Natural course of hemodynamically stable hemispheres contralateral to operated hemispheres in adult patients with ischemic moyamoya diseases.

The necessity of bilateral bypass in adult moyamoya disease (MMD) remains unclear despite its recommendation for pediatric and hemorrhagic cases. We aimed to investigate the natural course of hemodynamically stable unoperated hemispheres after bypass surgery for symptomatic and hemodynamically unstable hemispheres in adult patients with ischemic MMD. Among 288 patients, the mean age at the first operation of the unstable hemispheres was 40.8 ± 12.2 years. The mean follow-up period was 62.9 ± 46.5 months. 45 patients (15.6%) experienced stroke events in the unoperated hemisphere, consisting of hemorrhagic stroke in 8 (2.8%) and ischemic stroke in 37 (12.8%), including progressive transient ischemic attack in 25 (8.7%) and infarction in 12 (4.2%). Among them, 39 patients (13.5%) underwent bypass surgery. The annual risk of total stroke is 3.0%/patient-year, with 2.5% for ischemic stroke and 0.5% for hemorrhagic stroke. The 5- and 10-year cumulative risks of ischemic stroke were 13.4% and 18.3%, respectively, and those of hemorrhagic stroke were each 3.2%. The natural course of hemodynamically stable hemispheres contralateral to the operated ones appeared fairly good. Additional bypass surgery on the unoperated hemispheres should be considered for symptomatic and hemodynamically unstable hemispheres in adult patients with ischemic MMD during the follow-up.

Scutellarin activates IDH1 to exert antitumor effects in hepatocellular carcinoma progression.

Isochlorate dehydrogenase 1 (IDH1) is an important metabolic enzyme for the production of α-ketoglutarate (α-KG), which has antitumor effects and is considered to have potential antitumor effects. The activation of IDH1 as a pathway for the development of anticancer drugs has not been attempted. We demonstrated that IDH1 can limit glycolysis in hepatocellular carcinoma (HCC) cells to activate the tumor immune microenvironment. In addition, through proteomic microarray analysis, we identified a natural small molecule, scutellarin (Scu), which activates IDH1 and inhibits the growth of HCC cells. By selectively modifying Cys297, Scu promotes IDH1 active dimer formation and increases α-KG production, leading to ubiquitination and degradation of HIF1a. The loss of HIF1a further leads to the inhibition of glycolysis in HCC cells. The activation of IDH1 by Scu can significantly increase the level of α-KG in tumor tissue, downregulate the HIF1a signaling pathway, and activate the tumor immune microenvironment in vivo. This study demonstrated the inhibitory effect of IDH1-α-KG-HIF1a on the growth of HCC cells and evaluated the inhibitory effect of Scu, the first IDH1 small molecule agonist, which provides a reference for cancer immunotherapy involving activated IDH1.

Integrated metabolic profiles and microbial communities to reveal the beneficial effect of red pitaya on early constipation.

Pitaya is a well-known fruit widely cultivated in tropical and subtropical tropical regions, and is characterized by its flesh colour into red, white, and yellow pitaya. Red pitaya has dark red flesh and is the preferred choice among consumers due to its superior taste compared to other varieties. Red pitaya has been known to cause diarrhoea, and studies have reported that pitaya does this by drawing moisture into the intestines, resulting in defecation. However, the exact mechanism of action is still unclear. In this study, mass spectrometry was employed to identify small molecular compounds in red pitaya powder, and a loperamide hydrochloride-induced early constipation mouse model was used to assess the efficacy of red pitaya. 16S rDNA and non-targeted metabolomics techniques were used to systematically reveal the regulatory characteristics of the intestinal flora and to identify the intestinal metabolites associated with constipation. The results showed that 44 novel small molecular compounds were identified from red pitaya powder, including a variety of phenolic acids and flavonoids. Pathological results showed that administration of red pitaya powder at a high dose (1000 mg kg-1) significantly ameliorated the abnormal expansion of intestinal goblet cells observed in the early stages of constipation. In addition, early constipation increased metabolites such as serotonin and 5-hydroxytryptophol, which were normalized following the ingestion of red pitaya powder. Furthermore, Erysipelatoclostridium, Parasutterella, and other abnormal gut microbiota associated with early constipation returned to healthy levels after the ingestion of red pitaya powder. Finally, significant correlations were observed between the expression of 33 different serum metabolites and the abundance of eight kinds of intestinal flora. Consequently, red pitaya holds potential as a safe food supplement for the prevention or amelioration of early-stage constipation.

Dihydrophenanthro[b]furan derivatives from the tubers of Bletilla striata.

Two pairs of new dihydrophenanthro[b]furan enantiomers blephebibnols G-H (1-2), one new dihydrophenanthro[b]furan derivative blephebibnol I (3), along with four known analogues (4-7), were isolated from the tubers of Bletilla striata. Their structures including the absolute configurations were determined by the combination of spectroscopic data analysis, ECD and NMR calculations. Compounds 1a, 1b, and 2b showed inhibition of NO production in LPS-stimulated BV-2 cells, with IC50 values ranging from 4.11 to 14.65 µM. Further mechanistic study revealed that 1a suppressed the phosphorylation of p65 subunit to regulate the NF-κB signaling pathway. In addition, some compounds displayed selective cytotoxic activities against HCT-116, HepG2, A549, or HGC27 cancer cell lines with IC50 values ranging from 0.1 to 8.23 µM.

Light-strand bias and enriched zones of embedded ribonucleotides are associated with DNA replication and transcription in the human-mitochondrial genome.

Abundant ribonucleoside-triphosphate (rNTP) incorporation into DNA by DNA polymerases in the form of ribonucleoside monophosphates (rNMPs) is a widespread phenomenon in nature, resulting in DNA-structural change and genome instability. The rNMP distribution, characteristics, hotspots and association with DNA metabolic processes in human mitochondrial DNA (hmtDNA) remain mostly unknown. Here, we utilize the ribose-seq technique to capture embedded rNMPs in hmtDNA of six different cell types. In most cell types, the rNMPs are preferentially embedded on the light strand of hmtDNA with a strong bias towards rCMPs; while in the liver-tissue cells, the rNMPs are predominately found on the heavy strand. We uncover common rNMP hotspots and conserved rNMP-enriched zones across the entire hmtDNA, including in the control region, which links the rNMP presence to the frequent hmtDNA replication-failure events. We show a strong correlation between coding-sequence size and rNMP-embedment frequency per nucleotide on the non-template, light strand in all cell types, supporting the presence of transient RNA-DNA hybrids preceding light-strand replication. Moreover, we detect rNMP-embedment patterns that are only partly conserved across the different cell types and are distinct from those found in yeast mtDNA. The study opens new research directions to understand the biology of hmtDNA and genomic rNMPs.

Allantoin Derived From Dioscorea opposita Thunb Ameliorates Cyclophosphamide-Induced Premature Ovarian Failure in Female Rats by Attenuating Apoptosis, Autophagy and Pyroptosis.

Background and objectives Cyclophosphamide (CP) is widely used as a chemotherapy drug for the treatment of malignant tumors and autoimmune diseases, but it has strong toxic and side effects and can cause permanent damage to the ovaries, which affects women's quality of life. This study aimed to investigate the anti-premature ovarian failure protective effect of allantoin isolated from Dioscorea opposita Thunb. Methods Firstly, 75 mg/kg CP was injected into rats to establish an in vivo model of premature ovarian failure (POF). The POF rats were divided into the normal control group (NC), premature ovarian failure group (POF), and POF group treated with allantoin (ALL I 140 mg/kg and ALL II 70 mg/kg, daily 21 days). It investigated the estrous cycles, hormone levels, apoptosis rate, mitochondrial membrane potential (MMP), reactive oxygen species (ROS), mitophagy, and protein marker (Bax, Bcl2, LC3B, L-1ß, caspase-1 and NLRP3). Results The results indicated that allantoin alleviated cyclophosphamide-induced premature ovarian failure in female rats, decreased the anoestrum, increased the level of estradiol (E2), and decreased the levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), decreased apoptosis rate, MMP, mitophagy and ROS in ovarian granulosa cells of POF rats, down-regulated L-1ß, caspase-1, LC3B-II/LC3B-I in ovarian tissue, and up-regulated the Bcl2 and NLRP3. Conclusions Our study revealed the ovarian-protective effect of allantoin in CP-induced premature ovarian failure for the first time, the effect was achieved through attenuation of the apoptosis, autophagy, and pyroptosis. The study underlines the potential clinical application of allantoin as a protectant agent for premature ovarian failure.

The Tale of DJ-1 (PARK7): A Swiss Army Knife in Biomedical and Psychological Research.

DJ-1 (also known as PARK7) is a multifunctional enzyme in human beings that is highly conserved and that has also been discovered in diverse species (ranging from prokaryotes to eukaryotes). Its complex enzymatic and non-enzymatic activities (such as anti-oxidation, anti-glycation, and protein quality control), as well as its role as a transcriptional coactivator, enable DJ-1 to serve as an essential regulator in multiple cellular processes (e.g., epigenetic regulations) and make it a promising therapeutic target for diverse diseases (especially cancer and Parkinson's disease). Due to its nature as a Swiss army knife enzyme with various functions, DJ-1 has attracted a large amount of research interest, from different perspectives. In this review, we give a brief summary of the recent advances with respect to DJ-1 research in biomedicine and psychology, as well as the progress made in attempts to develop DJ-1 into a druggable target for therapy.

Spontaneous Chirality Induction in the Assembly of a Single Layer 2D Network with Switchable Pores.

Although two-dimensional (2D) chiral sheet structures are attractive because of their unique chemical and physical properties, single layer 2D chiral network structures with switchable pore interior remain elusive. Here we report spontaneous chirality induction in a single layer 2D network structure formed from the self-assembly of tetrapod azobenzene molecules. The chirality induction arises from multiple sublayers slipped in a preferred direction in which the sublayer consists of unidentical molecular arrangements in the in-plane a and b directions, breaking both the plane of symmetry and inversion symmetry. The protruded azobenzene units in the pore interior can be selectively isomerized upon UV irradiation, resulting in a reversible deformation of the chiral pores while maintaining the 2D frameworks. The chiral network can thus selectively entrap one enantiomer from a racemic solution with near perfect enantioselectivity, and then release it upon UV irradiation.

Communication and Cross-Regulation between Chemically Fueled Sender and Receiver Reaction Networks.

Nature connects multiple fuel-driven chemical/enzymatic reaction networks (CRNs/ERNs) via cross-regulation to hierarchically control biofunctions for a tailored adaption in complex sensory landscapes. Herein, we introduce a facile example of communication and cross-regulation among two fuel-driven DNA-based ERNs regulated by a concatenated RNA transcription regulator. ERN1 ("sender") is designed for the fuel-driven promoter formation for T7 RNA polymerase, which activates RNA transcription. The produced RNA can deactivate or activate DNA in ERN2 ("receiver") by toehold-mediated strand displacement, leading to a communication between two ERNs. The RNA from ERN1 can repress or promote the fuel-driven state of ERN2; ERN2 in turn feedbacks to regulate the lifetime of ERN1. Furthermore, the incorporation of RNase H allows for RNA degradation and enables the autonomous recovery of ERN2. We believe that concatenation of multiple CRNs/ERNs provides a basis for the design of more elaborate autonomous regulatory mechanisms in systems chemistry and synthetic biology.

Molecular subgrouping of medulloblastoma in pediatric population using the NanoString assay and comparison with immunohistochemistry methods.

PURPOSE: Molecular subgrouping of medulloblastoma has become important due to its impact on risk group stratification. Immunohistochemistry (IHC) has been widely used but it has innate limitations. The NanoString assay has been proposed as an alternative method. This study aims to present the characteristics of medulloblastoma subgrouped by the NanoString assay and to compare the subgrouping results with the IHC method. METHODS: Pediatric patients with histological diagnosis of medulloblastoma who underwent surgery from 2007 to 2021 were included. Clinical characteristics, pathological findings were reviewed. Molecular subgrouping was performed by IHC and by NanoString nCounter Elements TagSets assay. Test for concordance between two methods was made. RESULTS: Among a total of 101 patients analyzed, subgrouping using the NanoString assay resulted in 14 (13.8%) WNT, 20 (19.8%) SHH, 18 (17.8%) Group 3, and 39 (38.6%) Group 4 subgroup cases. Survival analysis revealed the following from best to worse prognosis: WNT, Group 4, SHH, and Group 3. In SHH subgroup the large cell/anaplastic histology was present in 30% of cases. Seventy-one cases were analyzed for concordance between NanoString and IHC. Cohen's kappa value indicated moderate agreement but identification of Groups 3 and 4 with IHC using NPR3 and KCNA1 markers exhibited poor results. CONCLUSIONS: The NanoString assay of Korean medulloblastoma patients revealed a more aggressive clinical course in the SHH subgroup which may be explained by a higher proportion of large cell/anaplastic histology being present in this subgroup. IHC did not distinguish Group 3 or 4 accurately. The NanoString assay may represent a good alternative method for practical use in the clinical field.

Dissipative Organization of DNA Oligomers for Transient Catalytic Function.

The development of synthetic non-equilibrium systems opens doors for man-made life-like materials. Yet, creating distinct transient functions from artificial fuel-driven structures remains a challenge. Building on our ATP-driven dynamic covalent DNA assembly in an enzymatic reaction network of concurrent ATP-powered ligation and restriction, we introduce ATP-fueled transient organization of functional subunits for various functions. The programmability of the ligation/restriction site allows to precisely organize multiple sticky-end-encoded oligo segments into double-stranded (ds) DNA complexes. We demonstrate principles of ATP-driven organization into sequence-defined oligomers by sensing barcode-embedded targets with different defects. Furthermore, ATP-fueled DNAzymes for substrate cleavage are achieved by transiently ligating two DNAzyme subunits into a dsDNA complex, rendering ATP-fueled transient catalytic function.

Switchable Aromatic Nanopore Structures: Functions and Applications.

Nanopore structures in nature play a crucial role in performing many sophisticated functions such as signal transduction, mass transport, ion channel, and enzyme reaction. Inspired by pore-forming proteins, considerable effort has been made to design self-assembling molecules that are able to form nanostructures with internal pores in aqueous media. These nanostructures offer ample opportunity for applications because their internal pores are able to perform a number of unique functions required for a confined nanospace. However, unlike nanopore assembly in nature, the synthetic nanopore structures are mostly based on a fixed pore that impedes performing adaptable regulation of properties to environmental change. This limitation can be overcome by integration of hydrophilic oligo(ethylene oxide) dendrons into aromatic building blocks for nanopore self-assembly, because the dendritic chains undergo large conformational changes triggered by environmental change. The transition of the oligoether chains triggers the aromatic nanopore assembly to undergo reversible pore deformation through closing, squeezing, and shape change without structural collapse. These switching properties allow the aromatic nanopore structures to perform adaptable, complex functions which are difficult to achieve using a fixed pore assembly.In this Account, we summarize our recent progress in the development of switchable nanopore structures by self-assembly of rigid aromatic amphiphiles grafted by hydrophilic oligo(ethylene oxide) dendrons in aqueous media. We show that combining oligoether chains into aromatic segments generates switchable aromatic nanopore structures in aqueous media such as hollow tubules, toroidal structures, and 2D porous sheets depending on the shape of the aromatic building block. Next, we discuss the chemical principle behind the switching motion of the aromatic nanopore structures triggered by external stimuli. We show that the internal pores of the aromatic nanostructures are able to undergo reversible switching between open-closed or expanded-contracted states triggered by external stimuli such as temperature, pH, and salts. In the case of toroidal structures, closed ring-like aromatic frameworks can be spirally open triggered by heat treatment, which spontaneously initiate helical polymerization. Additionally, we discuss switchable functions carried out by the aromatic nanopores such as driving helicity inversion of DNA, consecutive enzymatic action, reversible actuation of lipid vesicles, and pumping of captured guests out of internal pores. By understanding the underlying chemical principle required for dynamic mechanical motion, aromatic assembly can be exploited more broadly to create emergent nanopore structures with functions as complex as those of biological systems.

Phenanthrene, 9,10-dihydrophenanthrene and bibenzyl enantiomers from Bletilla striata with their antineuroinflammatory and cytotoxic activities.

Thirteen undescribed phenanthrene and bibenzyl derivatives, named blestanols A-M, including one pair of biphenanthrene enantiomers, two bis 9,10-dihydrophenanthrene ethers, five pairs of 9,10-dihydrophenanthrene/bibenzyl atropisomers, one racemic 9,10-dihydrophenanthrene/bibenzyl dimer, one 9,10-dihydrophenanthrenebibenzyl ether, two pairs of bibenzyl derivatives, and one stilbene, together with 12 known analogues were isolated from the tubers of Bletilla striata. The structures were elucidated via spectroscopic data analysis. 15 compounds were purified to yield enantiomers (a, b) via chiral-phase HPLC, and their configurations were determined by optical rotation values and the comparison of the experimental and calculated electronic circular dichroism (ECD) curves. Blestanols K-L possessed a cycloheptene moiety, which is rarely observed in bibenzyl derivatives. A putative biosynthetic pathway for the identified components is deduced. Among these compounds, 14 compounds showed inhibition of NO production, with IC50 values ranging from 5.0 to 19.0 µM. Eight compounds displayed selective cytotoxic activities against HCT-116, HepG2, BGC-823, A549 or U251 cancer cell lines, with IC50 values ranging from 1.4 to 8.3 µM. In addition, their structure-activity relationships are discussed briefly.

Cyclopropyl Scaffold: A Generalist for Marketed Drugs.

In recent decades, much attention has been given to cyclopropyl scaffolds, which commonly exist in natural products and synthetic organic molecules. Clinical drug molecules with cyclopropyl rings are an area of focus in therapeutic research due to their interesting chemical properties and unique pharmacology activity. These molecular drugs against different targets are applicable in some therapeutic treatment fields including cancer, infection, respiratory disorder, cardiovascular and cerebrovascular diseases, dysphrenia, nervous system disorders, endocrine and metabolic disorders, skin disease, digestive disorders, urogenital diseases, otolaryngological and dental diseases, and eye diseases. This review is a guide for pharmacologists who are in search of valid preclinical/clinical drug compounds where the progress, from 1961 to the present day, of approved marketed drugs containing cyclopropyl scaffold is examined.

[Multidisciplinary team model for patients with oral cancer and systemic diseases: an expert consensus].

Large general hospitals currently play an increasingly important role in the diagnosis and treatment for acute critical patients and difficult diseases because of the development of dual referral system and hierarchical diagnosis, as well as the formation of medical treatment alliance. Patients with oral cancers are often associated with systemic diseases, which increases the complexity of the condition. Thus, meeting the demand through the traditional single medical model is difficult. As such, a multidisciplinary team (MDT) model has been proposed and has achieved a good clinical effect. To standardize the application of this model, we organized an event in which relevant experts discussed and formulated a consensus to provide standardized suggestions on the MDT process and the diagnosis and treatment of common systemic diseases as reference for clinical practice.

Effect of chidamide on treating hepatosplenic T-cell lymphoma: A case report.

BACKGROUND: Hepatosplenic T-cell lymphoma (HSTCL) is a rare subtype of non-Hodgkin's lymphoma, which has an aggressive clinical course and an extremely poor prognosis. Chidamide is a novel, orally active, benzamide-type histone deacetylase (HDAC) inhibitor that has been used for peripheral T-cell lymphoma (PTCL) treatment. However, to date, there has been no report of the treatment and effect of the HDAC inhibitor chidamide in HSTCL, which is a special subtype of PTCL. CASE SUMMARY: A 45-year-old male patient was admitted with splenomegaly and slight bicytopenia. He was diagnosed with HSTCL via splenectomy. The patient was treated with fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine regiment as inductive therapy. Unfortunately, the disease progressed rapidly during chemotherapy before a suitable allogeneic gene transplant donor was found. The chidamide-combined chemotherapy regimen and single-drug oral maintenance regimen achieved complete remission, duration of response of 9 mo, and overall survival of 15 mo. CONCLUSION: The novel agent chidamide can be used in HSTCL to achieve deep remission and improve the duration of response and overall survival.

Concise synthesis of 2-methoxyestradiol through C(sp2)-H methoxylation.

An efficient and concise synthesis of 2-methoxyestradiol (4) from 17ß-estradiol (1) has been achieved in three synthetic steps with a 63.3% overall yield. The key step was the palladium-catalyzed direct C(sp2)-H methoxylation of 2-aryloxypyridines. Using 2-pyridyloxyl as the directing group, Pd(OAc)2 as the catalyst, PhI(OAc)2 as the oxidant and methanol as both the methoxylation reagent and solvent, the methoxy group could be handily installed at the 2-position of 3-(2-pyridoxy) estradiol (2). Subsequently, the pyridyl group could be easily removed by nucleophilic substitution with a methoxy anion after being oxidized to a pyridyl N-oxide by m-chloroperoxybenzoic acid, delivering the target product 2-methoxyestradiol (4) in quantitative yield. In contrast, when the pyridyl directing group was removed by the TfOMe-NaOMe/MeOH system as reported in the literature, TfOMe inevitably methylated the 17-OH of 2-methoxy-3-(2-pyridoxy) estradiol (3). In effect, we have fortuitously found a new method to cleave the pyridyl directing group, which is highly suitable for substrates bearing hydroxy groups.

Polymer Transformers: Interdigitating Reaction Networks of Fueled Monomer Species to Reconfigure Functional Polymer States.

Adaptivity is an essential trait of life. One type of adaptivity is the reconfiguration of a functional system states by correlating sensory inputs. We report polymer transformers, which can adaptively reconfigure their composition from a state of a mixed copolymer to being enriched in either monomer A or B. This is achieved by embedding and hierarchically interconnecting two chemically fueled activation/deactivation enzymatic reaction networks for both monomers via a joint activation pathway (network level) and an AB linker monomer reactive to both A and B (species level). The ratio of enzymes governing the individual deactivation pathways (our external signals) control the enrichment behavior in the dynamic state. The method shows high programmability of the reconfigured state, rejuvenation of transformation cycles, and quick in situ adaptation. As a proof-of-concept, we showcase this dynamic reconfiguration for colloidal surface functionalities.

Positron emission tomography/computed tomography findings of multiple cystic lymphangiomas in an adult: A case report.

BACKGROUND: Lymphangioma is a rare benign cystic tumor believed to be a proliferation of heterotopic lymphocytes. It is caused by congenital lymphatic dysplasia or other acquired factors related to surgery, trauma, infection, or cancer. In this article, we present the case of an adult patient who underwent multi-modal imaging and whose condition was finally confirmed to be multiple cystic lymphangiomas by pathological examination. CASE SUMMARY: A 61-year-old man was referred to our hospital for having suffered from painless gross hematuria for 2 wk. Multiple masses rising from the retroperitoneum and pelvis were found incidentally by urinary ultrasonography. Contrast-enhanced abdominal-pelvic computed tomography showed multiple well-defined hypodense cystic lesions without enhancement. The lesions showed no uptake on F-18-fluorodeoxyglucose positron emission tomography/computed tomography images. Exploratory laparotomy was performed, and the case was confirmed as multiple cystic lymphangiomas. CONCLUSION: When retroperitoneal and pelvic masses are found, clinicians should always consider cystic lymphangioma when making a differential diagnosis.

Structural Genomics of SARS-CoV-2 Indicates Evolutionary Conserved Functional Regions of Viral Proteins.

During its first two and a half months, the recently emerged 2019 novel coronavirus, SARS-CoV-2, has already infected over one-hundred thousand people worldwide and has taken more than four thousand lives. However, the swiftly spreading virus also caused an unprecedentedly rapid response from the research community facing the unknown health challenge of potentially enormous proportions. Unfortunately, the experimental research to understand the molecular mechanisms behind the viral infection and to design a vaccine or antivirals is costly and takes months to develop. To expedite the advancement of our knowledge, we leveraged data about the related coronaviruses that is readily available in public databases and integrated these data into a single computational pipeline. As a result, we provide comprehensive structural genomics and interactomics roadmaps of SARS-CoV-2 and use this information to infer the possible functional differences and similarities with the related SARS coronavirus. All data are made publicly available to the research community.