The therapeutic potential of curculigoside in poststroke depression: a focus on hippocampal neurogenesis and mitochondrial function.

OBJECTIVES: To investigate the effects and mechanism of curculigoside against poststroke depression (PSD). METHODS: In vivo, a PSD rat model was created by combining bilateral common carotid artery occlusion and chronic unpredictable mild stress stimulations. After 4-week modeling and intragastrically administration of curculigoside, the effects of curculigoside on behavior, hippocampal neurogenesis, and hippocampal mitochondrial oxidative phosphorylation (OxPhos) were investigated. In vitro, PSD-like primary neural stem cells (NSCs) model was established by oxygen-glucose deprivation/recovery (OGD/R) combing high-corticosterone (CORT) concentration, followed by treatment with curculigoside. The investigation subsequently examined the impact of curculigoside on mitochondrial OxPhos, proliferation, and differentiation of NSCs under OGD/R + CORT conditions. KEY FINDINGS: In vivo, PSD rats showed significantly depressive behaviors, dysfunctional neurogenesis in hippocampus, as well as decreased hippocampus adenosine triphosphate (ATP) levels, reduced electron transport chain complexes activity, and downregulates mitochondrial transcription factor A (TFAM) and PPAR-gamma coactivator 1 alpha (PGC-1α) expression in hippocampus. In vitro, OGD/R +CORT significantly injured the proliferation and differentiation, as well as impaired the mitochondrial OxPhos in NSCs. Curculigoside treatment was effective in improving these abnormal changes. CONCLUSION: Curculigoside may repair hippocampal neurogenesis in PSD rats by enhancing hippocampal mitochondrial OxPhos, and has shown a great potential for anti-PSD.

Pharmacokinetics and Safety of Oliceridine Fumarate Injection in Chinese Patients with Chronic Non-Cancer Pain: A Phase I, Single-Ascending-Dose, Open-Label Clinical Trial.

Background: Oliceridine is a novel G protein-biased ligand µ-opioid receptor agonist. This study aimed to assess the pharmacokinetics and safety profile of single-ascending doses of oliceridine fumarate injection in Chinese patients with chronic non-cancer pain. Methods: Conducted as a single-center, open-label trial, this study administered single doses of 0.75, 1.5, and 3.0 mg to 32 adult participants. The trial was conducted in two parts. First, we conducted a preliminary test comprising the administration of a single dose of 0.75mg to 2 participants. Then, we conducted the main trial involving intravenous administration of escalating doses of oliceridine fumarate (0.75 to 3 mg) to 30 participants. Pharmacokinetic (PK) parameters were derived using non-compartmental analysis. Additionally, the safety evaluation encompassed the monitoring of adverse events (AEs). Results: 32 participants were included in the PK and safety analyses. Following a 2-min intravenous infusion of oliceridine fumarate injection (0.75, 1.5, or 3 mg), Cmax and Tmax ranged from 51.293 to 81.914 ng/mL and 0.034 to 0.083 h, respectively. AUC0-t and half-life (t1/2) increased more than proportionally with dosage (1.85-2.084 h). Treatment emergent adverse events (TEAEs) were found to be consistent with the commonly reported adverse effects of opioids, both post-administration and as documented in the original trials conducted in the United States. Critically, no serious adverse events were observed. Conclusion: Oliceridine demonstrated comparable PK parameters and a consistent PK profile in the Chinese population, in line with the PK results observed in the original trials conducted in the United States. Oliceridine was safe and well tolerated in Chinese patients with chronic non-cancer pain at doses ranging from 0.75 mg to 3.0 mg. Trial Registration: The trial is registered at chictr.org.cn (ChiCTR2100047180).

A Poly(amino acid)-Based Nanomedicine Strategy: Telomere-Telomerase Axis Targeting and Magnetic Resonance Imaging in Hepatocellular Carcinoma Treatment.

Targeting telomere maintenance has emerged as a promising strategy for hepatocellular carcinoma (HCC) treatment. However, given the duality of the telomere-telomerase axis in telomere maintenance, a comprehensive strategy is urgently needed. Herein, we develop a poly(amino acid) (D-PAAs)-based strategy for spatiotemporal codelivery of telomerase inhibitor, BIBR1523, and AKT inhibitor, isobavachalcone. By leveraging D-PAAs' modifiability, we synthesize polymer-inhibitor conjugates (PB and PI) and a folic acid-decorated tumor-targeting vector (PF). These building blocks undergo micellization to fabricate a codelivery nanomedicine (P-BI@P-FA) by exploiting D-PAAs' noncovalent assembly. P-BI@P-FA improves the pharmacokinetics, tumor selectivity, and bioavailability of small molecule inhibitors and initiates a dual telomere-specific inhibition by combining telomerase deactivation with telomere disruption. Furthermore, a hybrid tumor-targeting magnetic nanosystem is designed using D-PAAs and manganese dioxide to showcase magnetic resonance imaging capacities. Our D-PAAs-based strategy addresses the pressing need for telomere-specific HCC treatment while allowing for diagnostic application, presenting a promising avenue for nanomedicine design.

Expression and significance of pigment epithelium-derived factor and vascular endothelial growth factor in colorectal adenoma and cancer.

BACKGROUND: The incidence and mortality of colorectal cancer (CRC) are among the highest in the world, and its occurrence and development are closely related to tumor neovascularization. When the balance between pigment epithelium-derived factors (PEDF) that inhibit angiogenesis and vascular endothelial growth factors (VEGF) that stimulate angiogenesis is broken, angiogenesis is out of control, resulting in tumor development. Therefore, it is very necessary to find more therapeutic targets for CRC for early intervention and later treatment. AIM: To investigate the expression and significance of PEDF, VEGF, and CD31-stained microvessel density values (CD31-MVD) in normal colorectal mucosa, adenoma, and CRC. METHODS: In this case-control study, we collected archived wax blocks of specimens from the Digestive Endoscopy Center and the General Surgery Department of Chengdu Second People's Hospital from April 2022 to October 2022. Fifty cases of specimen wax blocks were selected as normal intestinal mucosa confirmed by electronic colonoscopy and concurrent biopsy (normal control group), 50 cases of specimen wax blocks were selected as colorectal adenoma confirmed by electronic colonoscopy and pathological biopsy (adenoma group), and 50 cases of specimen wax blocks were selected as CRC confirmed by postoperative pathological biopsy after inpatient operation of general surgery (CRC group). An immunohistochemical staining experiment was carried out to detect PEDF and VEGF expression in three groups of specimens, analyze their differences, study the relationship between the two and clinicopathological factors in CRC group, record CD31-MVD in the three groups, and analyze the correlation of PEDF, VEGF, and CD31-MVD in the colorectal adenoma group and the CRC group. The F test or adjusted F test is used to analyze measurement data statistically. Kruskal-Wallis rank sum test was used between groups for ranked data. The chi-square test, adjusted chi-square test, or Fisher's exact test were used to compare the rates between groups. All differences between groups were compared using the Bonferroni method for multiple comparisons. Spearman correlation analysis was used to test the correlation of the data. The test level (α) was 0.05, and a two-sided P< 0.05 was considered statistically significant. RESULTS: The positive expression rate and expression intensity of PEDF were gradually decreased in the normal control group, adenoma group, and CRC group (100% vs 78% vs 50%, χ2 = 34.430, P < 0.001; ++~++ vs +~++ vs -~+, H = 94.059, P < 0.001), while VEGF increased gradually (0% vs 68% vs 96%, χ2 = 98.35, P < 0.001; - vs -~+ vs ++~+++, H = 107.734, P < 0.001). In the CRC group, the positive expression rate of PEDF decreased with the increase of differentiation degree, invasion depth, lymph node metastasis, distant metastasis, and TNM stage (χ2 = 20.513, 4.160, 5.128, 6.349, 5.128, P < 0.05); the high expression rate of VEGF was the opposite (χ2 = 10.317, 13.134, 17.643, 21.844, 17.643, P < 0.05). In the colorectal adenoma group, the expression intensity of PEDF correlated negatively with CD31-MVD (r = -0.601, P < 0.001), whereas VEGF was not significantly different (r = 0.258, P = 0.07). In the CRC group, the expression intensity of PEDF correlated negatively with the expression intensity of CD31-MVD and VEGF (r = -0.297, P < 0.05; r = -0.548, P < 0.05), while VEGF expression intensity was positively related to CD31-MVD (r = 0.421, P = 0.002). CONCLUSION: It is possible that PEDF can be used as a new treatment and prevention target for CRC by upregulating the expression of PEDF while inhibiting the expression of VEGF.

A new illudane sesquiterpene from the edible fungus Pholiota nameko.

Fungi have different genetic expression abilities and biosynthetic pathways under different cultivation conditions, which can produce various secondary metabolites. The "one strain many compounds" strategy is used to activate silent biosynthetic genes of fungi to produce various compounds, which is an effective method. In order to discover various new compounds in the edible fungus Pholiota nameko, a fermentation strategy involving precursor feeding and enzyme inhibitor addition has been employed. A new illudane sesquiterpene (1), along with one known indole diterpenoid alkaloid, cladosporine A (2) were isolated from the extracts of liquid culture of P. nameko. The new compound was identified by combination of 1D and 2D NMR, MS, optical rotation, and ECD calculations. We conducted experiments on the cytotoxicity of all isolated compounds on three cancer cell lines, but we did not observe any significant cytotoxicity (IC50 > 40 µM).

The erythromycin polyketide compound TMC-154 stimulates ROS generation to exert antibacterial effects against Streptococcus pyogenes.

The erythromycin polyketide compound TMC-154 is a secondary metabolite that is isolated from the rhizospheric fungus Clonostachys rogersoniana associated with Panax notoginseng, which possesses antibacterial activity. However, its antibacterial mechanism has not been investigated thus far. In this study, proteomics coupled with bioinformatics approaches was used to explore the antibacterial mechanism of TMC-154. KEGG pathway enrichment analysis indicated that eight signaling pathways were associated with TMC-154, including oxidative phosphorylation, cationic antimicrobial peptide (CAMP) resistance, benzoate degradation, heme acquisition systems, glycine/serine and threonine metabolism, beta-lactam resistance, ascorbate and aldarate metabolism, and phosphotransferase system (PTS). Cell biology experiments confirmed that TMC-154 could induce reactive oxygen species (ROS) generation in Streptococcus pyogenes; moreover, TMC-154-induced antibacterial effects could be blocked by the inhibition of ROS generation with the antioxidant N-acetyl L-cysteine. In addition, TMC-154 combined with ciprofloxacin or chloramphenicol had synergistic antibacterial effects. These findings indicate the potential of TMC-154 as a promising drug to treat S. pyogenes infections. SIGNIFICANCE: Streptococcus pyogenes is a nearly ubiquitous human pathogen that causes a variety of diseases ranging from mild pharyngitis and skin infection to fatal sepsis and toxic heat shock syndrome. With the increasing incidence of known antibiotic resistance, there is an urgent need to find novel drugs with good antibacterial activity against S. pyogenes. In this study, we found that TMC-154, a secondary metabolite from the fungus Clonostachys rogersoniana, inhibited the growth of various bacteria, including Staphylococcus aureus, S. pyogenes, Streptococcus mutans, Pseudomonas aeruginosa and Vibrio parahemolyticus. Proteomic analysis combined with cell biology experiments revealed that TMC-154 stimulated ROS generation to exert antibacterial effects against S. pyogenes. This study provides potential options for the treatment of S. pyogenes infections in the future.

Congenital leukemia: A case report and review of literature.

BACKGROUND: Acute leukemia in newborns is also known as neonatal or congenital leukemia (CL) and is a rare disease with an incidence rate of 1-5 per 1000000 live births. After birth, infants with CL exhibit infiltrative cutaneous nodules, hepatosplenomegaly, thrombocytopenia, and immature leukocytes in the peripheral blood. These symptoms are frequently accompanied by congenital abnormalities including trisomy 21, trisomy 9, trisomy 13, or Turner syndrome. Despite significant advances in disease management, the survival rate is approximately 25% at 2 years. CASE SUMMARY: Here, we document a case of trisomy 21-related acute myeloid leukemia (AML) in a female neonate. The baby was sent to the neonatal intensive care unit because of anorexia, poor responsiveness, and respiratory distress. She was diagnosed with AML based on bone marrow aspiration and immunophenotyping. Genetic sequencing identified a mutation in the GATA1 gene. After receiving the diagnosis, the parents decided against medical care for their child, and the baby died at home on day 9 after birth. CONCLUSIONS: The newborn infant was diagnosed with trisomy 21-related AML. Genetic sequencing identified a mutation in the GATA1 gene. The parents abandoned medical treatment for their infant after receiving the diagnosis, and the infant died at home on the 9th day after birth.

Sirolimus can promote the disappearance of renal angiomyolipoma associated with tuberous sclerosis complex: a prospective cohort study.

BACKGROUND: Renal angiomyolipoma (RAML) is the most common kidney lesion in patients with tuberous sclerosis complex (TSC), affecting about 80% of patients. It is a benign tumor that grows over time, usually bilaterally, and can easily lead to kidney complications such as acute hemorrhage. Herein, we investigated the efficacy and safety of sirolimus in children with TSC-associated RAML and explored the factors affecting tumor disappearance under sirolimus treatment through subgroup analysis. METHODS: A prospective cohort study was conducted. Sirolimus was initiated at 1 mg/(m2 × day), and dose adjustments were made by a 2-week titration period to attain a trough blood concentration of 5-10 ng/mL. The disappearance of RAML in children after sirolimus treatment was observed, and Cox regression was used to screen the factors affecting tumor disappearance. RESULTS: One hundred and twenty-six patients who met the criteria were analyzed. After 3 months, 6 months, 12 months, and 24 months of follow-up, tumors disappeared in 18 (14.3%), 30 (23.8%), 39 (31.0%), and 42 (33.3%) children, respectively. Tumors disappeared in 50 (39.7%) children by the last visit of each individual, and 30 (60%) of them occurred within 6 months. The multivariate Cox regression analysis showed that patients with a smaller maximum tumor diameter at baseline had a higher tumor disappearance rate. Thirty-six (29%) patients had stomatitis during the entire treatment period, and no serious adverse reactions were observed. CONCLUSIONS: Sirolimus could promote the disappearance of TSC-related RAML. The disappearance rate was correlated with the maximum diameter at baseline, and the smaller the tumor was, the higher the disappearance rate. It is well tolerated in the treatment of RAML associated with TSC.

[A cohort study of vincristine-induced peripheral neuropathy in children]. / é•¿æ˜¥æ–°ç¢±è¯±å¯¼çš„å‘¨å›´ç¥žç»ç— å˜çš„å„¿ç«¥é˜Ÿåˆ—ç ”ç©¶.

OBJECTIVES: To study the characteristics of vincristine-induced peripheral neuropathy (VIPN) in children with acute lymphoblastic leukemia (ALL) and the factors influencing the development of VIPN. METHODS: The children with ALL, aged 1-18 years, who were treated with CCCG-ALL2015 or CCCG-ALL2020 regimen in the Affiliated Hospital of Guizhou Medical University from January 2018 to February 2022 were enrolled as subjects. According to the influence of age on risk, the children were divided into 1-10 years group with 91 children and >10 years group with 29 children. VIPN was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (5th edition), and the incidence rate, severity, and type of VIPN were compared between different groups. RESULTS: A total of 120 children were enrolled in this study, among whom 56 (46.7%) developed VIPN. The >10 years group had a significantly higher incidence rate of VIPN than the 1-10 years group (69% vs 40%, P<0.05). Among the 56 children with VIPN, 12 (21%) had grade 3 VIPN or above, and 44 (79%) had grade 2 VIPN. There were 77 cases of autonomic nerve symptoms (59.7%), 42 cases of peripheral nerve injury (32.5%), and 10 cases of cranial nerve injury (7.8%). There were no significant differences in the severity and type of VIPN between the groups with different ages, sexes, degrees of risk, or treatment regimens (P>0.05). The results of binary logistic regression analysis showed that age is the influencing factor for the occurrence of VIPN (P>0.05). CONCLUSIONS: There is a relatively high incidence rate of VIPN in children with ALL, with the highest incidence rate of autonomic nervous symptoms. The incidence of VIP in children over 10 years old is relatively high.

Exploratory study of autophagy inducer sirolimus for childhood cerebral adrenoleukodystrophy.

Objectives: X-linked adrenoleukodystrophy (ALD) is a peroxisomal disease caused by mutations in the ABCD1 gene. Childhood cerebral ALD (CCALD) is characterized by inflammatory demyelination, rapidly progressing, often fatal. Hematopoietic stem cell transplant only delays disease progression in patients with early-stage cerebral ALD. Based on emergency humanitarianism, this study aims to investigate the safety and efficacy of sirolimus in the treatment of patients with CCALD. Methods: This was a prospective, single-center, one-arm clinical trial. We enrolled patients with CCALD, and all enrolled patients received sirolimus treatment for three months. Adverse events were monitored and recorded to evaluate the safety. The efficacy was evaluated using the neurologic function scale (NFS), Loes score, and white matter hyperintensities. Results: A total of 12 patients were included and all presented with CCALD. Four patients dropped out and a total of eight patients in the advanced stage completed a 3-month follow-up. There were no serious adverse events, and the common adverse events were hypertonia and oral ulcers. After sirolimus treatment, three of the four patients with an initial NFS > 10 showed improvements in their clinical symptoms. Loes scores decreased by 0.5-1 point in two of eight patients and remained unchanged in one patient. Analysis of white matter hyperintensities revealed a significant decrease in signal intensity (n = 7, p = 0.0156). Conclusions: Our study suggested that autophagy inducer sirolimus is safe for CCALD. Sirolimus did not improve clinical symptoms of patients with advanced CCALD significantly. Further study with larger sample size and longer follow-up is needed to confirm the drug efficacy.Clinical Trial registration: https://www.chictr.org.cn/historyversionpuben.aspx, identifier ChiCTR1900021288.

Probing the interaction between metastatic breast cancer cells and osteoblasts in a thread-based breast-bone co-culture device.

Breast cancer metastasis to bone is a leading killer in breast cancer patients. A type I collagen-modified thread (Col-I@thread) was prepared for 3-dimensional cell culture and breast cancer bone metastasis co-culture device assembly. First, the coating of Col-I on nylon threads for promoting cell adhesion and growth was studied. Through SEM, XPS, and protein concentration measurements, it was found that the lyophilization method remarkably preserved the Col-I activity and the internal structure of the thread, thereby promoting cell attachment and proliferation. RNA-sequencing (RNA-Seq) and quantitative PCR analysis showed that osteoblast cells (MC3T3-E1) grown on Col-I@thread had elevated RUNX2, ALP, OPN, and Col-I gene expression to promote osteoblast differentiation. Single-cell analysis found that osteoblast MC3T3-E1 cells growing on Col-I@thread had higher Ca2+ secretion activity and mineralized nodules, suggesting robust cell activity and bone matrix formation than cells growing on 2D culture plates. Col-I@threads were knotted in an interdigital cross-finger frame to assemble the breast cancer-bone co-culture model. Confocal microscopy and flow cytometry tests quantified the invasive breast cancer cells. Moreover, the thread-based co-culture devices allowed us to isolate the invasive and non-invasive breast cancer cells to compare their molecular characteristics. qPCR results showed that expression of CX43, CXCR5, and CSPG4 genes was significantly increased in breast cancer cells with bone metastasis. Meanwhile, the expression of RUNX2 and OPG genes in osteoblasts was inhibited. The co-culture model based on the Col-I@thread mimics the bone tissue microenvironment to reveal the cross-talk between cancer cells and bone tissue. Moreover, the thread-based co-culture device is easy to fabricate and operate, providing a platform for exploring the cellular and molecular mechanisms of breast cancer bone metastasis, and holds potential for high-throughput screening of anti-breast cancer bone metastasis drugs.

Inhibition of MALT1 reduces ferroptosis in rat hearts following ischemia/reperfusion via enhancing the Nrf2/SLC7A11 pathway.

The dysregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and/or solute carrier family 7 member 11 (SLC7A11) is believed to contribute to ferroptosis in the hearts suffered ischemia/reperfusion (I/R), but the mechanisms behind the dysregulation of them are not fully elucidated. Mucosa associated lymphoid tissue lymphoma translocation gene 1 (MALT1) can function as a paracaspase to cleave specified substrates and it is predicted to interact with Nrf2. This study aims to explore whether targeting MALT1 can reduce I/R-induced ferroptosis via enhancing the Nrf2/SLC7A11 pathway. The SD rat hearts were subjected to 1h-ischemia plus 3h-reperfusion to establish the I/R injury model, which showed myocardial injuries (increase in infarct size and creatine kinase release) and up-regulation of MALT1 while downregulation of Nrf2 and SLC7A11 concomitant with the increased ferroptosis, reflecting by an increase in glutathione peroxidase 4 (GPX4) level while decreases in the levels of acyl-CoA synthetase long chain family member 4 (ACSL4), total iron, Fe2+ and lipid peroxidation (LPO); these phenomena were reversed in the presence of MI-2, a specific inhibitor of MALT1. Consistently, similar results were achieved in the cultured cardiomyocytes subjected to 8h-hypoxia plus 12h-reoxygenation. Furthermore, micafungin, an antifungal drug, could also exert beneficial effect on mitigating myocardial I/R injury via inhibition of MALT1. Based on these observations, we conclud that inhibition of MALT1 can reduce I/R-induced myocardial ferroptosis through enhancing the Nrf2/SLC7A11 pathway; and MALT1 may be used as a potential target to seek novel or existing drugs (such as micafungin) for treating myocardial infarction.

Recent Advances in Well-Designed Therapeutic Nanosystems for the Pancreatic Ductal Adenocarcinoma Treatment Dilemma.

Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant tumor with an extremely poor prognosis and low survival rate. Due to its inconspicuous symptoms, PDAC is difficult to diagnose early. Most patients are diagnosed in the middle and late stages, losing the opportunity for surgery. Chemotherapy is the main treatment in clinical practice and improves the survival of patients to some extent. However, the improved prognosis is associated with higher side effects, and the overall prognosis is far from satisfactory. In addition to resistance to chemotherapy, PDAC is significantly resistant to targeted therapy and immunotherapy. The failure of multiple treatment modalities indicates great dilemmas in treating PDAC, including high molecular heterogeneity, high drug resistance, an immunosuppressive microenvironment, and a dense matrix. Nanomedicine shows great potential to overcome the therapeutic barriers of PDAC. Through the careful design and rational modification of nanomaterials, multifunctional intelligent nanosystems can be obtained. These nanosystems can adapt to the environment's needs and compensate for conventional treatments' shortcomings. This review is focused on recent advances in the use of well-designed nanosystems in different therapeutic modalities to overcome the PDAC treatment dilemma, including a variety of novel therapeutic modalities. Finally, these nanosystems' bottlenecks in treating PDAC and the prospect of future clinical translation are briefly discussed.

A new chamigrane sesquiterpene from the rice fermentation of Antrodiella albocinnamomea.

A new chamigrane sesquiterpene, albocimea A (1), and one known compound, 6-hydroxy-8-methoxy-3S,5-dimethylisochroman (2), were isolated from the rice fermentation of the fungus Antrodiella albocinnamomea. The structure of new compound was elucidated by extensive spectroscopic analyses and electronic circular dichroism (ECD) calculations. Both compounds were evaluated for their cytotoxicity against five human cancer cell lines, but no significant cytotoxicity was found (IC50 values > 40 µM).

A new chamigrane sesquiterpene from the basidiomycete Antrodiella albocinnamomea.

One new chamigrane sesquiterpene, antroalbol A (1), was isolated from the cultures of the higher fungus Antrodiella albocinnamomea. Its structure was established by means of spectroscopic methods, and the absolute configuration of 1 was confirmed by single crystal x-ray diffraction analysis. The compound was evaluated for its cytotoxicity against five human cancer cell lines, but no significant cytotoxicity was found.

The Weakened Interaction Between HECTD4 and GluN2B in Ischemic Stroke Promotes Calcium Overload and Brain Injury Through a Mechanism Involving the Decrease of GluN2B and MALT1 Ubiquitination.

Glutamate receptor ionotropic NMDA 2B (GluN2B) plays an essential role in calcium overload during excitotoxicity. Reverse-phase nano-liquid chromatography-tandem mass spectrometry has revealed an interaction between GluN2B and HECT domain E3 ubiquitin protein ligase 4 (HECTD4), an E3 ubiquitin ligase highly expressed in the brain. As a potential substrate for HECTD4, mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) acts as a scaffold with hydrolysis activity. This study explores the relationship between HECTD4, GluN2B, and MALT1, focusing on their role in brain injury in ischemic stroke. Rats were subjected to 2 h-ischemia followed by 24-h reperfusion to establish an ischemic stroke model. We observed the downregulation of HECTD4 and the upregulation of MALT1. Additionally, an increased GluN2B phosphorylation was concomitant with weakened interactions between HECTD4 and GluN2B, followed by decreased striatal-enriched protein phosphatase (STEP61). Knockdown of HECTD4 exacerbated hypoxia- or NMDA-induced injury in nerve cells coincident with a decrease in GluN2B and MALT1 ubiquitination, and an increase in GluN2B phosphorylation as well as an increase in intracellular calcium level, which were counteracted by MALT1 siRNA. Blockage of MALT1 with its inhibitor or siRNA reduced STEP61 degradation, accompanied by a decrease in GluN2B phosphorylation, intracellular calcium concentration, and brain cell injury, which were reversed by overexpression of MALT1. Based on these observations, we conclude that the downregulation of HECTD4 in ischemic stroke rat brain accounts for calcium overload and brain injury due to activating GluN2B directly and indirectly through a mechanism involving the reduced ubiquitination of GluN2B and MALT1, respectively.

[Accuracy evaluation of static guided implant placement using an intraoral scan method].

PURPOSE: To evaluate the accuracy of static guided implant placement with intraoral scanning technology and to analyze the influencing factors of guided surgery. METHODS: Totally 27 cases were included in this retrospective study. The implant designs were made in 3Shape Implant Studio and then guided implant surgeries were performed with CAD-CAM templates. Postoperative implant positions were detected with an intraoral scanner (3Shape TRIOS) and deviation of implantation was evaluated using established CAD/CAM based evaluation method. SAS 9.4 software package was used for data analysis. RESULTS: The mean deviation of entrance point and apical point was (1.182±0.609) mm and (1.658±0.741) mm, respectively. Angular deviation was (5.712±3.347)°. Implant quadrant, location of the implant site, guidance degree, supporting type and implant size influenced direction deviation, while angular deviation was mainly affected by guidance degree and number of missing teeth. CONCLUSIONS: Accuracy of static guided implant placement can be influenced by many factors. More research is needed to improve the accuracy of static guided implantation.

Extracellular matrix modulating enzyme functionalized biomimetic Au nanoplatform-mediated enhanced tumor penetration and synergistic antitumor therapy for pancreatic cancer.

BACKGROUND: Excessive extracellular matrix (ECM) deposition in pancreatic ductal adenocarcinoma (PDAC) severely limits therapeutic drug penetration into tumors and is associated with poor prognosis. Collagen is the most abundant matrix protein in the tumor ECM, which is the main obstacle that severely hinders the diffusion of chemotherapeutic drugs or nanomedicines. METHODS: We designed a collagenase-functionalized biomimetic drug-loaded Au nanoplatform that combined ECM degradation, active targeting, immune evasion, near-infrared (NIR) light-triggered drug release, and synergistic antitumor therapy and diagnosis into one nanoplatform. PDAC tumor cell membranes were extracted and coated onto doxorubicin (Dox)-loaded Au nanocages, and then collagenase was added to functionalize the cell membrane through lipid insertion. We evaluated the physicochemical properties, in vitro and in vivo targeting, penetration and therapeutic efficacy of the nanoplatform. RESULTS: Upon intravenous injection, this nanoplatform efficiently targeted the tumor through the homologous targeting properties of the coated cell membrane. During penetration into the tumor tissue, the dense ECM in the PDAC tissues was gradually degraded by collagenase, leading to a looser ECM structure and deep penetration within the tumor parenchyma. Under NIR irradiation, both photothermal and photodynamic effects were produced and the encapsulated chemotherapeutic drugs were released effectively, exerting a strong synergistic antitumor effect. Moreover, this nanoplatform has X-ray attenuation properties that could serve to guide and monitor treatment by CT imaging. CONCLUSION: This work presented a unique and facile yet effective strategy to modulate ECM components in PDAC, enhance tumor penetration and tumor-killing effects and provide therapeutic guidance and monitoring.

Successful treatment of pulmonary hypertension in a neonate with bronchopulmonary dysplasia: A case report and literature review.

BACKGROUND: Pulmonary hypertension (PH) is a severe complication of bronchopulmonary dysplasia (BPD) in premature neonates and is closely related to prognosis. However, there is no effective and safe treatment for PH due to BPD in infants. Successful treatment for cases of BPD-associated PH with Tadalafil combined with bosentan is rare. This case may make a significant contribution to the literature because PH is difficult to manage as a serious complication of BPD in preterm infants. Mortality is high, especially when it is complicated by heart failure. CASE SUMMARY: An extremely premature neonate with a gestational age of 26+5 wk and birth weight of 0.83 kg was diagnosed with BPD associated with PH; oral sildenafil did not improve the PH. The infant experienced sudden cardiac arrest and serious heart failure with severe PH. After a series of treatments, including cardiopulmonary resuscitation, mechanical ventilation, and inhaled nitric oxide (iNO), the respiratory and circulatory status improved but the pulmonary artery pressure remained high. Then oral sildenafil was replaced with oral tadalafil and bosentan; pulmonary artery pressure improved, and the infant recovered at our hospital. After 2 years of follow-up, she is in good condition, without any cardiovascular complications. CONCLUSION: INO can effectively improve the respiratory and circulatory status of infants with PH associated with premature BPD. B-type natriuretic peptide should be routinely measured during hospitalization to evaluate the risk and prognosis of BPD-associated PH in preterm infants. Tadalafil combined with bosentan for the treatment of PH associated with premature BPD was better than sildenafil in this case. Further studies are needed to explore the efficacy and safety of different vasodilators in the treatment of PH associated with premature BPD.