muscle effect and contact method was used to simulate the interaction within the TMJs and dentitions. The results showed that bimaxillary osteotomies could effectively improve the maxillofacial morphology and alleviate the overload in TMJ. The facial asymmetry and right chewing side preference could cause imbalanced stress distributions in the TMJs and interfere the surgical treatment.

Clinical application of digital technology in the use of anterolateral thigh lobulated perforator flaps to repair complex soft tissue defects of the limbs.

Background: It is challenging to repair wide or irregular defects with traditional skin flaps, and anterolateral thigh (ALT) lobulated perforator flaps are an ideal choice for such defects. However, there are many variations in perforators, so good preoperative planning is very important. This study attempted to explore the feasibility and clinical effect of digital technology in the use of ALT lobulated perforator flaps for repairing complex soft tissue defects in limbs. Methods: Computed tomography angiography (CTA) was performed on 28 patients with complex soft tissue defects of the limbs, and the CTA data were imported into Mimics 20.0 software in DICOM format. According to the perforation condition of the lateral circumflex femoral artery and the size of the limb defect, one thigh that had two or more perforators from the same source vessel was selected for 3D reconstruction of the ALT lobulated perforator flap model. Mimics 20.0 software was used to visualize the vascular anatomy, virtual design and harvest of the flap before surgery. The intraoperative design and excision of the ALT lobulated perforator flap were guided by the preoperative digital design, and the actual anatomical observations and measurements were recorded. Results: Digital reconstruction was successfully performed in all patients before surgery; this reconstruction dynamically displayed the anatomical structure of the flap vasculature and accurately guided the design and harvest of the flap during surgery. The parameters of the harvested flaps were consistent with the preoperative parameters. Postoperative complications occurred in 7 patients, but all flaps survived uneventfully. All of the donor sites were closed directly. All patients were followed up for 13-27 months (mean, 19.75 months). The color and texture of each flap were satisfactory and each donor site exhibited a linear scar. Conclusions: Digital technology can effectively and precisely assist in the design and harvest of ALT lobulated perforator flaps, provide an effective approach for individualized evaluation and flap design and reduce the risk and difficulty of surgery.

Effects of bilateral sagittal split ramus osteotomy and bimaxillary osteotomies on stress distribution of temporomandibular joints in patients with maxillofacial deformity under asymmetric occlusions.

Bilateral sagittal split ramus osteotomy (BSSRO) and bimaxillary osteotomies (BSSRO plus Lefort1 osteotomy) are representative surgeries to solve maxillofacial deformity. It is important to understand the biomechanical impact of the surgeries on the temporomandibular joint (TMJ). The purpose of this study is to compare the stress variations of the patients before and after the two surgeries. Twenty-four patients with maxillofacial deformities and 14 asymptomatic subjects were recruited to be the preoperative group and control group in this study. Ten patients were performed BSSRO and other 14 underwent bimaxillary osteotomies. Finite element models of the preoperative, postoperative, and control groups were established according to the CBCT data of the subjects. The muscle forces of the left and right unilateral occlusion were applied on the models. And the contact was used to simulate the interaction within the TMJs and between the maxillary and mandibular teeth. Under the asymmetric occlusion, bimaxillary osteotomies were found to be superior to BSSRO in the stress distributions of the TMJs. The magnitude of the asymmetric stresses was strongly correlated with the TMD symptoms in the patients. And the stress variation of the postoperative TMJs was the cause of the improvement or aggravation of the TMD symptoms.

Aging-related decrease of histone methyltransferase SUV39H1 in adipose-derived stem cells enhanced SASP.

Aging-related diseases are closely associated with the state of inflammation, which is known as "inflammaging." Senescent cells are metabolically active, as exemplified by the secretion of inflammatory cytokines, chemokines, and growth factors, which is termed the senescence-associated secretory phenotype (SASP). Epigenetic regulation, especially the structural regulation of chromatin, is closely linked to the regulation of SASP. In our previous study, the suppressor of variegation 3-9 homolog 1 (SUV39H1) was elucidated to interact with Lhx8 and determine the cell fate of mesenchyme stem cells. However, the function of SUV39H1 during aging and the underlying mechanism of its epigenetic regulation remains controversial. Therefore, the C57BL/6 J CAG-Cre; SUV39H1fl/fl knockout mice and irradiation-induced cellular senescence model were built in this study to deepen the understanding of epigenetic regulation by SUV39H1 and its relation to SASP. In vivo and in vitro studies demonstrated that SUV39H1 decreased with aging and served as an inhibitor of SASP, especially IL-6, MCP-1, and Vcam-1, by altering H3K9me3 enrichment in their promoter region. These results provide new insights into the epigenetic regulation of SASP.

Gypenosides suppress hepatocellular carcinoma cells by blocking cholesterol biosynthesis through inhibition of MVA pathway enzyme HMGCS1.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors with high morbidity and mortality. Targeting abnormal cholesterol metabolism is a potential therapeutic direction. Therefore, more natural drugs targeting cholesterol in HCC need to be developed. Gypenosides (Gyp), the major constituent of Gynostemma pentaphyllum, has been demonstrated to have pharmacological properties on anti-cancer, anti-obesity, and hepatoprotective. We investigated whether Gyp, isolated and purified by our lab, could inhibit HCC progression by inhibiting cholesterol synthesis. The present research showed that Gyp inhibited proliferation and migration, and induced apoptosis in Huh-7 and Hep3B cells. Metabolomics, transcriptomics, and target prediction all suggested that lipid metabolism and cholesterol biosynthesis were the mechanisms of Gyp. Gyp could limit the production of cholesterol and target HMGCS1, the cholesterol synthesis-related protein. Downregulation of HMGCS1 could suppress the progression and abnormal cholesterol metabolism of HCC. In terms of mechanism, Gyp suppressed mevalonate (MVA) pathway mediated cholesterol synthesis by inhibiting HMGCS1 transcription factor SREBP2. And the high expression of HMGCS1 in HCC human specimens was correlated with poor clinical prognosis. The data suggested that Gyp could be a promising cholesterol-lowering drug for the prevention and treatment of HCC. And targeting SREBP2-HMGCS1 axis in MVA pathway might be an effective HCC therapeutic strategy.

Protective effect of heat-processed Gynostemma pentaphyllum on high fat diet-induced glucose metabolic disorders mice.

Glucose metabolic disorders (GMD) can promote insulin resistance (IR) and diabetes, and damage liver and kidney. Gynostemma pentaphyllum is commonly used in the clinical treatment of diabetes, but the research on its main active constituents and GMD has not been reported yet. This study explores the therapeutic potential of gypenosides of heat-processed Gynostemma pentaphyllum (HGyp) on high-fat diet-induced GMD in mice. HGyp was administered at different doses for 12 weeks. The investigation encompassed an array of parameters, including body weight, blood lipids, blood glucose, and liver tissue components. Metabolomic and network analyses were conducted to uncover potential targets and pathways associated with HGyp treatment. The results revealed that HGyp alleviated GMD by reducing body weight, blood glucose, and improving blood lipids levels, while increasing liver glycogen and antioxidant enzyme levels. Additionally, HGyp exhibited protective effects on liver and kidney health by reducing tissue damage. Fourteen blood components were detected by LC-MS. Metabolomic and network analyses indicated the potential engagement of the AGE-RAGE signaling pathway in the therapeutic effects of HGyp.Furthermore, Western blot and ELISA assays confirmed that HGyp upregulated GLO1 and GLUT4 while down-regulating AGEs and RAGE expression in liver tissue. In light of these findings, HGyp demonstrates promise as a potential therapeutic candidate for combating GMD, warranting further exploration in the development of therapeutic strategies or functional products.

Biomechanical effects of high acceleration on the temporomandibular joint.

The symptoms of temporomandibular disorders (TMD) are easily developed in pilots after long flights, such as joint pain, anterior displacement disc and so on. Related studies have suggested that abnormal high acceleration would cause temporomandibular joint (TMJ) lesions. Therefore, the purpose of this study is to analyze the biomechanical effects of high acceleration on the TMJs. The 3D models of the maxilla, mandible, articular disc were generated by Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) of a healthy volunteer without any TMD symptoms. Then, the loads were added according to the various operating conditions of the aircraft. The maximum tensile stress, occurred in the anterior band of the discs, exceeded the failure stress. Compared with the low acceleration, the contact stresses between the discs and the articular cartilages were much greater under the high acceleration. High acceleration had a negative impact on the stress distributions of the articular discs and cartilages and easily led to TMJ damage. Lateral acceleration will cause asymmetric stress distribution of the TMJs.

Dearomatization [4+2] Cycloaddition of Nonactivated Benzene Derivatives.

Dearomatization reactions have recently emerged as a powerful tool for the rapid buildup of molecular complexity. Here, an unparalleled thermal dearomatization [4+2] cycloaddition reaction between benzene derivatives and a 2H-phosphindole tungsten complex was reported. The unique reactivity of the in situ-generated 2H-phosphindole complex toward benzene was revealed by density functional theory calculations. We thus provide new insights into the dearomatization of nonactivated arenes and pave the way for the manipulation of the dearomatization for further applications.