TNFAIP3 Derived from Skeletal Stem Cells Alleviated Rat Osteoarthritis by Inhibiting the Necroptosis of Subchondral Osteoblasts.

Recent investigations have shown that the necroptosis of tissue cells in joints is important in the development of osteoarthritis (OA). This study aimed to investigate the potential effects of exogenous skeletal stem cells (SSCs) on the necroptosis of subchondral osteoblasts in OA. Human SSCs and subchondral osteoblasts isolated from human tibia plateaus were used for Western blotting, real-time PCR, RNA sequencing, gene editing, and necroptosis detection assays. In addition, the rat anterior cruciate ligament transection OA model was used to evaluate the effects of SSCs on osteoblast necroptosis in vivo. The micro-CT and pathological data showed that intra-articular injections of SSCs significantly improved the microarchitecture of subchondral trabecular bones in OA rats. Additionally, SSCs inhibited the necroptosis of subchondral osteoblasts in OA rats and necroptotic cell models. The results of bulk RNA sequencing of SSCs stimulated or not by tumor necrosis factor α suggested a correlation of SSCs-derived tumor necrosis factor α-induced protein 3 (TNFAIP3) and cell necroptosis. Furthermore, TNFAIP3-derived from SSCs contributed to the inhibition of the subchondral osteoblast necroptosis in vivo and in vitro. Moreover, the intra-articular injections of TNFAIP3-overexpressing SSCs further improved the subchondral trabecular bone remodeling of OA rats. Thus, we report that TNFAIP3 from SSCs contributed to the suppression of the subchondral osteoblast necroptosis, which suggests that necroptotic subchondral osteoblasts in joints may be possible targets to treat OA by stem cell therapy.

FOXC1 and FOXC2 Ablation Causes Abnormal Valvular Endothelial Cell Junctions and Lymphatic Vessel Formation in Myxomatous Mitral Valve Degeneration.

BACKGROUND: Mitral valve (MV) disease including myxomatous degeneration is the most common form of valvular heart disease with an age-dependent frequency. Genetic evidence indicates that mutations of the transcription factor FOXC1 are associated with MV defects, including MV regurgitation. In this study, we sought to determine whether murine Foxc1 and its closely related factor, Foxc2, are required in valvular endothelial cells (VECs) for the maintenance of MV leaflets, including VEC junctions and the stratified trilaminar ECM (extracellular matrix). METHODS: Adult mice carrying tamoxifen-inducible, vascular endothelial cell (EC), and lymphatic EC-specific, compound Foxc1;Foxc2 mutations (ie, EC-Foxc-DKO and lymphatic EC-Foxc-DKO mice, respectively) were used to study the function of Foxc1 and Foxc2 in the maintenance of MVs. The EC and lymphatic EC mutations of Foxc1/c2 were induced at 7 to 8 weeks of age by tamoxifen treatment, and abnormalities in the MVs of these mutant mice were assessed via whole-mount immunostaining, immunohistochemistry/RNAscope, Movat pentachrome/Masson Trichrome staining, and Evans blue injection. RESULTS: EC deletions of Foxc1 and Foxc2 in mice resulted in abnormally extended and thicker MVs by causing defects in the regulation of ECM organization with increased proteoglycan and decreased collagen. Notably, reticular adherens junctions were found in VECs of control MV leaflets, and these reticular structures were severely disrupted in EC-Foxc-DKO mice. PROX1 (prospero homeobox protein 1), a key regulator in a subset of VECs on the fibrosa side of MVs, was downregulated in EC-Foxc1/c2 mutant VECs. Furthermore, we determined the precise location of lymphatic vessels in murine MVs, and these lymphatic vessels were aberrantly expanded and dysfunctional in EC-Foxc1/c2 mutant MVs. Lymphatic EC deletion of Foxc1/c2 also resulted in similar structural/ECM abnormalities as seen in EC-Foxc1/c2 mutant MVs. CONCLUSIONS: Our results indicate that Foxc1 and Foxc2 are required for maintaining the integrity of the MV, including VEC junctions, ECM organization, and lymphatic vessel formation/function to prevent myxomatous MV degeneration.

Passive immunotherapy for Alzheimer's disease: challenges & future directions.

Passive immunotherapy with specific antibodies targeting Amyloid ß (Aß) peptide or tubulin-associated unit (tau) protein has emerged as a promising therapeutic approach in Alzheimer's disease (AD). However, in a recent phase III clinical study, Sperling et al. (N Engl J Med 10.1056/NEJMoa2305032, 2023) reported that solanezumab, a monoclonal antibody targeting Aß peptide, failed to slow cognitive decline in AD patients. Previously, three other anti-Aß antibodies, bapineuzumab, crenezumab, and gantenerumab, have also failed to show similar beneficial effects. In addition, three humanized antibodies targeting tau protein failed in their phase II trials. However, other anti-Aß antibodies, such as lecanemab (a humanized mAb binds to soluble Aß protofibrils), donanemab (a humanized mAb binds to insoluble, N-terminal truncated form of Aß peptides) and aducanumab (a human mAb binds to the aggregated form of Aß), have been shown to slow the decline of cognitive functions in early stage AD patients. The specific targets used in passive immunotherapy in these clinical trials may explain the divergent clinical outcomes. There are several challenges and limitations of passive immunotherapy using anti-Aß antibodies and long term longitudinal studies are needed to assess their efficacy, side effects and cost effectiveness in a wider spectrum of subjects, from pre-dementia to more advanced dementia. A combination therapeutic approach using both anti-Aß antibodies and other pharmaceutical agents should also be explored.

Synthesis and Application of Specific N2H4 Fluorescent Probes with AIE Effect Based on Pyrazole Structure.

Two fluorescent probes, Y1-2 were synthesized from 2-acetonaphthone, 4-acetylbiphenyl, and phenyl hydrazine by Vilsmeier-Haack reaction and Knoevenagel condensation. Their recognition efficacies for N2H4 were tested by UV-visible absorption spectroscopy and fluorescence emission spectroscopy. The recognition mechanism were studies by density-functional theory calculations, and the effect of pH on N2H4 recognition was also studied. The results showed that the probe Y1-2 has high selectivity and a low detection limit for N2H4, and the recognition of N2H4 can be accomplished at physiological pH. The probes have had obvious aggregation-induced luminescence effect, large Stokes shift, high sensitivity, and can be successfully applied to live cell imaging.

Human amniotic epithelial stem cell is a cell therapy candidate for preventing acute graft-versus-host disease.

Graft-versus-host disease (GVHD), an immunological disorder that arises from donor T cell activation through recognition of host alloantigens, is the major limitation in the application of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Traditional immunosuppressive agents can relieve GVHD, but they induce serious side effects. It is highly required to explore alternative therapeutic strategy. Human amniotic epithelial stem cells (hAESCs) were recently considered as an ideal source for cell therapy with special immune regulatory property. In this study, we evaluated the therapeutic role of hAESCs in the treatment of GVHD, based on our previous developed cGMP-grade hAESCs product. Humanized mouse model of acute GVHD (aGVHD) was established by injection of huPBMCs via the tail vein. For prevention or treatment of aGVHD, hAESCs were injected to the mice on day -1 or on day 7 post-PBMC infusion, respectively. We showed that hAESCs infusion significantly alleviated the disease phenotype, increased the survival rate of aGVHD mice, and ameliorated pathological injuries in aGVHD target organs. We demonstrated that hAESCs directly induced CD4+ T cell polarization, in which Th1 and Th17 subsets were downregulated, and Treg subset was elevated. Correspondingly, the levels of a series of pro-inflammatory cytokines were reduced while the levels of the anti-inflammatory cytokines were upregulated in the presence of hAESCs. We found that hAESCs regulated CD4+ subset polarization in a paracrine mode, in which TGFß and PGE2 were selectively secreted to mediate Treg elevation and Th1/Th17 inhibition, respectively. In addition, transplanted hAESCs preserved the graft-versus-leukemia (GVL) effect by inhibiting leukemia cell growth. More intriguingly, hAESCs infusion in HSCT patients displayed potential anti-GVHD effect with no safety concerns and confirmed the immunoregulatory mechanisms in the preclinical study. We conclude that hAESCs infusion is a promising therapeutic strategy for post-HSCT GVHD without compromising the GVL effect. The clinical trial was registered at www.clinicaltrials.gov as #NCT03764228.

Genetic Association Studies in Restless Legs Syndrome: Risk Variants & Ethnic Differences.

BACKGROUND: Genetic association studies have not produced consistent results in restless legs syndrome (RLS). OBJECTIVES: To conduct a systematic review on genetic association studies in RLS to highlight the common gene variants and ethnic differences. METHODOLOGY: We conducted Pubmed, Embase, and Cochrane search using terms "Genetic association studies" and "restless legs syndrome" for candidate gene-based studies. Out of the initial 43 studies, 18 case control studies (from 2012 to 2022) were included. Thirteen studies including 10794 Caucasian subjects (4984 RLS cases and 5810 controls) and five studies involving 2009 Asian subjects (796 RLS cases and 1213 controls) were tabulated and analyzed. In addition, three Genome-Wide Association Studies (GWAS) in Asians and Europeans/Caucasians were included for comparisons. RESULTS: In the Asian population, gene variants in BST1, SNCA Rep1, IL1B, BTBD9, and MAP2K5/SKOR1 increased the risk of RLS (odds ratio range 1.2-2.8). In Caucasian populations, examples of variants that were associated with an increased risk of RLS (odds ratio range 1.1-1.9) include those in GABRR3 TOX3, ADH1B, HMOX1, GLO1, DCDC2C, BTBD9, SKOR1, and SETBP1. Based on the meta-analysis of GWAS studies, the rs9390170 variant in UTRN gene was identified to be a novel genetic marker for RLS in Asian cohorts, whereas rs113851554 in MEIS1 gene was a strong genetic factor among the >20 identified gene variants for RLS in Caucasian populations. CONCLUSION: Our systemic review demonstrates that multiple genetic variants modulate risk of RLS in Caucasians (such as MEIS1 BTBD9, MAP2K5) and in Asians (such as BTBD9, MAP2K5, and UTRN).

A strategy to distinguish similar traditional Chinese medicines by liquid chromatography-mass spectrometry, electronic senses, and gas chromatography-ion mobility spectrometry: Marsdeniae tenacissimae Caulis and Paederiae scandens Caulis as examples.

INTRODUCTION: Marsdeniae tenacissimae Caulis (MTC), a popular traditional Chinese medicine, has been widely used in the treatment of tumor diseases. Paederiae scandens Caulis (PSC), which is similar in appearance to MTC, is a common counterfeit product. It is difficult for traditional methods to effectively distinguish between MTC and PSC. Therefore, there is an urgent need for a rapid and accurate method to identify MTC and PSC. OBJECTIVES: The aim is to distinguish between MTC and PSC by analyzing the differences in nonvolatile organic compounds (NVOCs), taste, odor, and volatile organic compounds (VOCs). METHODS: Liquid chromatography-mass spectrometry (LC-MS) was utilized to analyze the NVOCs of MTC and PSC. Electronic tongue (E-tongue) and electronic nose (E-nose) were used to analyze their taste and odor respectively. Gas chromatography-ion mobility spectrometry (GC-IMS) was applied to analyze VOCs. Finally, multivariate statistical analyses were conducted to further investigate the differences between MTC and PSC, including principal component analysis, orthogonal partial least squares discriminant analysis, discriminant factor analysis, and soft independent modeling of class analysis. RESULTS: The results of this study indicate that the integrated strategy of LC-MS, E-tongue, E-nose, GC-IMS, and multivariate statistical analysis can be effectively applied to distinguish between MTC and PSC. Using LC-MS, 25 NVOCs were identified in MTC, while 18 NVOCs were identified in PSC. The major compounds in MTC are steroids, while the major compounds in PSC are iridoid glycosides. Similarly, the distinct taste difference between MTC and PSC was precisely revealed by the E-tongue. Specifically, the pronounced bitterness in PSC was proven to stem from iridoid glycosides, whereas the bitterness evident in MTC was intimately tied to steroids. The E-nose detected eight odor components in MTC and six in PSC, respectively. The subsequent statistical analysis uncovered notable differences in their odor profiles. GC-IMS provided a visual representation of the differences in VOCs between MTC and PSC. The results indicated a relatively high relative content of 82 VOCs in MTC, contrasted with 32 VOCs exhibiting a similarly high relative content in PSC. CONCLUSION: In this study, for the first time, the combined use of LC-MS, E-tongue, E-nose, GC-IMS, and multivariate statistical analysis has proven to be an effective method for distinguishing between MTC and PSC from multiple perspectives. This approach provides a valuable reference for the identification of other visually similar traditional Chinese medicines.

Tyrosine Hydroxylase Inhibitors and Dopamine Receptor Agonists Combination Therapy for Parkinson's Disease.

There are currently no disease-modifying therapies for Parkinson's disease (PD), a progressive neurodegenerative disorder associated with dopaminergic neuronal loss. There is increasing evidence that endogenous dopamine (DA) can be a pathological factor in neurodegeneration in PD. Tyrosine hydroxylase (TH) is the key rate-limiting enzyme for DA generation. Drugs that inhibit TH, such as alpha-methyltyrosine (α-MT), have recently been shown to protect against neurodegeneration in various PD models. DA receptor agonists can activate post-synaptic DA receptors to alleviate DA-deficiency-induced PD symptoms. However, DA receptor agonists have no therapeutic effects against neurodegeneration. Thus, a combination therapy with DA receptor agonists plus TH inhibitors may be an attractive therapeutic approach. TH inhibitors can protect and promote the survival of remaining dopaminergic neurons in PD patients' brains, whereas DA receptor agonists activate post-synaptic DA receptors to alleviate PD symptoms. Additionally, other PD drugs, such as N-acetylcysteine (NAC) and anticholinergic drugs, may be used as adjunctive medications to improve therapeutic effects. This multi-drug cocktail may represent a novel strategy to protect against progressive dopaminergic neurodegeneration and alleviate PD disease progression.

[Application and development of electronic sensing technologies represented by electronic nose in modern traditional Chinese medicine preparations].

Odor is one of the important indicators evaluating the quality of traditional Chinese medicines. Research data has shown that there are increasing methods available for evaluating the odors of traditional Chinese medicines. Compared with conventional odor sensing techniques, electronic noses stand out for their convenience, high speed, and objectivity. The progress in the pharmaceutical technology of traditional Chinese medicines has provided new formulas and dosage forms for the innovative development in this field. The electronic nose with versatility can be customized to be equipped with a variety of cross-sensors, which can well satisfy the needs of the traditional Chinese medicine preparation technology. This study summarizes the characteristics, application status, and representative products of the current electronic nose, and analyzes the application and feasibility of electronic nose in the production of traditional Chinese medicine preparations based on the current status of odor evaluation. This review is expected to provide new methods, techno-logies, and ideas for electronic nose to play its unique role in the whole-process quality control and pharmaceutical process of traditional Chinese medicine preparations.

BN-Isosteres of Nonacene with Antiaromatic B2 C4 and N2 C4 Heterocycles: Synthesis and Strong Luminescence.

Embedding both boron and nitrogen into the backbone of acenes to generate their isoelectronic structures has significantly enriched the acene chemistry to offer appealing properties. However, only small BN-heteroacenes have been extensively investigated, with BN-heptacenes as the hitherto longest homologue. Herein, we report the synthesis of three new nonacene BN-isosteres via incorporating a pair of antiaromatic B2 C4 and N2 C4 heterocycles, representing a new length record for BN-heteroacenes. The distance between the B2 C4 and N2 C4 rings affects the contribution of the charge-separated resonance forms, leading to tunable antiaromaticity of the two heterocycles. The adjusted local antiaromaticity manifests substantial influence on the molecular orbital arrangement, and consequently, the radiative transition rate of BN-3 is greatly enhanced compared with BN-1 and BN-2, realizing a high fluorescence quantum yield of 92 %. This work provides a novel design concept of large acene BN-isosteres and reveals the importance of BN/CC isosterism on their luminescent properties.

[Safety of modified T-piece resuscitator versus nasal cannula oxygen in electronic bronchoscopy for infants: a prospective randomized controlled study]. / 改良Tç»„åˆå¤è‹å™¨ä¸Žé¼»å¯¼ç®¡å¸æ°§ç”¨äºŽå©´å„¿ç”µå­æ”¯æ°”ç®¡é•œæ£€æŸ¥çš„å®‰å ¨æ€§æ¯”è¾ƒï¼šä¸€é¡¹å‰çž»æ€§éšæœºå¯¹ç §ç ”ç©¶.

OBJECTIVES: To optimize the oxygen therapy regimens for infants with pulmonary diseases during bronchoscopy. METHODS: A prospective randomized, controlled, and single-center clinical trial was conducted on 42 infants who underwent electronic bronchoscopy from July 2019 to July 2021. These infants were divided into a nasal cannula (NC) group and a modified T-piece resuscitator (TPR) group using a random number table. The lowest intraoperative blood oxygen saturation was recorded as the primary outcome, and intraoperative heart rate and respiratory results were recorded as the secondary outcomes. RESULTS: Compared with the NC group, the modified TPR group had a significantly higher level of minimum oxygen saturation during surgery and a significantly lower incidence rate of hypoxemia (P<0.05). In the modified TPR group, there were 6 infants with mild hypoxemia, 2 with moderate hypoxemia, and 1 with severe hypoxemia, while in the NC group, there were 3 infants with mild hypoxemia, 5 with moderate hypoxemia, and 9 with severe hypoxemia (P<0.05). The modified TPR group had a significantly lower incidence rate of intraoperative respiratory rhythm abnormalities than the NC group (P<0.05), but there was no significant difference in the incidence rate of arrhythmias between the two groups (P>0.05). CONCLUSIONS: Modified TPR can significantly reduce the risk of hypoxemia in infants with pulmonary diseases during electronic bronchoscopy, and TPR significantly decreases the severity of hypoxemia and the incidence of respiratory rhythm abnormalities compared with traditional NC.

Clinical implications of micro lymph node metastasis for patients with gastric cancer.

BACKGROUND: Lymph node size is considered as a criterion for possible lymph node metastasis in imageology. Micro lymph nodes are easily overlooked by surgeons and pathologists. This study investigated the influencing factors and prognosis of micro lymph node metastasis in gastric cancer. METHODS: 191 eligible gastric cancer patients who underwent D2 lymphadenectomy from June 2016 to June 2017 in the Third Surgery Department at the Fourth Hospital of Hebei Medical University were retrospectively analyzed. Specimens were resected en bloc and the postoperative retrieval of micro lymph nodes was carried out by the operating surgeon for each lymph node station. Micro lymph nodes were submitted for pathological examination separately. According to the results of pathological results, patients were divided into the "micro-LNM (micro lymph node metastasis)" group (N = 85) and the "non micro-LNM" group (N = 106). RESULTS: The total number of lymph nodes retrieved was 10,954, of which 2998 (27.37%) were micro lymph nodes. A total of 85 (44.50%) gastric cancer patients had been proven to have micro lymph node metastasis. The mean number of micro lymph nodes retrieved was 15.7. The rate of micro lymph node metastasis was 8.1% (242/2998). Undifferentiated carcinoma (90.6% vs. 56.6%, P = 0.034) and more advanced Pathological N category (P < 0.001) were significantly related to micro lymph node metastasis. The patients with micro lymph node metastasis had a poor prognosis (HR for OS of 2.199, 95% CI = 1.335-3.622, P = 0.002). For the stage III patients, micro lymph node metastasis was associated with shorter 5-year OS (15.6% vs. 43.6%, P = 0.0004). CONCLUSIONS: Micro lymph node metastasis is an independent risk factor for poor prognosis in gastric cancer patients. Micro lymph node metastasis appears to be a supplement to N category in order to obtain more accurate pathological staging.

Pontibacter kalidii sp. nov., isolated from rhizosphere soil of Kalidium foliatum.

A Gram-negative, aerobic, gliding motile, rod-shaped bacterium, designated XAAS-72T, was isolated from the rhizosphere soil of Kalidium foliatum sampled in the Xinjiang Uyghur Autonomous Region, PR China. Cells grew at 4-45 °C, pH 5.0-8.0 and 0-8% NaCl, with optimal growth at 20-30 °C, pH 6.0-7.0 and 1-2 % NaCl. Strain XAAS-72T is closely related to members of the genus Pontibacter, namely Pontibacter korlensis CCTCC AB 206081T (97.6%) and Pontibacter flavimaris ACCC 19859T (97.2 %), and <94.6 % related to other currently described Pontibacter strains. The average nucleotide identity values between XAAS-72T and P. korlensis CCTCC AB 206081T and P. flavimaris ACCC 19859T were 77.9 and 86.9 %, respectively; the corresponding digital DNA-DNA hybridization values were 21.7 and 31.8 %. Menaquinone-7 was the predominant respiratory menaquinone. The polar lipids consisted of phosphatidylethanolamine, two unidentified aminophospholipids, two unidentified glycolipids and five unidentified lipids. The major cellular fatty acids were summed feature 4 (containing iso-C17 : 1 I/anteiso-C17 : 1 B), summed feature 3 (containing C16 : 1 ω7c/C16 : 1 ω6c) and iso-C15 : 0. The genome length of strain XAAS-72T was 5 054 860 bp with a genomic DNA G+C content of 54.5 mol%. The phenotypic and genotypic data suggest that strain XAAS-72T represents a novel species of the genus Pontibacter, for which the name Pontibacter kalidii sp. nov. is proposed. The strain is XAAS-72T (CGMCC 16594T=KCTC 72095T).

The role of tyrosine hydroxylase-dopamine pathway in Parkinson's disease pathogenesis.

BACKGROUND: Parkinson's disease (PD) is characterized by selective and progressive dopamine (DA) neuron loss in the substantia nigra and other brain regions, with the presence of Lewy body formation. Most PD cases are sporadic, whereas monogenic forms of PD have been linked to multiple genes, including Leucine kinase repeat 2 (LRRK2) and PTEN-induced kinase 1 (PINK1), two protein kinase genes involved in multiple signaling pathways. There is increasing evidence to suggest that endogenous DA and DA-dependent neurodegeneration have a pathophysiologic role in sporadic and familial PD. METHODS: We generated patient-derived dopaminergic neurons and human midbrain-like organoids (hMLOs), transgenic (TG) mouse and Drosophila models, expressing both mutant and wild-type (WT) LRRK2 and PINK1. Using these models, we examined the effect of LRRK2 and PINK1 on tyrosine hydroxylase (TH)-DA pathway. RESULTS: We demonstrated that PD-linked LRRK2 mutations were able to modulate TH-DA pathway, resulting in up-regulation of DA early in the disease which subsequently led to neurodegeneration. The LRRK2-induced DA toxicity and degeneration were abrogated by wild-type (WT) PINK1 (but not PINK1 mutations), and early treatment with a clinical-grade drug, α-methyl-L-tyrosine (α-MT), a TH inhibitor, was able to reverse the pathologies in human neurons and TG Drosophila models. We also identified opposing effects between LRRK2 and PINK1 on TH expression, suggesting that functional balance between these two genes may regulate the TH-DA pathway. CONCLUSIONS: Our findings highlight the vital role of the TH-DA pathway in PD pathogenesis. LRRK2 and PINK1 have opposing effects on the TH-DA pathway, and its balance affects DA neuron survival. LRRK2 or PINK1 mutations can disrupt this balance, promoting DA neuron demise. Our findings provide support for potential clinical trials using TH-DA pathway inhibitors in early or prodromic PD.

Diagnostic performance of CA125, HE4, ROMA, and CPH-I in identifying primary ovarian cancer.

AIMS: To evaluate the ability of carbohydrate antigen 125 (CA125), human epididymis protein 4 (HE4), risk of ovarian malignancy algorithm (ROMA), and Copenhagen Index (CPH-I) to identify primary ovarian cancer (OC) from borderline and benign ovarian tumors (OTs) and explore ideal cutoff points. METHODS: A total of 684 OTs containing 276 OC patients, 116 ovarian borderline OTs and 292 benign OTs patients who underwent surgery in our hospital were included. We retrospectively searched the results of CA125 and HE4 before patients' surgery from the hospital's electronic medical records system. ROMA and CPH-I were calculated according to their menopausal status and age, respectively. Diagnostic performance of these four were assessed by drawing receiver operating characteristic (ROC) curves. RESULTS: CA125, HE4, ROMA, and CPH-I were all significantly higher in OC women compared with borderline OTs (p < 0.001), followed by benign OTs (p < 0.001). Area under the curves (AUCs) for distinguishing OC were 0.850 (0.818-0.882), 0.891 (0.865-0.916), 0.910 (0.888-0.933) and 0.906 (0.882-0.930), respectively, and the corresponding ideal cutoff values for CA125, HE4, ROMA, and CPH-I were 132.5, 68.6, 23.8, and 6.4, respectively. The difference between ROMA and CPH-I was not significant (p = 0.97), but both were higher than CA125 and HE4 (p < 0.05). HE4 showed a significantly higher AUC than CA125 (p < 0.05). For postmenopausal women, CA125 performed equivalently to ROMA (p = 0.73) and CPH-I (p = 0.91). CONCLUSIONS: In identifying patients with OC, ROMA and CPH-I outperformed single tumor marker. The diagnostic performance of HE4 was significantly higher than that of CA125. CA125 was more suitable for postmenopausal women.

Strepolyketide D, a new SEK15-derived polyketide compound from salt-lake-derived Streptomyces sp. DBC5.

A new SEK15-derived polyketide compound, strepolyketide D (1), was isolated from salt-lake-derived Streptomyces sp. DBC5, together with two known analogues (2-3). Their structures were elucidated based on spectroscopic analysis of IR, MS, 1 D and 2 D NMR. Compound 2 elicited moderate antioxidation with IC50 value of 39.26 µg/ml. The results of the study revealed that salt-lake actinomycetes of Lake Dabancheng appear to have immense potential as a source of polyketide compounds.

Neurodegenerative Diseases: Molecular Mechanisms and Therapies.

Neurodegenerative diseases are characterized by the progressive degeneration or death of neurons in the central or peripheral nervous system [...].

Resting-state functional magnetic resonance imaging in patients with Parkinson's disease with and without constipation: a prospective study.

PURPOSE: The etiology of constipation in Parkinson's disease is largely unknown. The aim of this study was to explore changes in regional neural activity and functional connections associated with constipation in a large cohort of individuals with Parkinson's disease. METHODS: We prospectively recruited 106 patients with Parkinson's disease with constipation and 73 patients with Parkinson's disease without constipation. We used resting-state functional magnetic resonance imaging for the first time to measure differences in regional neural activity and functional connections between the two patient groups. RESULTS: Patients with constipation showed significantly higher amplitude of low-frequency fluctuation than patients without constipation in the right dorsal pons extending into the cerebellum and in the right insula. The two types of patients also showed substantial differences in functional connections linking the superior temporal gyrus, particularly the right superior temporal gyrus, with multiple brain regions. CONCLUSION: Regional neural activity and functional connectivity in the brain differ substantially between patients with Parkinson's disease with or without constipation. These findings provide a foundation for understanding the pathophysiology of constipation in Parkinson's disease and for identifying therapeutic targets.

MCM2 promotes the proliferation, migration and invasion of cholangiocarcinoma cells by reducing the p53 signaling pathway.

The abnormal expressions of minichromosome maintenance protein 2 (MCM2) are closely related to the development of various kinds of cancers. We aimed to explore the functions and potential molecular mechanisms of MCM2 gene in cholangiocarcinoma (CCA) cell lines (Huh28 and RBE). First, the cell counting kit-8 (CCK-8), plate clone formation, transwell and invasion assays showed that MCM2 promotes the proliferation, migration and invasion of CCA cells. Flow cytometry assays showed that MCM2 significantly promotes the cell cycle, and inhibits the apoptosis of CCA cells. Further, by analyzing the RNA sequencing data of cholangiocarcinoma, we found that MCM2 gene is significantly negatively correlated with p53 signaling pathway. Quantitative real time polymerase chain reaction (qRT-PCR) and Western blotting (WB) assays confirmed that MCM2 in CCA cells significantly down-regulated the mRNA and protein expression levels of p53 and BAX, and up-regulated the mRNA and protein expression levels of BCL2 and CCND1. Flow cytometry, qRT-PCR and WB assays confirmed that MCM2 promotes CCA through p53 pathway. Finally, we found that MCM2 is up-regulated in CCA tissues compared to the matched non-tumor cholangiocarcinoma tissues, and the high expressions of MCM2 are significantly associated with the poor clinical outcomes of CCA patients. In conclusion, this study revealed that MCM2 promotes the development of CCA by reducing the p53 pathway, and its high expression levels predict poor prognosis in CCA patients. These results provide a theoretical basis for the development of new clinical diagnosis and treatment of cholangiocarcinoma in the future.

[Optimization of preparation technology for Acanthopanax senticosus total saponins microemulsion by D-optimal mixture design and intestinal absorption characteristics].

Following the preparation of Acanthopanax senticosus total saponins microemulsion, the formulation and preparation technology were optimized and the quality was evaluated. The absorption characteristics of A. senticosus total saponins microemulsion by the self-microemulsifying drug delivery system(SMEDDS) were investigated in the unidirectional intestinal perfusion model in vivo. The oil phase, mass ratio(K_m), number of revolutions, and drug concentration were subjected to single-factor investigation with the area of pseudo-ternary phase diagram as the index. The process was optimized by D-optimal mixture design with the particle size as the index, and then the appearance, morphology, and particle size were investigated. The mass concentrations of eleutherosides B and E in the microemulsion were determined. The results showed that the optimum formulation of A. senticosus total saponins microemulsion was determined as follows: 20.8% of water phase, 31.2% of isopropyl palmitate, and 48.0% of soybean phospholipid and absolute ethanol(K_m=1∶1). As revealed by the observation under a transmission electron microscope, the microemulsion exhibited homogeneous dispersion and was a spherical emulsion droplet in the water-in-oil type. At room temperature, the pH value was 5.19, the refractive index 1.416 5, the average particle size(26.47±0.04)nm, and the polydispersity index(PDI) 0.118±0.03. The content of the eleutherosides B and E was 0.038 9 and 0.166 4 mg·mL~(-1), respectively. The preliminary stability study showed that the solution was clear and transparent within 30 d, without stratification or content change, indicating good stability. The absorption of microemulsion in each intestinal segment was significantly improved as compared with that of the A. senticosus total saponins, with the best absorption effect detected in the ileum, which has laid a foundation for further development and utilization of A. senticosus.