Paraneoplastic neuromyelitis optica spectrum disorder associated with ovarian dysgerminoma: a case report and literature review.

Neuromyelitis optica spectrum disorder (NMOSD) is a clinical syndrome characterized by attacks of acute optic neuritis and transverse myelitis. We report a case with paraneoplastic NMOSD that improved after immunosuppressive therapy, surgical resection, and chemotherapy. A 48-year-old woman initially presented with gradual binocular visual loss over the course of one week. The patient was evaluated using magnetic resonance imaging (MRI), computed tomography (CT), visual evoked potential (VEP), pathological biopsy, immunohistochemistry, and autoimmune antibody testing. The brain MRI findings were normal. The VEP revealed prolonged P100 latencies in the right eye and an absence of significant waves in the left eye. Positive serum AQP4-IgG antibodies were found. The patient was diagnosed as NMOSD. Then the patient responded well to treatment with methylprednisolone. An ovarian tumor was found in the patient using abdominal MRI and CT. The tumor was surgically resected, and a pathological biopsy revealed that it was ovarian dysgerminoma. The patient received four rounds of chemotherapy after surgery. One month after the final chemotherapy treatment, a positron emission tomography (PET) scan revealed no tumor. The vision of the patient gradually recovered and serum AQP4 was negative. Furthermore, we summarized the characteristics of patients diagnosed with paraneoplastic NMOSD associated with ovarian neoplasms in previous studies. This is a characteristic case of overlapping NMOSD and ovarian dysgerminoma, demonstrating the importance of tumor therapy in cases of paraneoplastic NMOSD.

P. gingivalis in oral-prostate axis exacerbates benign prostatic hyperplasia via IL-6/IL-6R pathway.

BACKGROUND: Benign prostatic hyperplasia (BPH) is the most common disease in elderly men. There is increasing evidence that periodontitis increases the risk of BPH, but the specific mechanism remains unclear. This study aimed to explore the role and mechanism of the key periodontal pathogen Porphyromonas gingivalis (P. gingivalis) in the development of BPH. METHODS: The subgingival plaque (Sp) and prostatic fluid (Pf) of patients with BPH concurrent periodontitis were extracted and cultured for 16S rDNA sequencing. Ligature-induced periodontitis, testosterone-induced BPH and the composite models in rats were established. The P. gingivalis and its toxic factor P. gingivalis lipopolysaccharide (P.g-LPS) were injected into the ventral lobe of prostate in rats to simulate its colonization of prostate. P.g-LPS was used to construct the prostate cell infection model for mechanism exploration. RESULTS: P. gingivalis, Streptococcus oralis, Capnocytophaga ochracea and other oral pathogens were simultaneously detected in the Pf and Sp of patients with BPH concurrent periodontitis, and the average relative abundance of P. gingivalis was found to be the highest. P. gingivalis was detected in both Pf and Sp in 62.5% of patients. Simultaneous periodontitis and BPH synergistically aggravated prostate histological changes. P. gingivalis and P.g-LPS infection could induce obvious hyperplasia of the prostate epithelium and stroma (epithelial thickness was 2.97- and 3.08-fold that of control group, respectively), and increase of collagen fibrosis (3.81- and 5.02-fold that of control group, respectively). P. gingivalis infection promoted prostate cell proliferation, inhibited apoptosis, and upregulated the expression of inflammatory cytokines interleukin-6 (IL-6; 4.47-fold), interleukin-6 receptor-α (IL-6Rα; 5.74-fold) and glycoprotein 130 (gp130; 4.47-fold) in prostatic tissue. P.g-LPS could significantly inhibit cell apoptosis, promote mitosis and proliferation of cells. P.g-LPS activates the Akt pathway through IL-6/IL-6Rα/gp130 complex, which destroys the imbalance between proliferation and apoptosis of prostate cells, induces BPH. CONCLUSION: P. gingivalis was abundant in the Pf of patients with BPH concurrent periodontitis. P. gingivalis infection can promote BPH, which may affect the progression of BPH via inflammation and the Akt signaling pathway.

Downregulation of N6-methyladenosine-modified LINC00641 promotes EMT, but provides a ferroptotic vulnerability in lung cancer.

The prognosis of lung cancer is poor with few effective therapies. Targeting ferroptosis is a new promising strategy for cancer therapy. LINC00641 has been involved in several cancers, however, its specific roles in lung cancer treatment remain largely unknown. Here, we reported that LINC00641 was down-regulated in tumor tissues and its downregulation was associated with poor outcomes in lung adenocarcinoma. LINC00641 was localized primarily in the nucleus and was modified by m6A. The nuclear m6A reader YTHDC1 regulated LINC00641 expression by affecting its stability. We demonstrated that LINC00641 suppressed lung cancer by inhibiting migration and invasion in vitro and metastasis in vivo. Knockdown of LINC00641 upregulated HuR protein level (especially in the cytoplasm), which subsequently increased N-cadherin levels by stabilizing its mRNA, then ultimately promoted EMT. Interestingly, LINC00641 knockdown in lung cancer cells increased the arachidonic acid metabolism and promoted ferroptosis sensitivity. Our findings identified LINC00641 as a tumor suppressor through inhibiting EMT. In another aspect, low expression of LINC00641 caused a ferroptotic vulnerability in lung cancer cells, which may serve as a potential ferroptosis-related therapeutic target for lung cancer.

A potassium-chloride co-transporter promotes tumor progression and castration resistance of prostate cancer through m6A reader YTHDC1.

SLC12A5, a neuron-specific potassium-chloride co-transporter, has been reported to promote tumor progression, however, the underlying mechanism remains unclear. Here we report that SLC12A5 functions as an oncogene to promote tumor progression and castration resistance of prostate cancer through the N6-methyladenosine (m6A) reader YTHDC1 and the transcription factor HOXB13. We have shown that the level of SLC12A5 was increased in prostate cancer, in comparison to its normal counterparts, and further elevated in castration-resistant prostate cancer (CRPC). The enhanced expression of SLC12A5 mRNA was associated with neuroendocrine prostate cancer (NEPC) progression and poor survival in prostate cancer. Furthermore, we demonstrated that SLC12A5 promoted the castration resistance development of prostate cancer in addition to the cell proliferation and migration. Interestingly, SLC12A5 was detected in the cell nucleus and formed a complex with nuclear m6A reader YTHDC1, which in turn upregulated HOXB13 to promote the prostate cancer progression. Therefore, our findings reveal a mechanism that how the potassium-chloride cotransporter SLC12A5 promotes the tumor progression and provide a therapeutic opportunity for prostate cancer to apply the neurological disorder drug SLC12A5 inhibitors.

Periodontitis relates to benign prostatic hyperplasia via the gut microbiota and fecal metabolome.

Objectives: Periodontitis is associated with benign prostatic hyperplasia (BPH), whether it related to gut floramicrobiota and metabonomics is unclear. Methods: We established ligature-induced periodontitis (EP), testosterone-induced BPH, and composite rat models. Fecal samples were collected to detect gut microbiota by 16S rDNA sequencing and metabonomics were detected by liquid chromatography tandem mass spectrometry (LC-MS/MS). Results: Sequencing results revealed differential gut floramicrobiota composition between EP+BPH group and other three groups. The abundances of Ruminococcus flavefaciens were significantly increased in EP+BPH group compared with other groups. Tenericutes, Mollicutes, RF39 and Ruminococcus gnavus were significantly decreased in EP+BPH group compared with BPH group, while Ruminococcus callidus and Escherichia were significantly decreased compared with EP group. For gut metabonomics, LC-MS/MS showed that fecal metabolites and seven metabolic pathways were changed in EP+BPH group, such as biosynthesis of unsaturated fatty acids, steroid hormone biosynthesis. Correlation analysis showed that the alterations of gut metabolism were significantly correlated with differential gut floramicrobiota, such as Ruminococcus callidus and Ruminococcus flavefaciens. Conclusion: Our study highlights the relationship of periodontitis and BPH, the alterations of gut floramicrobiota and metabolites may be involved in two diseases, which provides new idea for prevention and treatment of patients with periodontitis concurrent BPH.

[Textual research on Wumei Pills].

Wumei Pills originates from Treatise on Cold Damage. A total of 128 records on it were screened out, involving 102 ancient books, 110 modern clinical studies, and 48 diseases. According to the records, the prescription origin, prescription composition, prescription explanation, main indications, dosage, medicinal processing, preparation, and usage, contraindications, and mo-dern clinical applications were analyzed. The result shows that Wumei Pills is composed of Mume Fructus, Asari Radix et Rhizoma, Zingiberis Rhizoma, Coptidis Rhizoma, Angelicae Sinensis Radix, Aconiti Lateralis Radix Praeparata, Zanthoxyli Pericarpium, Cinnamomi Ramulus, Ginseng Radix et Rhizoma, and Phellodendri Chinensis Cortex. The main indications expand over time, and it can be applied to diarrhea, dysentery, retching, chest pain, cough, Qi ascending from lower abdomen, and reversal cold of hands and feet with the syndromes of cold and heat in complexity and hyperactivity of liver Yang and spleen deficiency. According to modern clinical records, it is mainly used for the treatment of diseases in the digestive system, nervous system, endocrine system, metabolic system, etc., such as ulcerative colitis, diarrhea, insomnia, and type 2 diabetes mellitus. The dosage of Wumei Pills has gradually reduced from the Han Dynasty to the Qing Dynasty, but the proportions of the medicinals has remained basically unchanged. In this prescription, Aconiti Lateralis Radix Praeparata and Zanthoxyli Pericarpium need to be processed, while the rest medicinals are used in raw form. As for the medicinal selection, Zanthoxyli Pericarpium is examinable. Asari Radix et Rhizoma is derived from Aristolochiaceae, which is toxic to the liver and kidney, so the dosage should be kept in a safe range. In summary, Wumei Pills has great clinical value. The textual research on Wumei Pills helps clarify the development of Wumei Pills, which provides evidence in-depth research and development and rational clinical application of Wumei Pills.

Alterations and Correlations of Gut Microbiota and Fecal Metabolome Characteristics in Experimental Periodontitis Rats.

Objectives: Periodontitis affects the progression of many diseases, while its detailed mechanism remains unclear. This study hopes to provide new ideas for exploring its mechanism by analyzing the gut microbiota and fecal metabolic characteristics of experimental periodontitis rats. Methods: A total of 10 rats were randomly divided into ligature-induced experimental periodontitis (EP) group and healthy control group. After 4 weeks of the experiment, the feces of all rats were collected for sequencing through 16S ribosomal DNA (rDNA) sequencing technology and liquid chromatography-mass spectrometry (LC-MS). Results: 16S rDNA sequencing results showed that the ß-diversity of gut microbiota was significantly different between the EP and control group, and the levels of dominant genera were different. Compared with the control group, Ruminococcus, Escherichia, and Roseburia were significantly enriched in EP, and Coprococcus, Turicibacter, Lachnospira were significantly decreased. Correlation analysis showed that Roseburia exhibited the highest correlation within the genus. Of 3,488 qualitative metabolites, 164 metabolites were upregulated and 362 metabolites were downregulated in EP. Enrichment analysis showed that periodontitis significantly changed 45 positive/negative ion metabolic pathways. Five KEGG pathways, protein digestion and absorption, tyrosine metabolism, glycolysis/gluconeogenesis, niacin and nicotinamide metabolism, and oxidative phosphorylation, are enriched in both the microbiome and metabolome. Correlation analysis showed that the genera with significant differences in periodontitis were usually significantly correlated with more metabolites, such as Roseburia, Lachnospira, Escherichia, Turicibacter, and Ruminococcus. The genera with the same changing trend tended to have a similar correlation with some certain metabolites. In addition, vitamin D2 and protoporphyrin IX have the most significant correlations with microorganisms. Conclusion: Our study reveals that periodontitis alters gut microbiota and fecal metabolites. The correlation analysis of microbiota and metabolome provides a deeper understanding of periodontitis, and also provides a direction for the study of periodontitis affecting other diseases.

Cancer SIGVAR: A semiautomated interpretation tool for germline variants of hereditary cancer-related genes.

Cancer is one of the most important health issues globally and the accuracy of interpretation of cancer-related variants is critical for the clinical management of hereditary cancer. ClinGen Sequence Variant Interpretation Working Groups have developed many adaptations of American College of Medical Genetics and Genomics and the Association of Molecular Pathologists guidelines to improve the consistency of interpretation. We combined the most recent adaptations to expand the number of the criteria from 28 to 48 and developed a tool called Cancer SIGVAR to help genetic counselors interpret the clinical significance of cancer germline variants. Our tool can accept VCF files as input and realize fully automated interpretation based on 21 criteria and semiautomated interpretation based on 48 criteria. We validated the performance of our tool with the ClinVar and CLINVITAE benchmark databases, achieving an average consistency for pathogenic and benign assessment up to 93.71% and 79.38%, respectively. We compared Cancer SIGVAR with two similar tools, InterVar and PathoMAN, and analyzed the main differences in criteria and implementation. Furthermore, we selected 911 variants from another two in-house benchmark databases, and semiautomated interpretation reached an average classification consistency of 98.35%. Our findings highlight the need to optimize automated interpretation tools based on constantly updated guidelines. Cancer SIGVAR is publicly available at http://cancersigvar.bgi.com/.

TLC-bioautography directed isolation of antibacterial compounds from active fractionation of Ferula ferulioides.

A novel optimised isolation method, TLC-bioautography, was evaluated and utilised in this research. Antibacterial compounds which were isolated from the dichloromethane extract of Ferula ferulioides (Steud.) Korovin were detected by means of the method. Their structures were elucidated by extensive spectral and chemical methods. Their antibacterial activities against drug-resistant Staphylococcus aureus (S. aureus) strains were evaluated with broth microdilution method, and the results proved that TLC-bioautography was an effective and highly efficient way to screen natural compounds from plant extracts against drug-resistant strains.

Built-in microscale electrostatic fields induced by anatase-rutile-phase transition in selective areas promote osteogenesis.

Bone has a built-in electric field because of the presence of piezoelectric collagen. To date, only externally applied electric fields have been used to direct cell behavior; however, these fields are not safe or practical for in vivo use. In this work, for the first time, we use a periodic microscale electric field (MEF) built into a titanium implant to induce osteogenesis. Such a MEF is generated by the periodic organization of a junction made of two parallel semiconducting TiO2 zones: anatase and rutile with lower and higher electron densities, respectively. The junctions were formed through anatase-rutile-phase transition in selective areas using laser irradiation on the implants. The in vitro and in vivo studies confirmed that the built-in MEF was an efficient electrical cue for inducing osteogenic differentiation in the absence of osteogenic supplements and promoted bone regeneration around the implants. Our work opens up a new avenue toward bone repair and regeneration using built-in MEF.

Surface-Selective Preferential Production of Reactive Oxygen Species on Piezoelectric Ceramics for Bacterial Killing.

Reactive oxygen species (ROS) can be used to kill bacterial cells, and thus the selective generation of ROS from material surfaces is an emerging direction in antibacterial material discovery. We found the polarization of piezoelectric ceramic causes the two sides of the disk to become positively and negatively charged, which translate into cathode and anode surfaces in an aqueous solution. Because of the microelectrolysis of water, ROS are preferentially formed on the cathode surface. Consequently, the bacteria are selectively killed on the cathode surface. However, the cell experiment suggested that the level of ROS is safe for normal mammalian cells.

Ti nanorod arrays with a medium density significantly promote osteogenesis and osteointegration.

Ti implants are good candidates in bone repair. However, how to promote bone formation on their surface and their consequent perfect integration with the surrounding tissue is still a challenge. To overcome such challenge, we propose to form Ti nanorods on their surface to promote the new bone formation around the implants. Here Ti nanorod arrays (TNrs) with different densities were produced on pure Ti surfaces using an anodizing method. The influence of TNr density on the protein adsorption as well as on the adhesion, proliferation, and osteogenic differentiation of MC3T3-E1 pre-osteoblastic cells were assessed. The TNrs were also implanted into the bone defects in rabbits to test their application in promoting bone formation and osteointegration at the implant-bone interface. TNrs with the medium density were found to show the best capability in promoting the protein adsorption from surrounding medium, which in turn efficiently enhanced osteogenic differentiation in vitro and osteointegration in vivo. Our work suggests that growing TNrs with a medium density on the surface of traditional Ti implants is an efficient and facile method for promoting bone formation and osteointegration in bone repair.

Periodic Nanoneedle and Buffer Zones Constructed on a Titanium Surface Promote Osteogenic Differentiation and Bone Calcification In Vivo.

Rapid and effective bone mineralization at the bone/implant interface is required for successful orthopedic and dental implants. In this study, two periodic microscale functionalized zones on titanium (MZT) are created, namely, nanoneedle zones and buffer zones. The aim of this design is to provide spatially regulated topographical cues on titanium to enhance the efficacy of bone regeneration. This goal is achieved using a versatile and effective technique in which nanoneedle structures are hydrothermally constructed on the surface of titanium sheets, after which selective laser irradiation is used to construct buffer zones. The zonal structures of the MZT overcome the suppressive effect of the nanoneedle film on osteoblasts. Additionally, the MZT exhibits zone-selective apatite deposition and protein adsorption. The accelerated in vitro osteoblast differentiation and nodule deposition on the MZT are confirmed. Elemental analysis of the bone nodules formed by the osteoblasts growing on the titanium and MZT demonstrates they have different compositions. Histological and scanning electron microscope analysis of the bone formation on in vivo implants shows that this process is also enhanced by the MZT implant. The concept of constructing functionalized zones on titanium implant could facilitate future research on improving the design of orthopedic and dental implant surfaces.

Influence of Surrounding Cations on the Surface Degradation of Magnesium Alloy Implants under a Compressive Pressure.

The effect of cations in the surrounding solutions on the surface degradation of magnesium alloys, a well-recognized biodegradable biomaterial, has been neglected compared with the effect of anions in the past. To better simulate the compressive environment where magnesium alloys are implanted into the body as a cardiovascular stent, a device is designed and employed in the test so that a pressure, equivalent to the vascular pressure, can be directly applied to the magnesium alloy implants when the alloys are immersed in a medium containing one of the cations (K(+), Na(+), Ca(2+), and Mg(2+)) found in blood plasma. The surface degradation behaviors of the magnesium alloys in the immersion test are then investigated using hydrogen evolution, mass loss determination, electron microscopy, pH value, and potentiodynamic measurements. The cations are found to promote the surface degradation of the magnesium alloys with the degree decreased in the order of K(+) > Na(+) > Ca(2+) > Mg(2+). The possible mechanism of the effects of the cations on the surface degradation is also discussed. This study will allow us to predict the surface degradation of magnesium alloys in the physiological environment and to promote the further development of magnesium alloys as biodegradable biomaterials.

Sesquiterpenoids with Anti-MDR Staphylococcus aureus activities from Ferula ferulioides.

Seven new sesquiterpenoids together with 21 known sesquiterpenoid derivatives were isolated from the medicinal plant Ferula ferulioides (Steud.) Korovin. Their structures were elucidated by comprehensive spectroscopic analyses and chemical transformations. The isolated compounds were evaluated for their antibacterial activities against a panel of bacteria including multidrug-resistant (MDR) and methicillin-resistant Staphylococcus aureus (MRSA), displaying minimum inhibitory concentration (MIC) values in the range of 0.5-128 mg/l.

Flavonoids from Sophora moorcroftiana and their synergistic antibacterial effects on MRSA.

Synergy is now a widely recognized approach that has direct applicability for new pharmaceuticals. The ethanolic extract of the aerial parts of the herb Sophora moorcroftiana showed significant antibacterial activity against drug-resistant Staphylococcus aureus, and its minimum inhibitory concentration (MIC) was 8 µg/mL. In a phytochemical study of the extract, five flavonoids were obtained. However, the isolates exhibited antibacterial activity in the range of 32-128 µg/mL, which was weaker than the extract. In combination with antibiotics, the antibacterially inactive compound genistein (1) and diosmetin (4) showed significant synergistic activity against drug-resistant S. aureus. In combination with norfloxacin, genistein (1) reduced the MIC to 16 µg/mL and showed synergy against strain SA1199B with a fractional inhibitory concentration index (FICI) of 0.38. With the antibiotics norfloxacin, streptomycin and ciprofloxacin, diosmetin (4) showed synergy against SA1199B, RN4220 and EMRSA-15, with FICI values of 0.38, 0.38 and 0.09, respectively. In an efflux experiment to elucidate a plausible mechanism for the observed synergy, genistein showed marginal inhibition of the NorA efflux protein.

Multiwall carbon nano-onions induce DNA damage and apoptosis in human umbilical vein endothelial cells.

Growing evidence has indicated the potential adverse effects on cardiovascular system of some nanomaterials, including fullerenes. In this study, we have evaluated the biological effects of multiwall carbon nano-onions (MWCNOs) (average size of 31.2 nm, ζ potential of 1.6 mV) on human umbilical vein endothelial cells (HUVECs). It was found that MWCNOs exhibited a dose-dependent inhibitory effect on cell growth; EC50 was 44.12 µg/mL. Thus, three concentrations were chosen (0.2, 1, and 5 µg/mL) for further experiments. Flow cytometry analysis revealed that 1 and 5 µg/mL MWCNOs could induce apoptosis in HUVECs, the apoptotic rates were 12% and 24% at 24 h after exposure. On the other hand, MWCNOs did not affect the cell cycle distribution during 24 h period. Using γH2AX foci formation as an indicator for DNA damage, it was shown that 5 µg/mL MWCNOs can induce γH2AX foci formation in HUVECs at 6, 12, and 24 h after treatment, whereas 0.2 µg/mL MWCNOs induced γH2AX foci formation only at 6 h after treatment. In addition, all three concentrations of MWCNOs induced the generation of reactive oxygen species (ROS), and inhibition of ROS generation can partially decrease the γH2AX foci formation induced by MWCNOs. Taken together, these data first suggested that MWCNOs can induce DNA damage and apoptosis in HUVECs, and that ROS might be involved in this process.