Cucurbitane-type triterpenoids from the fruits of Citrullus colocynthis.

A phytochemical investigation of the fruits of Citrullus colocynthis resulted in the isolation of 21 structurally diverse cucurbitane triterpenoids, including 9 previously undescribed ones, colocynins A-I (1-9). Their absolute configurations were elucidated by means of quantum chemical electronic circular dichroism (ECD) calculations, CD exciton chirality method, and single-crystal X-ray crystallography. Colocynins A-C (1-3) represent the first examples of nonanorcucurbitane-type triterpenoids. An anti-acetylcholinesterase activity assay showed that 6, 10, 13, 18, and 20 exhibited inhibitory activities, with IC50 values ranging from 5.0 to 21.7 µM. In addition, 18 and 21 showed significant cytotoxicity against PACA, A431, and HepG2 cells, with IC50 values ranging from 0.042 to 0.60 and 3.6-14.4 µM, respectively.

Combined Hepatotoxicity and Toxicity Mechanism of Intermedine and Lycopsamine.

Pyrrolizidine alkaloids (PAs) are common constituents of plants and have serious hepatotoxicity. Intermedine (Im) and lycopsamine (La) are two monoesters of PAs that frequently coexist in the PA-containing plants (e.g., comfrey and tea). The present study aimed to explore the combined hepatotoxicity and toxicity mechanism of the Im and La mixture. In vitro, the combined cytotoxicity of the Im and La mixture on human hepatocytes (HepD) was examined by CCK-8, colony formation, wound healing, and Annexin V/PI staining assays. The combination of Im and La inhibited the ability of HepD cells to proliferate, colonize, and migrate and induced hepatocytes apoptosis in a dose-dependent manner. In addition to significantly causing a burst of intracellular reactive oxygen species (ROS), mitochondrial apoptosis, and endoplasmic reticulum (ER) stress, the Im and La mixture can also cause an increase in intracellular Ca2+, triggering the PERK/eIF2α/ATF4/CHOP apoptosis pathway. This study provided the first direct evidence that the combined PAs induced hepatotoxicity through ER-mediated apoptosis. These results supplemented the basic toxicity data for the combined PAs and provided a new perspective for the risk assessment of combined PA toxicity.

3D printed PCLA scaffold with nano-hydroxyapatite coating doped green tea EGCG promotes bone growth and inhibits multidrug-resistant bacteria colonization.

OBJECTIVES: 3D-printing scaffold with specifically customized and biomimetic structures gained significant recent attention in tissue engineering for the regeneration of damaged bone tissues. However, constructed scaffolds that simultaneously promote bone regeneration and in situ inhibit bacterial proliferation remains a great challenge. This study aimed to design a bone repair scaffold with in situ antibacterial functions. MATERIALS AND METHODS: Herein, a general strategy is developed by using epigallocatechin-3-gallate (EGCG), a major green tea polyphenol, firmly anchored in the nano-hydroxyapatite (HA) and coating the 3D printed polymerization of caprolactone and lactide (PCLA) scaffold. Then, we evaluated the stability, mechanical properties, water absorption, biocompatibility, and in vitro antibacterial and osteocyte inductive ability of the scaffolds. RESULTS: The coated scaffold exhibit excellent activity in simultaneously stimulating osteogenic differentiation and in situ resisting methicillin-resistant Staphylococcus aureus colonization in a bone repair environment without antibiotics. Meanwhile, the prepared 3D scaffold has certain mechanical properties (39.3 ± 3.2 MPa), and the applied coating provides the scaffold with remarkable cell adhesion and osteogenic conductivity. CONCLUSION: This study demonstrates that EGCG self-assembled HA coating on PCLA surface could effectively enhance the scaffold's water absorption, osteogenic induction, and antibacterial properties in situ. It provides a new strategy to construct superior performance 3D printed scaffold to promote bone tissue regeneration and combat postoperative infection in situ.

Limb loss experience evoked by electric cortical stimulation.

Limb loss experience is a type of body illusion characterized by the sensation of a missing limb or body part. We aimed to investigate the brain areas involved in this unusual somatosensory experience evoked by electric cortical stimulation with stereo-electroencephalography electrodes. We retrospectively reviewed the data of patients with medical intractable epilepsy, from October 2015 to December 2020, who underwent stereo-electroencephalography implantation and electric cortical stimulation in order to locate the epileptogenic zone and obtain a functional map. We included patients who reported experiences of limb loss during the process of electric cortical stimulation for functional mapping. Three patients reported experiences of limb loss in the process of electric cortical stimulation. Limb loss experience (including the right hand, right upper limb and right side of the body) occurred when the cortex of the left posterior insula, posterior dorsal cingulate and parietal operculum were stimulated. Limb loss experience can be evoked by electric cortical stimulation of the posterior insula, parietal operculum, and posterior cingulate cortex, and provides additional evidence that these cortices play a role in the integration of body sensory perception.

Comparison of efficiency between VNS and ANT-DBS therapy in drug-resistant epilepsy: A one year follow up study.

Vagus nerve stimulation (VNS) and anterior thalamic deep brain stimulation (ANT-DBS) have both been used for treatments of drug-resistant epilepsy (DRE). However, there is no comparative study on the effectiveness of two methods from one single center. 17 patients with DRE who underwent VNS therapy and 18 patients who underwent DBS were enrolled. A retrospective study was performed starting from baseline before operation extending to 12 months after operation. The seizure types, duration of epilepsy, age at implantation, failed numbers of antiepileptic drugs (AEDs) before operation, history of craniotomy, stimulation parameters and response rate were described. The analysis of liner regression on the age of onset, duration of epilepsy, numbers of AEDs, and the seizure reduction at 12 months after operation was applied. The mean seizure reduction in patients with DBS at 3, 6, 9 and 12 months after the operation was 57.22%, 61.61%, 63.94% and 65.28%, and that in cases with VNS was 36.06%, 39.94%, 45.24% and 48.35%, respectively. At 1 year after the operation, the patients with older operation age, focal seizures and older age of onset responded better to VNS; and those older operation age, focal generalized seizures, history of craniotomy and longer duration of disease responded better to DBS. The efficiency of ANT-DBS was higher than that of VNS at each follow up time point. Patients can choose the appropriate treatment according to the individual clinical characteristics.

Functional characteristics of the human primary somatosensory cortex: An electrostimulation study.

The common knowledge of the functional organization of the human primary somatosensory cortex (S1) had been primarily established by Penfield who electrically stimulated the exposed surface [referred as Brodmann area (BA)1] of S1 under neurosurgical conditions. Nevertheless, the functional information regarding the deep surface (BA 2 and 3) of S1 is poorly understood. We retrospectively analyzed all the clinical manifestations induced by extra-operative cortical electrical stimulation (ES) in 33 patients with medically intractable epilepsy who underwent stereo-electroencephalography (SEEG) monitoring for presurgical assessment. Demographic and clinical data were gathered and evaluated to delineate the determinants of the occurrence of positive responses, types of responses, and size of body regions involved. The stimulation of 244 sites in S1 yielded 198 positive sites (81.1%), most of which were located in the sulcal cortex. In multivariable analyses, no clinical or demographic factors predicted the occurrence of responses or their threshold levels. The size of body region involved in the responses had ordinal association with the stimulated BA sites (p < 0.001). Various types of responses elicited from the S1 were documented and classified, and the predictors of those responses were also assessed. Our analysis revealed the functional characteristics of the entire S1 and proved the multiplicity of functions of S1.

The thalamus-precentral gyrus functional connectivity changes in epilepsy patients following vagal nerve stimulation.

Vagal nerve stimulation (VNS) is an effective treatment for patients with drug-resistant epilepsy who are unsuitable for surgical epilepsy treatment. However, the mechanism of action of VNS remains unclear, and the efficacy of VNS treatment regarding seizure frequency reduction cannot be assessed before surgery. This study measured changes in functional connectivity between thalamus and precentral gyrus which are activated as vital targets of deep brain stimulation (DBS) and transcranial magnetic stimulation (TMS) using resting-state functional MRI to evaluate the effects of VNS. 16 epilepsy patients who underwent VNS were collected and scanned by resting-state functional MRI before and after operation. The functional connections (regions of interest: thalamus, precentral gyrus) were examined. After three months of stimulation, there were eight responders (≥50 % seizure reduction) and eight non-responders to VNS. No significant difference in thalamus-precentral gyrus functional connectivity was found between responders and nonresponders before operation. Enhanced functional connections were observed between bilateral thalamus and bilateral precentral gyrus in responders, which decreased in nonresponders, while functional connections between bilateral thalamus decreased in both responders and nonresponders. Short-term stimulation may cause thalamus-precentral gyrus functional connectivity changes in DRE patients, and control seizures by enhancing functional connections between bilateral thalamus and bilateral precentral gyrus.

The effect of vagal nerve stimulation on hippocampal-thalamic functional connectivity in epilepsy patients.

BACKGROUND: Vagal nerve stimulation (VNS) is widely used as an auxiliary treatment for patients with intractable epilepsy. Up to now, the therapeutic mechanisms remain elusive, and no surgical prediction criteria has been proposed. METHODS: In this study, the resting-state functional magnetic resonance imaging (rs-fMRI) was chosen to explore aberrant intrinsic brain activity and functional connections in 14 epilepsy patients with VNS stimulators between March 2019 and April 2019. Seven patients who ≥ 50 % seizure reduction was defined as responders, and seven non-responders. All patients had got rs-fMRI scan before and after operation. The hippocampal - thalamic connections (hippocampal and thalamus as regions of interest) were detected to evaluate the diversity in all 14 patients and seven responders with stimulation at 0, 0.5, 1.0, and 1.5 mA. The hippocampal-thalamic connections before operation were also examined between responders and non-responders. RESULTS: The preoperative left hippocampal - left thalamic connections and left hippocampal - right thalamic connections in responders were lower than those in non-responders (p < 0.05). While, there was no significant difference in hippocampal - thalamic connections in all epilepsy patients or responders with different current intensities (p > 0.05). CONCLUSIONS: VNS may be more suitable for patients with lower left hippocampal - left thalamic connections and/or left hippocampal - right thalamic connections. The current intensity ≤ 1.5 mA and stimulation time ≤ 3 months may not cause significant changes in hippocampal-thalamic functional connectivity.

[Proximal femoral nail anti rotation under local anesthesia for femoral intertrochanteric fractures in high-risk patients].

OBJECTIVE: To compare the clinical efficacy under local anesthesia and general anesthesia proximal femoral nail anti-rotation(PFNA) fixation for intertrochanteric fracture of femur in high risk patients. METHODS: From February 2018 to February 2019, 32 patients underwent PFNA operation due to intertrochanteric fracture of femur, including 16 patients undergoing PFNA operation under local anesthesia, 9 males and 7 females, aged 54 to 98 (82.43±9.30) years and hospitalized for (10.94±5.30) days;16 patients undergoing PFNA operation under general anesthesia, 6 males and 10 females, aged 51 to 83 (72.69±9.48) years and hospitalized for (12.88±4.12) days. The patients' gender, age, fracture AO classification, preoperative VAS (visual analogue score), preoperative ASA condition grade, postoperative 1st day resting state VAS, hospitalization cost and length of stay were recorded. RESULTS: All patients recovered well, the wound healed well, and the ability of lower limb activity was restored. The average follow-up time was 4.6 months. There was significant difference in age between two groups (P< 0.05);there was no significant difference in sex ratio, AO classification of fracture and VAS before operation (P>0.05). There was no significant difference on ASA between two groups (P>0.05), but there was significant difference on ASA≥grade Ⅲ between two groups (P<0.05). In local anesthesia group, VAS pain score was 4.19±1.50, which was tolerable. There was no significant difference in postoperative 1st day resting state VAS, average hospitalization cost and average length of stay between two groups(P>0.05). CONCLUSION: Under the multi-disciplinary diagnosisand treatment mode, the method of PFNA operation is safe and feasible, the patients with local anesthesia are older, and the proportion of patients with ASA≥grade Ⅲ is higher, which is better for some elderly high-risk patients than general anesthesia.

Application of organoids in translational research of human diseases with a particular focus on gastrointestinal cancers.

Gastrointestinal (GI) cancers constitute the largest portion of all human cancers and represent a significant health burden on modern society. Conventional therapeutic approaches such as chemotherapy and surgical resections often fail due to poor treatment response or tumour relapse. Unfortunately, drug discovery for GI cancers has stalled as current cancer models fail to recapitulate critical features of the parent tumour, leading to poor translation from bench to bedside. Recent advances in three-dimensional (3D) cell culturing techniques have driven the surge of interest in stem cell-derived organoid models, a promising platform with a plethora of potential applications due to its ability to retain crucial architectural, genomic and transcriptional properties of the native tissue. In this review article, we discuss current applications and advantages of organoid models in the translational research of GI cancers with a particular focus on primary liver cancer that currently lack effective curative treatments.

The clinical efficacy of Shi-style lumbar manipulations for symptomatic degenerative lumbar spondylolisthesis: protocol for a randomized, blinded, controlled trial.

BACKGROUND: Symptomatic degenerative lumbar spondylolisthesis (DLS) presents spinal problems in daily life. Shi-style lumbar manipulation (SLM), as an alternative treatment for DLS, is popular in China. SLM is based on the channels and collaterals theory of the traditional Chinese medicine, in which the symptoms are believed to result from channel blockage and joint displacement. However, there is no solid evidence to show the effect of the SLM on the management of symptomatic DLS. METHODS/DESIGN: We conduct a prospective randomized, blinded, controlled trial to compare the effectiveness of SLM with mechanical lumbar traction and explore whether it could be a potential therapy for symptomatic DLS. A total of 60 patients with symptomatic DLS will be enrolled and treated with the SLM or mechanical lumbar traction for 2 weeks. VAS score and SF-36 questionnaire were assessed at baseline and at 2, 4, 12, and 24 weeks. Any signs of acute adverse reactions, such as lower limb paralysis or syndrome of cauda equina, will be recorded at each visit during treatment. DISCUSSION: Although the SLM has been used in China for many years to treat symptomatic DLS, there is a lack of consensus about its effectiveness. This trial will provide convincing evidence about the effect of SLM on symptomatic DLS. TRIAL REGISTRATION: Registered on 6 January 2019; the trial number is ChiCTR1900020519 .

High-Dose Electron Radiation and Unexpected Room-Temperature Self-Healing of Epitaxial SiC Schottky Barrier Diodes.

Silicon carbide (SiC) has been widely used for electronic radiation detectors and atomic battery sensors. However, the physical properties of SiC exposure to high-dose irradiation as well as its related electrical responses are not yet well understood. Meanwhile, the current research in this field are generally focused on electrical properties and defects formation, which are not suitable to explain the intrinsic response of irradiation effect since defect itself is not easy to characterize, and it is complex to determine whether it comes from the raw material or exists only upon irradiation. Therefore, a more straightforward quantification of irradiation effect is needed to establish the direct correlation between irradiation-induced current and the radiation fluence. This work reports the on-line electrical properties of 4H-SiC Schottky barrier diodes (SBDs) under high-dose electron irradiation and employs in situ noise diagnostic analysis to demonstrate the correlation of irradiation-induced defects and microscopic electronic properties. It is found that the electron beam has a strong radiation destructive effect on 4H-SiC SBDs. The on-line electron-induced current and noise information reveal a self-healing like procedure, in which the internal defects of the devices are likely to be annealed at room temperature and devices' performance is restored to some extent.

Fusaricates H-K and fusolanones A-B from a mangrove endophytic fungus Fusarium solani HDN15-410.

Seven compounds including four undescribed fusaric acid derivatives, namely fusaricates H-K, and two undescribed γ-pyrone derivatives, named fusolanones A-B, as well as a known compound fusaric acid, were isolated from a mangrove endophytic fungus Fusarium solani. Fusaricates H-K represent the first cases of fusaric acid butanediol esters and are diastereoisomers. Their structures including absolute configurations were elucidated based on NMR, MS, chemical synthesis, chiral HPLC analysis and ECD calculations. The antibacterial activity of all undescribed compounds were tested and fusolanone B showed the best activity with MIC value 6.25 µg/mL on Vibrio parahaemolyticus.

High-frequency stimulation of anterior nucleus of thalamus desynchronizes epileptic network in humans.

Epilepsy has been classically seen as a brain disorder resulting from abnormally enhanced neuronal excitability and synchronization. Although it has been described since antiquity, there are still significant challenges achieving the therapeutic goal of seizure freedom. Deep brain stimulation of the anterior nucleus of the thalamus has emerged as a promising therapy for focal drug-resistant epilepsy; the basic mechanism of action, however, remains unclear. Here, we show that desynchronization is a potential mechanism of deep brain stimulation of the anterior nucleus of the thalamus by studying local field potentials recordings from the cortex during high-frequency stimulation (130 Hz) of the anterior nucleus of the thalamus in nine patients with drug-resistant focal epilepsy. We demonstrate that high-frequency stimulation applied to the anterior nucleus of the thalamus desynchronizes ipsilateral hippocampal background electrical activity over a broad frequency range, and reduces pathological epileptic discharges including interictal spikes and high-frequency oscillations. Furthermore, high-frequency stimulation of the anterior nucleus of the thalamus is capable of decoupling large-scale neural activity involving the hippocampus and distributed cortical areas. We found that stimulation frequencies ranging from 15 to 45 Hz were associated with synchronization of hippocampal local field potentials, whereas higher frequencies (>45 Hz) promoted desynchronization of ipsilateral hippocampal activity. Moreover, reciprocal effective connectivity between the anterior nucleus of the thalamus and the hippocampus was demonstrated by hippocampal-thalamic evoked potentials and thalamic-hippocampal evoked potentials. In summary, high-frequency stimulation of the anterior nucleus of the thalamus is shown to desynchronize focal and large-scale epileptic networks, and here is proposed as the mechanism for reducing seizure generation and propagation. Our data also demonstrate position-specific correlation between deep brain stimulation applied to the anterior nucleus of the thalamus and patients with temporal lobe epilepsy and seizure onset zone within the Papaz circuit or limbic system. Our observation may prove useful for guiding electrode implantation to increase clinical efficacy.

Role of nutrition, gene polymorphism, and gut microbiota in non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the world. The nutrients play important roles in the development and progression of NAFLD. High-calorie diet, especially the diet rich in saturated fatty acids and cholesterol, as well as sugary drinks with high fructose content, induces hepatic steatosis and triggers progression of steatohepatitis, fibrosis, and even hepatocellular carcinoma. Disordered micronutrient status and gut microbiota are also involved in the pathogenesis of NAFLD. Nutrients related NAFLD could be aggravated by a genetic predisposition, for instance, genetic mutations in patatinlike phospholipase domain-containing 3 (PNPLA3) and transmembrane 6 superfamily member 2 (TM6SF2). Reduction of caloric intake through lifestyle interventions and use of dietary supplements such as omega-3 fatty acids, vitamins, and probiotics may help alleviate liver injury in NAFLD.

Electrostatic Spray Ionization from 384-Well Microtiter Plates for Mass Spectrometry Analysis-Based Enzyme Assay and Drug Metabolism Screening.

We have realized the direct ionization of samples from wells of microtiter plates under atmospheric conditions for mass spectrometry analysis without any liquid delivery system or any additional interface. The microtiter plate is a commercially available 384-well plate without any modification, working as a container and an emitter for electrostatic spray ionization of analytes. The approach provides high throughput for the large batches of reactions and both the qualitative and quantitative analysis of a single compound or mixture. The limits of detection in small drug molecules, peptides, and proteins are similar in comparison with standard direct infusion electrospray ionization. The analysis time per well is only seconds. These analytical merits benefit many microtiter plate-based studies, such as combinatorial chemistry and high throughput screening in enzyme assay or drug metabolism. Herein, we illustrate the application in enzyme assay using tyrosine oxidation catalyzed by tyrosinase in the presence or absence of inhibitors. The potential application in drug development is also demonstrated with cytochrome P450-catalyzed metabolic reactions of two drugs in microtiter plates followed with direct ESTASI-MS/MS-based characterization of the metabolism products.

Embelin and Its Role in Chronic Diseases.

Embelia ribes Burm of Myrsinaceae family has been widely used as an herb in the traditional medicine of India. Embelin is an active component extracted from the fruits of Embelia ribes. It has a wide spectrum of biological activities and is not toxic at low dose. This review focuses on the physical-chemical properties and bioactivities of Embelin, as well as its effects on chronic diseases such as tumors, autoimmune inflammatory diseases, parasitic infections, microbial infections, diabetes, obesity, and cardio-cerebral vascular diseases. The underlying mechanisms of the effects are also discussed. As a multiple-targeted therapeutic agent, Embelin has the potential to be used widely for the treatment of a variety of chronic diseases, including malignant tumors.

TiO2 Band Restructuring by B and P Dopants.

An examination of the effect of B- and P-doping and codoping on the electronic structure of anatase TiO2 by performing density functional theory calculations revealed the following: (i) B- or P-doping effects are similar to atomic undercoordination effects on local bond relaxation and core electron entrapment; (ii) the locally entrapped charge adds impurity levels within the band gap that could enhance the utilization of TiO2 to absorb visible light and prolong the carrier lifetime; (iii) the core electron entrapment polarizes nonbonding electrons in the upper edges of the valence and conduction bands, which reduces not only the work function but also the band gap; and (iv) work function reduction enhances the reactivity of the carriers and band gap reduction promotes visible-light absorption. These observations may shed light on effective catalyst design and synthesis.

Garlic-derived allyl sulfides in cancer therapy.

Garlic (Allium sativam L.) is widely used in traditional herbal remedies and alternative medicine. The potential health benefits of garlic are largely attributed to its metabolic byproducts. Extensive in vivo and in vitro studies has demonstrated that the garlic derivatives possess anti-cancer effects, but the underlying mechanisms are not completely understood. In this mini-review, we aim to summarize the reported biological effects of garlic products as anti-tumor agents, and present the possible molecular mechanisms responsible for the anti-carcinogenesis effects of garlic and its derivatives.