Ginsenoside Rb1 reduces oxidative/carbonyl stress damage and dysfunction of RyR2 in the heart of streptozotocin-induced diabetic rats.

BACKGROUND: Oxidative stress may contribute to cardiac ryanodine receptor (RyR2) dysfunction in diabetic cardiomyopathy. Ginsenoside Rb1 (Rb1) is a major pharmacologically active component of ginseng to treat cardiovascular diseases. Whether Rb1 treat diabetes injured heart remains unknown. This study was to investigate the effect of Rb1 on diabetes injured cardiac muscle tissue and to further investigate its possible molecular pharmacology mechanisms. METHODS: Male Sprague-Dawley rats were injected streptozotocin solution for 2 weeks, followed 6 weeks Rb1 or insulin treatment. The activity of SOD, CAT, Gpx, and the levels of MDA was measured; histological and ultrastructure analyses, RyR2 activity and phosphorylated RyR2(Ser2808) protein expression analyses; and Tunel assay were performed. RESULTS: There was decreased activity of SOD, CAT, Gpx and increased levels of MDA in the diabetic group from control. Rb1 treatment increased activity of SOD, CAT, Gpx and decreased the levels of MDA as compared with diabetic rats. Neutralizing the RyR2 activity significantly decreased in diabetes from control, and increased in Rb1 treatment group from diabetic group. The expression of phosphorylation of RyR2 Ser2808 was increased in diabetic rats from control, and were attenuated with insulin and Rb1 treatment. Diabetes increased the apoptosis rate, and Rb1 treatment decreased the apoptosis rate. Rb1 and insulin ameliorated myocardial injury in diabetic rats. CONCLUSIONS: These data indicate that Rb1 could be useful for mitigating oxidative damage, reduced phosphorylation of RyR2 Ser2808 and decreased the apoptosis rate of cardiomyocytes in diabetic cardiomyopathy.

A model of pregnancy-associated malaria for inducing adverse pregnancy outcomes in ICR mouse.

BACKGROUND: Based on understanding of placental pathological features and safe medication in pregnancy-associated malaria (PAM), establishment of a stable pregnant mouse infection model with Plasmodium was urgently needed. METHODS: ICR mice with vaginal plugs detected were randomly divided into post-pregnancy infection (Malaria+) and uninfected pregnancy (Malaria-) cohorts. Age-matched mice that had not been mated were infected as pre-pregnancy infection group (Virgin control), which were subsequently mated with ICR males. All mice were inoculated with 1 × 106Plasmodium berghei ANKA-infected RBCs by intraperitoneal injection, and the same amount of saline was given to Malaria- group. We recorded the incidence of adverse pregnancy outcomes and the amounts of offspring in each group. RESULTS: The Virgin group mice were unable to conceive normally, and vaginal bleeding, abortion, or stillbirth appeared in the Malaria+ group. The incidence of adverse pregnancy outcomes was extremely high and statistically significant compared with the control (Malaria-) group (P < 0.05), of which placenta exhibited pathological features associated with human gestational malaria. CONCLUSIONS: The intraperitoneal injection of 1 × 106Plasmodium berghei ANKA-infected RBCs could establish a model of pregnancy-associated malaria in ICR mouse.

Lian-Mei-Yin formula alleviates diet-induced hepatic steatosis by suppressing Yap1/FOXM1 pathway-dependent lipid synthesis.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, with a global prevalence of 25%. Patients with NAFLD are more likely to suffer from advanced liver disease, cardiovascular disease, or type II diabetes. However, unfortunately, there is still a shortage of FDA-approved therapeutic agents for NAFLD. Lian-Mei-Yin (LMY) is a traditional Chinese medicine formula used for decades to treat liver disorders. It has recently been applied to type II diabetes which is closely related to insulin resistance. Given that NAFLD is another disease involved in insulin resistance, we hypothesize that LMY might be a promising formula for NAFLD therapy. Herein, we verify that the LMY formula effectively reduces hepatic steatosis in diet-induced zebrafish and NAFLD model mice in a time- and dose-dependent manner. Mechanistically, LMY suppresses Yap1-mediated Foxm1 activation, which is crucial for the occurrence and development of NAFLD. Consequently, lipogenesis is ameliorated by LMY administration. In summary, the LMY formula alleviates diet-induced NAFLD in zebrafish and mice by inhibiting Yap1/Foxm1 signaling-mediated NAFLD pathology.

How I do it? Surgical clipping of a large right internal carotid artery-superior hypophyseal artery aneurysm.

BACKGROUND: Microsurgery alone often proves to be challenging in treating paraclinoid internal carotid artery (ICA) aneurysms, which are known for their complex anatomy. METHOD: A 53-year-old female with a large right ICA-superior hypophyseal artery (SHA) aneurysm underwent clipping repair. Mixed reality technology was utilized in the preoperative planning and anatomical study. During the surgery, the anterior clinoid process was removed intradurally to improve access to the aneurysm neck. The aneurysm was then secured with a long curved clip. The patient's recovery was successful without any complications. CONCLUSION: This report aims to shed light on the intricacies involved in clipping ICA-SHA aneurysms.

An improved attention module based on nnU-Net for segmenting primary central nervous system lymphoma (PCNSL) in MRI images1.

BACKGROUND: Accurate volumetric segmentation of primary central nervous system lymphoma (PCNSL) is essential for assessing and monitoring the tumor before radiotherapy and the treatment planning. The tedious manual segmentation leads to interindividual and intraindividual differences, while existing automatic segmentation methods cause under-segmentation of PCNSL due to the complex and multifaceted nature of the tumor. OBJECTIVE: To address the challenges of small size, diffused distribution, poor inter-layer continuity on the same axis, and tendency for over-segmentation in brain MRI PCNSL segmentation, we propose an improved attention module based on nnUNet for automated segmentation. METHODS: We collected 114 T1 MRI images of patients in the Huashan Hospital, Shanghai. Then randomly split the total of 114 cases into 5 distinct training and test sets for a 5-fold cross-validation. To efficiently and accurately delineate the PCNSL, we proposed an improved attention module based on nnU-Net with 3D convolutions, batch normalization, and residual attention (res-attention) to learn the tumor region information. Additionally, multi-scale dilated convolution kernels with different dilation rates were integrated to broaden the receptive field. We further used attentional feature fusion with 3D convolutions (AFF3D) to fuse the feature maps generated by multi-scale dilated convolution kernels to reduce under-segmentation. RESULTS: Compared to existing methods, our attention module improves the ability to distinguish diffuse and edge enhanced types of tumors; and the broadened receptive field captures tumor features of various scales and shapes more effectively, achieving a 0.9349 Dice Similarity Coefficient (DSC). CONCLUSIONS: Quantitative results demonstrate the effectiveness of the proposed method in segmenting the PCNSL. To our knowledge, this is the first study to introduce attention modules into deep learning for segmenting PCNSL based on brain magnetic resonance imaging (MRI), promoting the localization of PCNSL before radiotherapy.

The compound artemisinin-hydroxychloroquine ameliorates bleomycin-induced pulmonary fibrosis in rats by inhibiting TGF-ß1/Smad2/3 signaling pathway.

Pulmonary fibrosis (PF) is a lethal disease characterized by a progressive decline in lung function. Currently, lung transplantation remains the only available treatment for PF. However, both artemisinin (ART) and hydroxychloroquine (HCQ) possess potential antifibrotic properties. This study aimed to investigate the effects and mechanisms of a compound known as Artemisinin-Hydroxychloroquine (AH) in treating PF, specifically by targeting the TGF-ß1/Smad2/3 pathway. To do this, we utilized an animal model of PF induced by a single tracheal drip of bleomycin (BLM) in Sprague-Dawley (SD) rats. The PF animal models were administered various doses of AH, and the efficacy and safety of AH were evaluated through pulmonary function testing, blood routine tests, serum biochemistry tests, organ index measurements, and pathological examinations. Additionally, Elisa, western blotting, and qPCR techniques were employed to explore the potential molecular mechanisms of AH in treating PF. Our findings reveal that AH effectively and safely alleviate PF by inhibiting BLM-induced specific inflammation, reducing extracellular matrix (ECM) deposition, and interfering with the TGF-ß1/Smad2/3 signaling pathway. Notably, the windfall for this study is that the inhibition of ECM may initiate self-healing in the BLM-induced PF animal model. In conclusion, AH shows promise as a potential therapeutic drug for PF, as it inhibits disease progression through the TGF-ß1/Smad2/3 signaling pathway.

Erythrocyte membrane with CLIPPKF as biomimetic nanodecoy traps merozoites and attaches to infected red blood cells to prevent Plasmodium infection.

BACKGROUND: Malaria remains a serious threat to global public health. With poor efficacies of vaccines and the emergence of drug resistance, novel strategies to control malaria are urgently needed. RESULTS: We developed erythrocyte membrane-camouflaged nanoparticles loaded with artemether based on the growth characteristics of Plasmodium. The nanoparticles could capture the merozoites to inhibit them from repeatedly infecting normal erythrocytes, owing to the interactions between merozoites and heparin-like molecules on the erythrocyte membrane. Modification with a phosphatidylserine-targeting peptide (CLIPPKF) improved the drug accumulation in infected red blood cells (iRBCs) from the externalized phosphatidylserine induced by Plasmodium infection. In Plasmodium berghei ANKA strain (pbANKA)-infected C57BL/6 mice, the nanoparticles significantly attenuated Plasmodium-induced inflammation, apoptosis, and anemia. We observed reduced weight variation and prolonged survival time in pbANKA-challenged mice, and the nanoparticles showed good biocompatibility and negligible cytotoxicity. CONCLUSION: Erythrocyte membrane-camouflaged nanoparticles loaded with artemether were shown to provide safe and effective protection against Plasmodium infection.

How we do it? Performing a protective superficial temporal artery-middle cerebral artery bypass with endoscopic transnasal cavernous sinus lesion operation.

BACKGROUND: To describe the concept of a protective superficial temporal artery-middle cerebral artery (STA-MCA) bypass performed prior to endoscopic transnasal cavernous sinus (CS) lesion resection in order to reduce the risk of perioperative cerebral ischemia due to internal carotid artery (ICA) vasospasm, occlusion, and even injury. METHOD: We illustrated the procedure of a 14-year-old female accepting a protective STA-MCA bypass with endoscopic transnasal CS lesion resection. CONCLUSION: A protective bypass may be a prophylactic strategy in selected endoscopic transnasal CS surgery cases, particularly where the diagnosis is uncertain, or the risk of ICA injury or occlusion is high.

How I do it? The surgical resection of the fourth ventricle choroid plexus papilloma.

BACKGROUND: The surgical resection of the large fourth ventricle choroid plexus papilloma (CPP) is complicated, where the challenge is to minimize the impairment of the vermis and the brainstem and restore the cerebrospinal fluid circulation. METHOD: We report a case of large CPP that wholly occluded the fourth ventricle, extended to the Luschka foramen, and underwent radical resection via telovelar approach. The intraoperative endoscope was applied to inspect the tumor residue and the aqueduct's opening. CONCLUSION: This case demonstrates the surgical nuance of the fourth ventricle CPP.

How I do it? Basilar bifurcation and left anterior choroidal artery aneurysms clipping.

BACKGROUND: Despite advancements in endovascular techniques, microsurgical treatment for posterior circulation aneurysms remains challenging. METHOD: This report highlights the successful clipping surgery of a 17-year-old female patient with an aneurysm located at the basilar artery (BA) bifurcation and left anterior choroidal artery (AChoA). To improve exposure, the posterior communicating artery was transected. A straight fenestrated clip was then placed to repair the BA bifurcation aneurysm, followed by a curved mini clip for the AChoA aneurysm. CONCLUSION: This report demonstrates the nuances of microsurgery in the treatment of select complex cases, which can benefit from microsurgery to achieve optimal treatment outcomes.

How I do it? Surgical removal of a corpus callosum arteriovenous malformation using a robotic digital microscope.

BACKGROUND: This report described the surgical nuance of a challenging deep-seated corpus callosum arteriovenous malformation (AVM) using a novel robotic digital microscope. METHOD: A 64-year-old male was admitted to treat a ruptured corpus callosum AVM. In order to facilitate surgical manipulation under the robotic digital microscope, a gravity-assisted supine position was utilized. Intraoperatively, identifying and preserving the transit and bystander artery is important while skeletonizing the anterior cerebral artery. The nidus was totally resected and the patient was discharged without sequella. CONCLUSION: It is feasible to perform complicated AVM resection under the robotic digital microscope with a rigorous surgical plan.

How I do it? Preoperative Microsoft HoloLens 2 planning-assisted surgical clipping of a fetal posterior cerebral artery aneurysm.

BACKGROUND: The treatment of intracranial aneurysms has predominantly shifted towards endovascular strategies, but complex cases still necessitate microsurgery. Preoperative stimulation can be beneficial for inexperienced young neurosurgeons in preparing for safe microsurgery. METHOD: A 72-year-old female with a left irregular fetal posterior cerebral artery (PCA) aneurysm underwent clipping repair. Microsoft HoloLens 2, utilizing mixed reality technology, was employed for preoperative stimulation and anatomical study. During the operation, we successfully identified the planned relationship between the aneurysm and the fetal PCA. The patient was cured without any complications. CONCLUSION: We hope that this report will highlight the significance of Microsoft HoloLens 2 in microsurgical planning and education.

How we do it: the double keyhole micro-endoscopic combined complex pituitary adenoma surgery.

BACKGROUND: Surgical removal of complex pituitary adenomas (PA) is a technically challenging procedure. To ensure safe and efficient surgery, we employ the micro-endoscopic combination technique. METHOD: In this study, we present our approach to the removal of a complex PA using the micro-endoscopic combination strategy. We describe our surgical setup and workflow in detail. CONCLUSION: Our experience with this case highlights the effectiveness of the micro-endoscopic combination technique in the management of complicated skull base surgeries with good teamwork and cooperation.

How we do it? The surgical resection of a medial parietal arteriovenous malformation under multimodal imaging technology-guided hybrid operation.

BACKGROUND: This report described the surgical resection of a challenging medial parietal lobe arteriovenous malformation (AVM) using the hybrid operation theater with a multimodal imaging-guided technology. METHOD: A 29-year-old male was admitted to treat a ruptured medial parietal AVM. The deep and diffusive compartment of the nidus was embolized before resection. Preoperatively and intraoperatively, mixed reality technology with multimodality imaging was utilized for surgical planning and navigation. The nidus was totally resected and confirmed by intraoperative angiography. The patient recovered without sequella. CONCLUSION: We hope this report provides new insights into applying multimodal imaging technology-guided hybrid operation for brain AVM.

Acute and subacute oral toxicity of artemisinin-hydroxychloroquine sulfate tablets in beagle dogs.

Artemisinin-hydroxychloroquine sulfate tablets (AH) are regarded as a relatively inexpensive and novel combination therapy for the treatment of various forms of malaria, particularly aminoquinoline drugs-resistant strains of Plasmodium falciparum. Our aim was to conduct acute and subacute oral toxicity studies in non-rodents to obtain more nonclinical data on the safety of AH. Acute toxicity evaluation was performed in beagle dogs at single doses of 230, 530, 790, 1180, 2660, and 5000 mg/kg. Beagle dogs at doses of 0, 56, 84, and 126 mg/kg were used to assess subacute toxicity for 14 days. The approximate lethal dose range for acute oral administration of AH in dogs is found to be 790-1180 mg/kg, and toxic symptoms prior to death include gait instability, limb weakness, mental fatigue, tachypnea, and convulsion. Repeated doses of AH in dogs caused vomiting, soft feces, decreased activity, anorexia, and splenic red pulp vacuolation. Of note, AH could reduce body weight gain and prolong the QTc interval of individual dogs. Therefore, the no-observed-adverse-effect level (NOAEL) and lowest-observed-adverse-effect level (LOAEL) of oral administration of AH for 14 days in dogs are determined to be 84 mg/kg and 126 mg/kg, respectively.

GB1a Activates SIRT6 to Regulate Lipid Metabolism in Mouse Primary Hepatocytes.

Lipid accumulation, oxidative stress, and inflammation in hepatocytes are features of nonalcoholic fatty liver disease (NAFLD). Garcinia biflavonoid 1a (GB1a) is a natural product capable of hepatic protection. In this study, the effect of GB1a on anti-inflammatory, antioxidant, and regulation of the accumulation in HepG2 cells and mouse primary hepatocytes (MPHs) was investigated, and its regulatory mechanism was further explored. The result showed that GB1a reduced triglyceride (TG) content and lipid accumulation by regulating the expression of SREBP-1c and PPARα; GB1a reduced reactive oxygen species (ROS) and improved cellular oxidative stress to protect mitochondrial morphology by regulating genes Nrf2, HO-1, NQO1, and Keap1; and GB1a reduced the damage of hepatocytes by inhibiting the expression of inflammatory cytokines interleukin-6 (IL-6), interleukin-1ß (IL-1ß), tumor necrosis factor-alpha (TNF-α), and nuclear factor kappa B (NF-κB) p65. The activities of GB1a were lost in liver SIRT6-specific knockout mouse primary hepatocytes (SIRT6-LKO MPHs). This indicated that activating SIRT6 was critical for GB1a to perform its activity, and GB1a acted as an agonist of SIRT6. It was speculated that GB1a may be a potential drug for NAFLD treatment.

Giant Aneurysm Management.

The treatment of giant aneurysms has always been a challenge in the field of neurovascular disease. Giant aneurysms are larger in size and are associated with thrombosis development and the calcification of the aneurysmal wall and neck, which often interfere with direct clipping. Most giant aneurysms have a wide neck with an incomplete thrombus, making complete embolization almost impossible. Giant aneurysms of different sites have entirely different hemodynamic characteristics. Moreover, aneurysms at the same site may exhibit very different hemodynamics among different individuals. Therefore, careful assessment of each case is required before and during treatment to develop and carry out an individualized treatment plan.

Acute and subacute oral toxicity of artemisinin-hydroxychloroquine sulfate tablets in rats.

Artemisinin-hydroxychloroquine sulfate tablets (AH) are considered a relatively inexpensive and novel combination therapy for treating all forms of malaria, especially aminoquinoline drugs-resistant strains of P.falciparum. We aim to carry out acute and subacute oral toxicity studies in rats to acquire preclinical data on the safety of AH. Acute toxicity was evaluated in Sprague-Dawley (SD) rats at a single dose of 1980, 2970, 4450, 6670, and 10000 mg/kg. A 14-days subacute toxicity was assessed in SD rats at doses of 0, 146, 219, 328, and 429 mg/kg. The median lethal dose (LD50) of acute oral administration of AH in rats is found to be 3119 mg/kg, and toxic symptoms include decreased spontaneous activity, dyspnea, bristling, soft feces, spasticity, and convulsion. Repeated doses of AH have toxic effects on the nervous system, skin, blood system, liver, kidney, and spleen in rats. The main toxic reactions include epilation, emaciation, mental irritability, decreased body weight gain and food consumption, changes in the hematological and biochemical parameters, especially pathological lesions in the liver, kidney, and spleen. The no-observed-adverse-effect level (NOAEL) and lowest-observed-adverse-effect level (LOAEL) of AH are considered to be 219 mg/kg and 328 mg/kg, respectively.

How I do it? A multimodality-guided awake hybrid operation for a language-area brain arteriovenous malformation and multiple intracranial aneurysms.

BACKGROUND: The cure of an eloquent brain arteriovenous malformation (BAVM) and multiple intracranial aneurysms with preservation of neurological function and the minimal procedures is challenging. METHOD: A 53-year-old male was admitted to treat a left frontal language-area BAVM and concomitant five bilateral intracranial aneurysms. After repairing the ruptured right middle cerebral artery (MCA) bifurcation aneurysms and the other two unruptured ones, at the second-stage multimodality-guided awake hybrid operation, we successfully obliterated the left frontal BAVM and two other left MCA aneurysms. CONCLUSION: The multimodality-guided awake hybrid operation may be a promising technique to treat complicated cerebrovascular disease.

How I Do It: endoscope-assisted resection of a large dumbbell-shaped cervical schwannoma.

BACKGROUND: Cervical dumbbell-shaped schwannomas are often challenging in terms of complete resection. There are few reports on the use of endoscope-assisted surgery for foraminal schwannomas. METHOD: We used the wide-angle endoscope to assist in resecting a large cervical 3-4 dumbbell-shaped schwannoma. The well-designed set-up allowed the surgeon to achieve easier manipulation ins a straight surgical trajectory with minimal intraoperative adjustment. The endoscope allowed surgeons to visualize and operate in regions beyond the straight line of sight, without the need for facetectomy and subdural inspection. CONCLUSION: We believe that this case demonstrates the feasibility of applying endoscope-assisted surgery for large cervical dumbbell-shaped schwannomas.