Discovery and Biomimetic Semisynthesis of Spirophyllines A-D from Uncaria rhynchophylla.

Spirophyllines A-D (1-4), four new spirooxindole alkaloids all characterized by the spiro[pyrrolidin-3,3'-oxindole] core and a rare isoxazolidine ring, were isolated from Uncaria rhynchophylla. Their structures were determined by spectroscopic methods and confirmed by X-ray crystallography. Based on the biomimetic semisynthesis strategy, compounds 1-8 were synthesized in three steps via the key reactions of 1,3-dipolar cycloaddition and Krapcho decarboxylation from corynoxeine. Interestingly, compound 3 showed moderate inhibitory activity against the Kv1.5 potassium channel (IC50 = 9.1 µM).

Development of a novel phosphoramidite-selenide ligand for Pd-catalyzed asymmetric allylic substitution.

A novel chiral P,Se-heterodonor ligand has been designed and prepared through an efficient and simple operation. This ligand can be successfully applied to Pd-catalyzed asymmetric allylic substitution with C- and N-nucleophiles, producing a diverse range of chiral allylic products in high yields and enantioselectivities (up to 99% yield and 95% ee).

Eleven undescribed alkaloids from the rhizomes of Sinomenium acutum and their IDO1 and TDO inhibitory activities.

Eleven previously undescribed alkaloids, named sinometumines A-K, along with three known alkaloids, were isolated from the rhizomes of Sinomenium acutum. The chemical structures of these unreported compounds were established using extensive spectroscopic methods (IR, UV, HRESIMS, and NMR), and their absolute configurations were determined by single crystal X-ray diffraction analyses and calculated electronic circular dichroism spectroscopy (ECD). Sinometumine D was the first aporphine-type derived alkaloid inner salt with a rearranged dibenzofuran ring backbone. Sinometumine E was a rare protoberberine-type alkaloid with a complex 6/6/6/6/6/6 hexacyclic skeleton. This was the first report of alkaloids with these two skeletons isolated from S. acutum. All isolates were evaluated for their inhibitory activities against indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO). Lysicamine possessed noteworthy inhibitory activities as an IDO1/TDO dual inhibitor with IC50 values of 6.22 ± 0.26 µM and 23.76 ± 2.93 µM, respectively, and liriodenine revealed moderate dual inhibition with IC50 values of 31.65 ± 4.44 µM and 15.64 ± 0.26 µM. The intermolecular interactions and binding modes between lysicamine and IDO1/TDO were elaborated by molecular docking studies.

Cassane diterpenoids from the seeds of Caesalpinia bonduc and their nitric oxide production and α-glucosidase inhibitory activities.

Ten previously undescribed cassane diterpenoids, cassabonducins A-J, and eleven known compounds were isolated from the seeds of Caesalpinia bonduc. The structures of the undescribed compounds were elucidated by extensive analysis of spectroscopic data (IR, HRESIMS, and 1H, 13C and 2D NMR) and their absolute configurations were determined by the ECD data and single-crystal X-ray diffraction analysis. ε-Caesalpin-Ⅶ was obtained from natural resources for the first time. Cassabonducin A possessed noteworthy inhibitory activity against LPS-induced nitric oxide (NO) production in RAW 264.7 macrophages with IC50 value of 6.12 µM. Cassabonducin D and neocaesalpin N showed moderate α-glucosidase inhibition at the concentration of 50 µM with inhibitory capacities of 47.17% and 43.83%, respectively.

Rhynchines A-E: Cav3.1 Calcium Channel Blockers from Uncaria rhynchophylla.

Rhynchines A-E (1-5), five new indole alkaloids with an unprecedented skeleton, were isolated from Uncaria rhynchophylla. The new skeleton was characterized by an indole moiety and a 2-oxa-8-azatricyclo[6,5,01,5,01,8]tridecane core, forming a unique 6/5/7/5/5 ring system. Their structures were determined by nuclear magnetic resonance, high-resolution electrospray ionization mass spectrometry, infrared spectroscopy, and calculated electronic circular dichroism (ECD) and were confirmed by X-ray crystallography. Interestingly, 1 and 2 showed strong inhibitory activities against the Cav3.1 calcium channel with IC50 values of 6.86 and 10.41 µM.

Functional Magnetic Resonance Imaging Reveals Early Connectivity Changes in the Auditory and Vestibular Cortices in Idiopathic Sudden Sensorineural Hearing Loss With Vertigo: A Pilot Study.

The underlying pathophysiology of idiopathic sudden sensorineural hearing loss (ISSNHL) with vertigo has yet to be identified. The aims of the current study were (1) to elucidate whether there are functional changes of the intrinsic brain activity in the auditory and vestibular cortices of the ISSNHL patients with vertigo using resting-state functional magnetic resonance imaging (rs-fMRI) and (2) whether the connectivity alterations are related to the clinical performance associated with ISSNHL with vertigo. Twelve ISSNHL patients with vertigo, eleven ISSNHL patients without vertigo and eleven healthy subjects were enrolled in this study. Rs-fMRI data of auditory and vestibular cortices was extracted and regional homogeneity (ReHo) and seed-based functional connectivity (FC) were evaluated; the chi-square test, the ANOVA and the Bonferroni multiple comparison tests were performed. Significantly decreased ReHo in the ipsilateral auditory cortex, as well as increased FC between the inferior parietal gyrus and the auditory cortex were found in the ISSNHL with vertigo groups. These findings contribute to a characterization of early plastic changes in ISSNHL patients with vertigo and cultivate new insights for the etiology research.

Neo-clerodane Diterpenoids with Hypoglycemic Effects in Vivo from the Aerial Parts of Salvia hispanica L.

A new neo-clerodane diterpenoid, salvihispin H (1), and six known ones (2-7) were identified from the aerial parts of Salvia hispanica L. The structure and absolute configuration of 1 were elucidated by extensive analysis of spectroscopic (1 H, 13 C, and 2D NMR, and HR-ESI-MS) and single-crystal X-ray diffraction data. The anti-diabetic effects of salvihispin H (1) and salvifaricin (2) were evaluated in diabetic db/db mice. The data showed that 1 and 2 could significantly reduce fasting blood glucose level and improve insulin resistance, and compound 1 exerted glucose-lowering effect more quickly than metformin. In addition, 1 and 2 could also reduce serum TG level in db/db mice. These results demonstrated that compounds 1 and 2 could be considered as potent candidates for the therapy of type 2 diabetes mellitus (T2DM).

A Comparison of Triamcinolone Acetonide Econazole Cream and Nystatin Suspension in Treatment of Otomycosis.

OBJECTIVES/HYPOTHESIS: To compare the efficacy and adverse effects of triamcinolone acetonide econazole cream and nystatin suspension in the treatment of otomycosis, and to determine the clinical features, predisposing factors, and etiology of otomycosis. STUDY DESIGN: A prospective study. METHODS: A prospective clinical trial was conducted on 786 patients diagnosed with otomycosis. The study population was randomly divided into two treatment groups of triamcinolone acetonide econazole cream (TAEC) and nystatin suspension in a 1:1 ratio. After clearing all fungal deposits in the external auditory canal, the antimycotic drugs were locally applied for at least 2 weeks. The efficacy and adverse effects were compared between the two antifungal reagents by statistical analysis. Meanwhile, patient clinical data were collected to find out the clinical features, predisposing factors, and etiology. RESULTS: Pruritis was the most common symptom and Aspergillus niger was the leading fungal pathogen. There was high association (44.5%) of otomycosis with a history of unclean ear picking. The cure rate was 97.6% in the TAEC group and 73.5% in the nystatin group (P < .01). Treatment with TAEC resulted in 2.4% of patients complaining of discomforts (irritant dermatitis, otalgia, or headache) versus 59.8% of patients complaining discomforts treated with nystatin (P < .01). The residue rate of antifungals was 1.9% in the TAEC group and 89.9% in the nystatin group (P < .01) at the end of treatment. CONCLUSIONS: Thoroughly cleaning of the external auditory canal followed by local use of TAEC under endotoscope is an effective, convenient, and well-tolerated treatment for otomycosis. LEVEL OF EVIDENCE: 1 Laryngoscope, 131:E1640-E1646, 2021.

[Short-term postoperative outcome of laser-assisted stapedotomy in patients with otosclerosis].

Objective:To assess the short-term efficacy of laser-assisted stapedotomy in patients with otosclerosis. Method:The clinical data of twenty-one patients with otosclerosis who underwent laser-assisted stapedotomy were retrospectively analyzed . Preoperative and 3-month postoperative standardized audiometric evaluations were carried out in all patients. The occurrence of surgical complications was observed. Result:The mean preoperative and postoperative air conduction （AC） thresholds were （58.2±12.7） dB HL and （43.0±23.1）dB HL respectively; the postoperative AC threshold decreased by 15.2 dB HL which was statistically significant at 0.5, 1, 2, and 4 kHz （P<0.01）. The mean preoperative and postoperative bone conduction （BC） thresholds were （31.4±10.3）dB HL and （33.3±16.6）dB HL, and there was not significant difference between them as well as BC thresholds at each frequency. Overclosure >10 dB HL was occured in 3 ears （14.3%） while sensorineural hearing loss>10 dB HL was found in 2 ears （9.5%）. The mean ABG decreased by 17.4 dB HL （P<0.01） from preoperative （27.0±9.1） dB HL to postoperative （9.6±9.9） dB HL, and the ABG at each frequency had significant decrease. Fourteen ears （66.7%） had postoperative ABG of ≤10 dB HL while 18 ears （85.7%） had postoperative ABG of ≤20 dB HL. Sensorineural hearing loss occurred in 2 ears （9.5%） after surgery, tinnitus in 15 ears （71.4%） and vertigo in 3 ears （14.3%）. But all were relieved on the third day after operation. Conclusion:Laser-assisted stapedotomy is a safe and effective treatment of otosclerosis. Although BC thresholds was slightly increased after surgery, it did not affect the overall hearing outcomes.

Rearranged neoclerodane diterpenoids from the aerial parts of Salvia hispanica L.

Six new rearranged neoclerodane diterpenoids (1-6), as well as three known ones, were obtained from the aerial part of Salvia hispanica L. Their structures were elucidated by extensive analysis of spectroscopic data (1D, 2D NMR, and HRESIMS) and Mosher's method. The absolute configurations of 1, 2, and 4 were determined by single-crystal X-ray diffraction analysis. All isolated compounds were evaluated for their cardioprotective effects against H2O2-induced cardiomyocytes injury, and compound 5 showed statistically significant cardioprotective effect in vitro assays.

Huperserratines A and B, Two Macrocyclic Lycopodium Alkaloids with an Unusual Skeleton from Huperzia serrata.

Huperserratines A (1) and B (2), two Lycopodium alkaloids with an unprecedented 5-aza-bicyclo[10.4.0]hexadecane skeleton and an oxime function, were isolated from Huperzia serrata. Their structures including absolute configurations were determined by extensive NMR spectroscopic and X-ray diffraction analysis. Compounds 1 and 2 were the first examples of macrocyclic Lycopodium alkaloids with an aza-12-membered ring. A plausible biogenetic pathway of these compounds was also proposed. Compound 1 exhibited moderate anti-HIV-1 activity with an EC50 of 52.91 µg/mL and a therapy index greater than 3.78.

Phytochemical constituents of the pericarps of Illicium difengpi and their anti-inflammatory activity.

Phytochemical investigation on the pericarps of Illicium difengpi lead to the isolation and structure elucidation of a new sesquiterpene, sesquicaranoic acid C (1), a new neolignan, difengpiol C (2), and 10 known compounds. The structures and absolute configurations of two new compounds were determined by a combination of NMR and CD spectroscopic analyses. All isolates were evaluated for their inhibitory effects on lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW264.7 cells.

The Role of Endolymphatic Hydrops in Patients with Pantonal Idiopathic Sudden Sensorineural Hearing Loss: A Cause or Secondary Reaction.

The purpose of this study was to investigate the presence of endolymphatic hydrops (EH) in both affected and unaffected ears of patients with pantonal unilateral idiopathic sudden sensorineural hearing loss (ISSNHL) using three-dimensional fluid-attenuated inversion recovery magnetic resonance imaging (3D-FLAIR MRI) and further evaluate the significance of EH in this disorder. Twenty-seven ISSHL patients were enrolled in this study. 3D-FLAIR MRI was performed 24 h after intratympanic injection of gadolinium-diethylenetriaminepentaacetic acid (Gd-DPTA). The incidences of EH in the affected ears and contralateral unaffected ears were compared and the correlations of EH with vertigo or prognosis were analyzed using the Chi-square test. The results showed that the incidence of EH was 68.0% (17/25) in the affected ears and 34.8% (8/23) in the unaffected ears. There was a statistically significant difference between affected ears and unaffected ears in regard to the incidence of EH (P<0.05). There were no significant correlations of EH with vertigo (P=1.000) or with prognosis (P=0.359) in the affected ears. In conclusion, there is EH in the inner ear of patients with pantonal ISSNHL; EH is not related to vertigo, a concomitant symptom of ISSNHL, and the prognosis of this condition. The presence of EH may be a secondary reaction following the impairment of the inner ears with pantonal ISSNHL.

Neo-clerodane diterpenoids from aerial parts of Salvia hispanica L. and their cardioprotective effects.

Ten undescribed neo-clerodane diterpenoids, named hispanins A-J, together with six known ones, were isolated from the aerial parts of Salvia hispanica L. Their structures were established by extensive spectroscopic analysis. The absolute configurations of the undescribed compounds were determined by the ECD data and single crystal X-ray diffraction analysis. Hispanins B and C represented the first neo-clerodane diterpenoids with a unique oxygen bridge between C-19 and C-20. All isolated compounds were evaluated for their protective effects against H2O2-induced cardiomyocyte injury. Five of these compounds showed significant cardioprotective effects.

[Effect of electrical stimulation at auricular points combined with sound masking on the expression of CREB, BDNF and TrkB in the auditory cortex of tinnitus rats].

OBJECTIVE: To explore the effect of electrical stimulation at auricular points (EAS) combined with sound masking on the expression of cAMP-response element binding protein (CREB), brain-derived neurotrophic factor (BDNF) and tyrosine receptor kinase B (TrkB) in the auditory cortex of tinnitus rats. METHODS: A total of 27 adult male SD rats were randomly divided into a control group, a model group and an EAS group. The rats in the model group and the EAS group were intervened with intraperitoneal injection of sodium salicylate to induce tinnitus model, while the rats in the control group were intervened with injection of 0.9% NaCl solution. After the model was successfully established, the rats in the EAS group were treated with electrical stimulation at "Shenmen" (TF4) and "Yidan" (CO11), combined with sound masking; the treatment was given once a day for 15 days. The gap prepulse inhibition of acoustic startle (GPIAS) and prepulse inhibition (PPI) testing were performed using the acoustic startle reflex starter package for rats. The expression of BDNF, TrkB, CREB and p-CREB in the auditory cortex of each group were measured with Western Blot analysis. RESULTS: ① Compared with the control group, the GPIAS values in 12 kHz, 16 kHz, 20 kHz and 28 kHz were significantly decreased in the model group (all P<0.05); compared with the model group, GPIAS values in 12 kHz, 16 kHz, 20 kHz and 28 kHz were significantly increased in the EAS group (all P<0.05). ② Compared with the control group, the expression of BDNF and p-CREB in the model group was significantly increased (P<0.01), and the expression of TrkB in the model group was significantly increased (P<0.05); the differences of expression of BDNF, TrkB, CREB and p-CREB between the model group and the EAS group had no statistics significance (all P>0.05). CONCLUSION: EAS could improve the GPIAS values of high-frequency background sound in tinnitus rats, which may be related with the upregulation of the BDNF/TrkB/CREB signaling pathway in the auditory cortex, leading to the reversion of the maladaptive plasticity.

Diterpenoids and sesquiterpenoids from the stem bark of Metasequoia glyptostroboides.

A phytochemical study on the stem bark of Metasequoia glyptostroboides led to the isolation of sixty-one diterpenoids and sesquiterpenoids, including seventeen previously undescribed compounds, metaglyptins A-Q. Their structures were elucidated by extensive analysis of spectroscopic data (IR, UV, HRESIMS, and 1H, 13C and 2D NMR). The absolute configurations of metaglyptins I, J, and O were determined by the ECD data and single-crystal X-ray diffraction analysis. The undescribed compounds were evaluated for their cytotoxicity against HeLa, AGS, and MDA-MB-231 cancer cell lines. The results revealed that metaglyptin A exhibited moderate cytotoxicity against MDA-MB-231 cell line with IC50 value of 20.02 µM.

Predictive factors for complications associated with penetrated fish bones outside the upper gastrointestinal tract.

PURPOSE: To investigate predictive risk factors for complications associated with migrating fish bones in the surrounding tissue of upper gastrointestinal tract. METHODS: A retrospective analysis over 12 years was conducted of 45 cases of buried fish bones in the surrounding tissue of upper gastrointestinal tract with complications. Meanwhile, a control group, including 39 cases of prolonged buried fish bones in the surrounding tissue of upper gastrointestinal tract without complications, was set. Patient clinical data were collected and analyzed to predict the risk factors for complications. RESULTS: The results of Chi-square test and univariate analysis both showed a significant difference in length of fish bone (> 2 cm), a history of concurrent medical illness (diabetes mellitus and renal hypofunction), symptoms (medium or heavy pain and dysphagia), and duration of significant symptoms (> 7 days) between the complication group and non-complication group. Multivariate analysis further identified length (> 2 cm), diabetes mellitus, medium or heavy pain, dysphagia, and duration of significant symptoms (> 7 days) as independent risk factors for complications. CONCLUSIONS: The consequences of fish bones migrating outside the upper gastrointestinal tract are various in different people. Awareness should be raised when encountering a patient ingesting a long fish bone, having a history of diabetes mellitus, presenting with significant discomforts, or these discomforts lasting for a long time. This study will help practitioners counsel their patients on the risks and `benefits of surgery versus observation of this condition.

Three new Lycopodium alkaloids from Lycopodium japonicum.

Three new Lycopodium alkaloids (1-3), together with 15 known alkaloids, were isolated from club moss Lycopodium japonicum. Their structures were determined by extensive spectroscopic analysis, including 1D and 2D NMR spectra. Compound 1 has an unusual ß-oriented methyl group substituted at C-15 and an α-hydroxy cyclopentenone moiety. All new alkaloids were evaluated for the inhibition of T-type calcium channel.

Expression of E-prostanoid receptors in nasal polyp tissues of smoking and nonsmoking patients with chronic rhinosinusitis.

BACKGROUND: Different inflammatory reactions have been observed in the polyp tissues of nonsmokers and smokers with chronic rhinosinusitis (CRS). E-prostanoid (EP) receptors play a role in the inflammatory processes. Cigarette smoke (CS) exposure regulates EP-receptor expression levels promoting inflammatory mediator release from various inflammatory cells. In this study, we characterize the EP-receptor expression profiles in the polyps of nonsmoking and smoking CRS patients to explore the possible role of CS in the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP). METHODS: Polyp biopsies were obtained from 28 non-smoking and 21 smoking CRSwNP patients. Histopathological characteristics were observed under a light microscope. The prostaglandin E2 (PGE2), TNF-α, and IL-8 contents in polyp tissues were detected using enzyme-linked immunosorbent assay. Immunostaining was used to locate EP receptors in polyps. Messenger RNA and protein expression of EP receptors were examined using quantitative real-time polymerase chain reaction and Western blot, respectively. RESULTS: More severe inflammatory reactions occurred in polyp tissues of smoking CRSwNP patients. The PGE2, TNF-α, and IL-8 in tissue homogenate levels were significantly higher in smoking CRSwNP patients than those in nonsmoking CRSwNP patients. Moreover, the distribution of each EP receptor subtype was similar in both groups. Compared with the EP-receptor expression in nonsmokers, messenger RNA and protein of EP2 and EP4 receptor were significantly down-expressed in smoking patients, but EP1 and EP3 receptors did not show significant differences. CONCLUSION: CS exposure downregulates the expression levels of EP2 and EP4 receptors and stimulates the production of PGE2 and the proinflammatory cytokine IL-8 and TNF-α in polyp tissues of CRS patients. The down-expressed EP2 and EP4 receptors might be associated with severe inflammatory reactions in smoking CRSwNP patients.

Transauricular vagus nerve stimulation at auricular acupoints Kindey (CO10), Yidan (CO11), Liver (CO12) and Shenmen (TF4) can induce auditory and limbic cortices activation measured by fMRI.

The purpose of this study was to explore the central mechanism of transauricular vagus nerve stimulation (taVNS) to human by fMRI and to find a suitable taVNS site for potential tinnitus treatment. 24 healthy subjects aged between 28 and 38 years were enrolled in the experiment. 8 subjects were stimulated in the auricular acupoints Kindey (CO10), Yidan (CO11), Liver (CO12) and Shenmen (TF4) in the left ear, 8 subjects were stimulated at the anterior wall of the auditory canal and left lower limb as an anterior stimulation group; 8 persons who were arranged in a sham group received taVNS at the left ear lobe and tail of the helix. Functional magnetic resonance imaging (fMRI) data from the cortices was collected and an Alphasim analysis was performed. We found that taVNS at auricular acupoints CO10-12, TF4 can instantly and effectively generate blood oxygenation level dependent (BOLD) signal changes in the prefrontal, auditory and limbic cortices of healthy subjects by fMRI. When comparing the acupoints group and the sham group in the left brain, the signals from the prefrontal cortex, the auditory ascending pathway including superior temporal gyrus, middle temporal gyrus, thalamus and limbic system regions such as putamen, caudate, posterior cingulate cortex, amygdala and parahippocampal gyrus were increased under our stimulation. The difference of the BOLD signal in the left brain between acupoints group and anterior group was in the superior temporal gyrus. We could also find signal differences in several regions of right brain among the groups. In conclusion, taVNS at acupoints CO10-12, TF4 could activate the prefrontal, auditory and limbic cortices of healthy brain and this scheme could be a promising tool for tinnitus treatment.