Artemisia argyi extracts overcome lapatinib resistance via enhancing TMPRSS2 activation in HER2-positive breast cancer.

Breast cancer stands as the predominant malignancy and primary cause of cancer-related mortality among females globally. Approximately 25% of breast cancers exhibit HER2 overexpression, imparting a more aggressive tumor phenotype and correlating with poor prognoses. Patients with metastatic breast cancer receiving HER2 tyrosine kinase inhibitors (HER2 TKIs), such as Lapatinib, develop acquired resistance within a year, posing a critical challenge in managing this disease. Here, we explore the potential of Artemisia argyi, a Chinese herbal medicine known for its anti-cancer properties, in mitigating HER2 TKI resistance in breast cancer. Analysis of the Cancer Genome Atlas (TCGA) revealed diminished expression of transmembrane serine protease 2 (TMPRSS2), a subfamily of membrane proteolytic enzymes, in breast cancer patients, correlating with unfavorable outcomes. Intriguingly, lapatinib-responsive patients exhibited higher TMPRSS2 expression. Our study unveiled that the compounds from Artemisia argyi, eriodictyol, and umbelliferone could inhibit the growth of lapatinib-resistant HER2-positive breast cancer cells. Mechanistically, they suppressed HER2 kinase activation by enhancing TMPRSS2 activity. Our findings propose TMPRSS2 as a critical determinant in lapatinib sensitivity, and Artemisia argyi emerges as a potential agent to overcome lapatinib via activating TMPRSS2 in HER2-positive breast cancer. This study not only unravels the molecular mechanisms driving cell death in HER2-positive breast cancer cells induced by Artemisia argyi but also lays the groundwork for developing novel inhibitors to enhance therapy outcomes.

The in vitro and in vivo depigmentation activity of coenzyme Q0, a major quinone derivative from Antrodia camphorata, through autophagy induction in human melanocytes and keratinocytes.

BACKGROUND: Coenzyme Q0 (CoQ0), a novel quinone derivative of Antrodia camphorata, has been utilized as a therapeutic agent (including antioxidant, anti-inflammatory, antiangiogenic, antiatherosclerotic, and anticancer agents); however, its depigmenting efficiency has yet to be studied. METHODS: We resolved the depigmenting efficiency of CoQ0 through autophagy induction in melanoma (B16F10) and melanin-feeding keratinocyte (HaCaT) cells and in vivo Zebrafish model. Then, MPLC/HPLC analysis, MTT assay, Western blotting, immunofluorescence staining, LC3 transfection, melanin formation, GFP-LC3 puncta, AVO formation, tyrosinase activity, and TEM were used. RESULTS: CoQ0-induced autophagy in B16F10 cells was shown by enhanced LC3-II accumulation, ATG7 expression, autophagosome GFP-LC3 puncta, and AVOs formation, and ATG4B downregulation, and Beclin-1/Bcl-2 dysregulation. In α-MSH-stimulated B16F10 cells, CoQ0 induced antimelanogenesis by suppressing CREB-MITF pathway, tyrosinase expression/activity, and melanin formation via autophagy. TEM data disclosed that CoQ0 increased melanosome-engulfing autophagosomes and autolysosomes in α-MSH-stimulated B16F10 cells. CoQ0-inhibited melanogenesis in α-MSH-stimulated B16F10 cells was reversed by pretreatment with the autophagy inhibitor 3-MA or silencing of LC3. Additionally, CoQ0-induced autophagy in HaCaT cells was revealed by enhanced LC3-II accumulation, autophagosome GFP-LC3 puncta and AVO formation, ATG4B downregulation, ATG5/ATG7 expression, and Beclin-1/Bcl-2 dysregulation. In melanin-feeding HaCaT cells, CoQ0 induced melanin degradation by suppressing melanosome gp100 and melanin formation via autophagy. TEM confirmed that CoQ0 increased melanosome-engulfing autophagosomes and autolysosomes in melanin-feeding HaCaT cells. Treatment with 3-MA reversed CoQ0-mediated melanin degradation in melanin-feeding HaCaT cells. In vivo study showed that CoQ0 suppressed endogenous body pigmentation by antimelanogenesis and melanin degradation through autophagy induction in a zebrafish model. CONCLUSIONS: Our results showed that CoQ0 exerted antimelanogenesis and melanin degradation by inducing autophagy. CoQ0 could be used in skin-whitening formulations as a topical cosmetic application.

Statin treatment in stroke patient with low-density lipoprotein cholesterol levels below 70 mg/dL.

BACKGROUND AND PURPOSE: The effectiveness of hyperlipidemia treatment in strokes secondary prevention has been established. However, whether pretreatment with statins could confer protective effects when a patient's baseline low-density lipoprotein cholesterol (LDL-C) level is <70 mg/dL remains uncertain. Additionally, the ability of statin treatment to reduce poststroke complications, mortality, and recurrence in this patient group is unclear. METHODS AND RESULTS: In this retrospective observational study, we enrolled patients who had experienced an ischemic stroke with LDL-C levels <70 mg/dL. We analyzed the association of statin use with baseline characteristics, stroke severity, in-hospital complications, mortality rates, stroke recurrence rate, and mortality rate. Patients who used and patients who did not use statins were similar in terms of age and sex. Patients using statins had higher rates of diabetes mellitus, hypertension, prior stroke, and coronary artery disease but a lower incidence of atrial fibrillation. Stroke severity was less pronounced in those using statins. We also evaluated the relationship between in-hospital statin use and complications. We noted that in-hospital statin use was associated with lower rates of infection, hemorrhagic transformation, gastrointestinal hemorrhage, and mortality, as well as higher rates of positive functional outcomes. The 1-year recurrence rate was similar in both groups. CONCLUSIONS: Statin use is associated with milder strokes and improved poststroke outcomes, even in patients with well-controlled LDL levels. Neurologists may consider prescribing statins for patients with ischemic stroke who do not overt hyperlipidemia. Further research into potential underlying mechanisms is warranted.

Inhibition of Autophagy Aggravates Arachis hypogaea L. Skin Extracts-Induced Apoptosis in Cancer Cells.

The skin of Arachis hypogaea L. (peanut or groundnut) is a rich source of polyphenols, which have been shown to exhibit a wider spectrum of noteworthy biological activities, including anticancer effects. However, the anticancer activity of peanut skin extracts against melanoma and colorectal cancer (CRC) cells remains elusive. In this study, we systematically investigated the cytotoxic, antiproliferative, pro-apoptotic, and anti-migration effects of peanut skin ethanolic extract and its fractions on melanoma and CRC cells. Cell viability results showed that the ethyl acetate fraction (AHE) of peanut skin ethanolic crude extract and one of the methanolic fractions (AHE-2) from ethyl acetate extraction exhibited the highest cytotoxicity against melanoma and CRC cells but not in nonmalignant human skin fibroblasts. AHE and AHE-2 effectively modulated the cell cycle-related proteins, including the suppression of cyclin-dependent kinase 4 (CDK4), cyclin-dependent kinase 6 (CDK6), phosphorylation of Retinoblastoma (p-Rb), E2F1, Cyclin A, and activation of tumor suppressor p53, which was associated with cell cycle arrest and paralleled their antiproliferative efficacies. AHE and AHE-2 could also induce caspase-dependent apoptosis and inhibit migration activities in melanoma and CRC cells. Moreover, it is noteworthy that autophagy, manifested by microtubule-associated protein light chain 3B (LC3B) conversion and the aggregation of GFP-LC3, was detected after AHE and AHE-2 treatment and provided protective responses in cancer cells. Significantly, inhibition of autophagy enhanced AHE- and AHE-2-induced cytotoxicity and apoptosis. Together, these findings not only elucidate the anticancer potential of peanut skin extracts against melanoma and CRC cells but also provide a new insight into autophagy implicated in peanut skin extracts-induced cancer cell death.

Potential natural product 3,4-seco-schitriterpenoids from Kadsura japonica L. as anti-neuroinflammatory agents.

In the present study, the undescribed schitriterpenoids, kadsujanonols A-I (1-9), and eleven reported compounds (10-20) were isolated from K. japonica L. vines. Their structures of 3,4-seco-schitriterpenoids were elucidated mainly by spectroscopic analyses including 1H-, 13C-, and 2D-NMR, IR, HRESIMS spectra. The spatial configurations were determined by the single-crystal X-ray diffraction analysis of kadsujapnonol A (1), 15, 17, and 18, CD data and computational analysis. Furthermore, all isolates were evaluated for the anti-neuroinflammatory activity on LPS-stimulated NO production in BV2 microglial cells and compounds 2, 4, 5, 7, 9, 11, 13-16, and 18 exposed better or comparable suppression abilities than PDTC. Among them, kadlongilactone B (14) showed the best significant inhibiting ability (IC50 = 0.87 µg/mL) and the effect is through the attenuation of the inflammatory transcription factor p65NF-κB. Preliminary structure-activity relationship revealed that δ-lactone at the side chain and 7-member lactone at C-3/C-4, and 3,4:9,10 ring opening are important.

Anti-Inflammatory Halogenated Monoterpenes from the Red Alga Portieria hornemannii.

The chemical investigation of a red alga Portieria hornemannii enabled the identification of three new halogenated monoterpenes (1-3) along with two previously identified metabolites (4 and 5). Their structures were determined by spectroscopic analysis and also by utilizing single-crystal diffraction analysis and quantum chemical calculation, as well as by comparison with literature data. Further corrections for dichloro and dibromo carbons using the sorted training set (STS) method were established in this study to significantly improve the accuracy in GIAO 13C NMR calculation of compounds 1-3. To discover the potential bioactive metabolites from P. hornemannii, the anti-inflammatory activities of all compounds were examined. Compounds 1 and 3-5 showed significant anti-inflammatory activity to inhibit the production of pro-inflammatory cytokines in the LPS-stimulated mature dendritic cells.

Carnosic acid and rosemary extract reversed the lipid accumulation induced by bisphenol A in the 3T3-L1 preadipocytes and C57BL/6J mice via SIRT1/FoxO1 pathway.

Bisphenol A (BPA) is an endocrine-disrupting chemical, widely used to produce polycarbonate plastic. Carnosic acid (CA) is a rosemary diterpene with an anti-obesity effect. In this study, we investigated the anti-adipogenic effect of CA in BPA-treated 3T3-L1 preadipocytes and C57BL/6 J mice. In vitro experiments showed that CA inhibited lipid accumulation by BPA in 3T3-L1 preadipocytes. CA displayed anti-adipogenic effects through the downregulation of differentiation and adipogenesis-related proteins, along with the upregulation of lipolytic protein and SIRT1/FoxO1 pathway. In vivo experiments, mice treated with BPA exhibited an increase in body weight gain and epididymal adipose tissue mass when compared to the control group. CA treatment improved the epididymal adipose tissue mass induced by BPA. CA and rosemary extract (RE) treatment ameliorated dyslipidemia in BPA-treated mice. We further showed that CA and RE exerted anti-adipogenesis effects in liver tissues of BPA-treated mice via increasing SIRT1, FoxO1, and ATGL proteins and decreasing FAS and aP2 proteins. Moreover, SIRT1 inhibitor sirtinol blocked CA to increase SIRT1, FoxO1, FAS, and aP2 proteins, decrease Ac-FoxO1 protein, and reduce lipid accumulation in BPA-treated cells. These findings indicated that CA and RE could reverse BPA-induced lipid accumulation by regulating adipocyte differentiation, adipogenesis, and lipolysis through SIRT1/FoxO1 pathway.

Effects of cancer on stroke recurrence and mortality: A single-center retrospective cohort study.

Background: Whether patients with stroke and cancer have specific characteristics remains controversial. In addition, research regarding the effects of individual cancer types on stroke outcomes remains scarce. This study investigated the mortality and stroke recurrence rates in patients with stroke and concomitant cancer and evaluated outcome predictors. Methods: This study retrospectively enrolled 2610 patients in the Taipei Veterans General Hospital Stroke Registry registered from January 2019 to December 2020. A total of 1868 patients were included after excluding those without acute ischemic stroke or hospitalization. The patients were then categorized into the following diagnostic groups: cancer-associated stroke (CAS), stroke and inactive cancer, and stroke without cancer. The discharge mortality rate, 1-year mortality rate, and 1-year stroke recurrence rate were compared. Multiple clinical characteristics and comorbidities-age, sex, stroke severity, coagulopathy, common vascular risk factors, and acute stroke treatment-were also assessed. Results: A total of 302 (16.2%) patients had concomitant cancer; 39 (2.1%) patients were classified as having CAS and 263 (14.1%) as having stroke with inactive cancer. The baseline characteristics, stroke severity, and type of acute reperfusion therapy were similar among the three groups. However, the stroke recurrence and mortality rates were much higher in the patients with CAS in both short-term and long-term follow-up. The 30-day and 1-year mortality rates for the CAS, inactive cancer, and no cancer groups were 17.9%, 12.5%, and 4.7%, (p < 0.001) and 51.3%, 33.8%, and 12.4%, (p < 0.001) respectively. Conclusion: Patients with stroke and active cancer had similar stroke severity. However, the 1-year mortality and stroke recurrence rates were higher in these patients than in patients with inactive cancer or the control group.

Umbelliferone and eriodictyol suppress the cellular entry of SARS-CoV-2.

BACKGROUND: Artemisia argyi (A. argyi), also called Chinese mugwort, has been widely used to control pandemic diseases for thousands of years since ancient China due to its anti-microbial infection, anti-allergy, and anti-inflammation activities. Therefore, the potential of A. argyi and its constituents in reducing the infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was investigated in this study. RESULTS: Among the phytochemicals in A. argyi, eriodictyol and umbelliferone were identified to target transmembrane serine protease 2 (TMPRSS2) and angiotensin-converting enzyme 2 (ACE2) proteins, the essential factors for the cellular entry of SARS-CoV-2, in both FRET-based enzymatic assays and molecular docking analyses. These two ingredients of A. argyi suppressed the infection of ACE2-expressed HEK-293 T cells with lentiviral-based pseudo-particles (Vpp) expressing wild-type and variants of SARS-CoV-2 spike (S) protein (SARS-CoV-2 S-Vpp) via interrupting the interaction between S protein and cellular receptor ACE2 and reducing the expressions of ACE2 and TMPRSS2. Oral administration with umbelliferone efficiently prevented the SARS-CoV-2 S-Vpp-induced inflammation in the lung tissues of BALB/c mice. CONCLUSIONS: Eriodictyol and umbelliferone, the phytochemicals of Artemisia argyi, potentially suppress the cellular entry of SARS-CoV-2 by preventing the protein binding activity of the S protein to ACE2.

Isosarcophytoxide Derivatives with a 2,5-Dihydrofuran Moiety from the Soft Coral Sarcophyton cinereum.

The present chemical investigation on the organic extract of the soft coral Sarcophyton cinereum has contributed to the isolation of four new cembranoids: 16ß- and 16α-hydroperoxyisosarcophytoxides (1 and 2), 16ß- and 16α-methoxyisosarcophytoxides (3 and 4), and a known cembranoid, lobocrasol (5). The structures of all isolates were elucidated by detailed spectroscopic analysis. Their structures were characterized by a 2,5-dihydrofuran moiety, of which the relative configuration was determined by DU8-based calculation for long-range coupling constants (4JH,H). The cytotoxicity and immunosuppressive activities of all isolates were evaluated in this study.

Two new chromones and a new coumarin from the fruit of Cnidium monnieri (L.) Cusson.

Two new chromones named cnidimol G (1) and cnidimol H (2), one new coumarin, 7-methoxy-8-(3-methoxy-3-methyl-2-oxobutyl)coumarin (3), and twenty known compounds were isolated from MeOH extract of the fruit of Cnidium monnieri (L.) Cusson. The structures of compounds were elucidated by extensive spectroscopic analyses including 1 D and 2 D NMR, HRESIMS, IR and UV. Anti-inflammatory activity of the selected isolated compounds were evaluated. Compounds 1 and 8 exhibited inhibitory activities against nitric oxide production.

Monogenic Causes in Familial Stroke Across Intracerebral Hemorrhage and Ischemic Stroke Subtypes Identified by Whole-Exome Sequencing.

Whole exome sequencing (WES) has been used to detect rare causative variants in neurological diseases. However, the efficacy of WES in genetic diagnosis of clinically heterogeneous familial stroke remains inconclusive. We prospectively searched for disease-causing variants in unrelated probands with defined familial stroke by candidate gene/hotspot screening and/or WES, depending on stroke subtypes and neuroimaging features at a referral center. The clinical significance of each variant was determined according to the American College of Medical Genetics guidelines. Among 161 probands (mean age at onset 53.2 ± 13.7 years; male 63.4%), 33 participants (20.5%) had been identified with 19 pathogenic/likely pathogenic variants (PVs; WES applied 152/161 = 94.4%). Across subtypes, the highest hit rate (HR) was intracerebral hemorrhage (ICH, 7/18 = 38.9%), particularly with the etiological subtype of structural vasculopathy (4/4 = 100%, PVs in ENG, KRIT1, PKD1, RNF213); followed by ischemic small vessel disease (SVD, 15/48 = 31.3%; PVs in NOTCH3, HTRA1, HBB). In contrast, large artery atherosclerosis (LAA, 4/44 = 9.1%) and cardioembolism (0/11 = 0%) had the lowest HR. NOTCH3 was the most common causative gene (16/161 = 9.9%), presenting with multiple subtypes of SVD (n = 13), ICH (n = 2), or LAA (n = 1). Importantly, we disclosed two previously unreported PVs, KRIT1 p.E379* in a familial cerebral cavernous malformation, and F2 p.F382L in a familial cerebral venous sinus thrombosis. The contribution of monogenic etiologies was particularly high in familial ICH and SVD subtypes in our Taiwanese cohort. Utilizing subtype-guided hotspot screening and/or subsequent WES, we unraveled monogenic causes in 20.5% familial stroke probands, including 1.2% novel PVs. Genetic diagnosis may enable early diagnosis, management and lifestyle modification. Among 161 familial stroke probands, 33 (20.5%) had been identified pathogenic or likely pathogenic monogenic variants related to stroke. The positive hit rate among all subtypes was high in intracerebral hemorrhage (ICH) and ischemic small vessel disease (SVD). Notably, two previously unreported variants, KRIT1 p.E379* in a familial cerebral cavernous malformation and F2 p.F382L in familial cerebral venous sinus thrombosis, were disclosed. CVT cerebral venous thrombosis; HTN Hypertensive subtype; LAA large artery atherosclerosis; SV structural vasculopathy; U Undetermined.

High-dose Tiger-Gian formula protects the knee joint from surgically induced osteoarthritis in rats.

AIM: Although the Tiger-Gian formula (TGF) has proven clinically effective at improving the symptoms of knee osteoarthritis (KOA), the pharmacological effects and underlying mechanisms of TGF have not been examined in any animal model. This study assessed the effects of TGF in male Sprague-Dawley rats with anterior cruciate ligament transection (ACLT) -induced KOA. METHODS: Thirty rats underwent ACLT surgery and were assigned to either the control group, ACLT alone, ACLT + low-dose TGF (1000 mg/kg), ACLT + high-dose TGF (3000 mg/kg), or ACLT + celecoxib (30 mg/kg). All rats were subjected to micro-computed tomography (micro-CT), weight-bearing behavioral testing, and histological inspections of the knee joint for evidence of structural changes in articular bone, cartilage and synovium. RESULTS: After 6 weeks, force discrepancies in weight-bearing distribution between the normal hind and postoperative limbs revealed superiority with high-dose TGF (18.00 ± 5.93 g) and celecoxib (18.68 ± 5.29 g) versus both ACLT alone (41.29 ± 7.06 g) and low-dose TGF (37.00 ± 7.40 g). Micro-CT images revealed that high-dose TGF and celecoxib similarly improved subchondral bone architecture, protected articular cartilage after ACLT, and downregulated proinflammatory cytokines interleukin-1ß and tumor necrosis factor-α in the cartilage and synovial sections. CONCLUSION: High-dose TGF induced the smallest amount of KOA-associated bone loss. Anti-inflammatory, anti-oxidative, and immunomodulatory effects of TGF were accompanied by reductions in proinflammatory cytokines and improvements in pain and function. TGF-induced anti-osteoporotic activity and inhibition of cartilage degradation were reflected by micro-CT and histological analysis. The findings help to explain how TGF alleviates symptoms of KOA.

Polyoxygenated Terpenoids and Polyketides from the Roots of Flueggea virosa and Their Inhibitory Effect against SARS-CoV-2-Induced Inflammation.

Six new polyoxygenated terpenoids, podovirosanes A-F (1-6), and two known polyketides (7 and 8) were isolated from the roots of F. virosa. Their structures, along with absolute configurations, were deduced using spectroscopic analysis as well as computational calculations, including TDDFT calculation of ECD spectra and GIAO NMR calculations combined with DP4+ probability analysis. Compounds 2, 3, 5, and 8 were found to reduce the phosphorylation levels of NF-κB p65 in SARS-CoV-2 pseudovirus-stimulated PMA-differentiated THP-1 cells.

Neuroprotective Effects of Alpinia oxyphylla Miq against Mitochondria-Related Apoptosis by the Interactions between Upregulated p38 MAPK Signaling and Downregulated JNK Signaling in the Subacute Phase of Cerebral Ischemia-Reperfusion in Rats.

Apoptosis in the penumbra region is the major cell death mechanism occurring during ischemia-reperfusion injury's early phase. Here, we evaluated how the Alpinia oxyphylla Miq (AOM) affects mitochondria-related apoptosis 3 days after transient middle cerebral artery occlusion (MCAo) and examined the mechanisms underlying the regulation of MAPK-mediated mitochondria-related apoptotic signaling in the peri-infarct cortex in rats. The rats were administered the AOM extract intraperitoneally at doses of 0.2[Formula: see text]g/kg (AOM-0.2[Formula: see text]g), 0.4[Formula: see text]g/kg (AOM-0.4[Formula: see text]g), or 0.8[Formula: see text]g/kg (AOM-0.8[Formula: see text]g) at MCAo initiation. The AOM-0.4[Formula: see text]g and AOM-0.8[Formula: see text]g significantly ameliorated apoptotic cell death and considerably downregulated cytochrome c (cyto c) and cleaved caspase-3 immunoreactivity 3 days after reperfusion. Simultaneously, they significantly downregulated cytosolic p-JNK/JNK, cathepsin B/actin, cyto c/actin, Smac/DIABLO/actin, cleaved caspase-3/actin, and AIF/actin and mitochondrial p53/HSP60 and Bax/HSP60 fractions but upregulated cytosolic p-p38 MAPK/p38 MAPK, p-p90RSK/actin, p-Bad/Bad, p-CREB/actin, and XIAP/actin and cytosolic and mitochondrial Bcl-2/Bax and Bcl-xL/Bax fractions in the peri-infarct cortex. Pretreatment with SB203580 - a p38 MAPK inhibitor - completely abrogated the effects of AOM-0.8[Formula: see text]g on the aforementioned protein expression, whereas treatment with SP600125 - a JNK inhibitor - exerted protective effects similar to those of AOM-0.8[Formula: see text]g. Treatment with 0.4 or 0.8[Formula: see text]g/kg AOM has neuroprotective effects against mitochondria-related apoptosis by suppressing cyto c, Smac/DIABLO, and AIF release from the mitochondria to cytosol. The anti-mitochondria related apoptotic effects of the AOM extract are attributable to the interactions between upregulated p38 MAPK/p90RSK-mediated p-Bad and CREB signaling and downregulated JNK/cathepsin B-mediated Bax and p53 signaling in the peri-infarct cortex 3 days after transient MCAo.

Anti-inflammatory sesquiterpene and triterpene acids from Mesona procumbens Hemsley.

Mesona procumbens Hemsley is a plant conventionally processed to provide popular food materials and herbal medicines in Asia. In this study, six triterpene acids, including five new ones (mesonaic acids D-H, 1-5), and one proximadiol-type sesquiterpene (7) were isolated from the methanolic extract of the air-dried M. procumbens. Chemical structures of 1‒7 were established by spectroscopic methods, especially 2D NMR techniques (1H-1H COSY, HSQC, HMBC, and NOESY) and HRESIMS. Concerning their biological activities, compounds 1, 2, 6, and 7 were examined manifesting high inhibition toward the pro-inflammatory NO production with EC50 values ranging from 12.88 to 21.21 µM, outrunning the positive control quercetin (24.12 µM). The mesoeudesmol B (7) identified from M. procumbens is the very first example, which exhibited high anti-inflammatory activity diminishing the level of the lipopolysaccharide-induced NO in RAW264.7 macrophage cells, thereby suppressing the secretion of pro-inflammatory cytokines TNF-α and IL-6 and the level of two critical downstream inflammatory mediators iNOS and COX-2.

Computationally Assisted Structural Elucidation of Cembranoids from the Soft Coral Sarcophyton tortuosum.

A persistent study on soft coral Sarcophyton tortuosum resulted in the characterization of two new cembranolides, tortuolides A and B (1 and 2), and a new related diterpene, epi-sarcophytonolide Q. Their structures were determined not only by extensive spectroscopic analysis but also by DFT calculations of ECD and NMR data, the latter of which was combined with statistical analysis methods, e.g., DP4+ and J-DP4 approaches. Anti-inflammatory and cytotoxicity activities were evaluated in this study.

Neritriterpenols A-G, euphane and tirucallane triterpenes from Euphorbia neriifolia L. and their bioactivity.

Euphorbia neriifolia L. is widely distributed in India, Thailand, and China and has been used to treat diseases such as rotten sores and asthma as well as for its antidiabetic and anticancer effects. In this study, seven undescribed triterpenes, including six euphanes, neritriterpenols A-B and D-G, and a tirucallane, neritriterpenol C, together with four known triterpenes, were isolated from ethanolic extracts of E. neriifolia stems. Their structures with absolute configurations were determined through detailed spectroscopic data, including 1D and 2D NMR data analyses, single-crystal X-ray diffraction analysis, ECD spectra, and DP4+ NMR data calculations as well as Mo2(OAc)4-induced ECD analysis. Furthermore, preliminarily evaluation of the anti-inflammatory and anti-proliferative effects of the isolated triterpenes leads to the structure-activity relationship (SAR) studies implying that the unsaturated functional group at the end of the C17 side chain on euphane-type triterpenes may be correlated with the increase of anti-inflammatory and anti-proliferative activities.

Snail Mucus Enhances Chemosensitivity of Triple-negative Breast Cancer Via Activation of the Fas Pathway.

BACKGROUND/AIM: The poor prognosis and chemoresistance of patients with triple-negative breast cancer (TNBC) urge the development of new therapeutic strategies. Snail mucus has shown its ability against inflammation, a process closely related to tumorigenesis, suggesting a potential anti-cancer activity. MATERIALS AND METHODS: The effect and mechanisms of snail mucus on cell viability were determined by IncuCyte Live-cell analysis and molecular biological methods. The anti-cancer fractions of snail mucus were isolated and identified by medium pressure liquid chromatography (MPLC) and nuclear magnetic resonance (NMR) spectrometry analysis. RESULTS: Snail mucus significantly decreased the viability of TNBC cells with relatively lower cytotoxicity to normal breast epithelial cells and enhanced their response to chemotherapy through activation of Fas signaling by suppressing nucleolin. Two peptide fractions have been identified as the anti-cancer ingredients of the snail mucus. CONCLUSION: Snail mucus can induce programmed cell death via the extrinsic apoptotic pathway and has therapeutic potential by achieving a chemo-sensitizing effect in TNBCs.

Etiology and risk factors of intracranial hemorrhage and ischemic stroke in young adults.

BACKGROUND: Young stroke incidence has increased worldwide with lifestyle changes. Etiology and risk factors for both ischemic and hemorrhagic stroke in young Asians remain underexplored. METHODS: We retrospectively reviewed consecutive acute stroke patients aged 16-45 years admitted to the Taipei Veterans General Hospital between 2009 and 2019 to analyze etiologic subtypes, risk factors, and serial modified Rankin Scale scores for 1 year and compare the age groups of 16-30 and 31-45 years. RESULTS: Among 670 young Taiwanese patients (mean age at onset 37.5 ± 7.0 years; male 65.1%), there were 366 nontraumatic spontaneous hemorrhagic stroke (including 259 intracerebral hemorrhage [ICH] and 107 subarachnoid hemorrhage, SAH), 292 ischemic stroke and 12 cerebral venous thromboses. Notably, ICH was more prevalent in patients aged 16-30 than in those aged 31-45 (54.8% vs 36.8%). Specifically, structural vasculopathy (e.g., arteriovenous malformation, cavernoma) was the most common etiologic subtype in patients aged 16-30 (p < 0.001), whereas hypertensive ICH was the most common subtype in patients aged 31-45 (p < 0.001). On the other hand, the top ischemic subtype for both age groups was other determined diseases (e.g., arterial dissection, autoimmune diseases, moyamoya disease, etc.) rather than large artery atherosclerosis. Hyperlipidemia, diabetes, and cigarette smoking were more common risk factors for infarction than ICH. Familial stroke patients whose first- or second-degree relatives had a stroke by age 80 (n = 104, 15.5%) had more infarctions than those without a familial stroke history. In multivariate analyses, initial stroke severity, and infarction type were important predictors of favorable outcomes after 3 months. At the 1-year follow-up, patients with ICH and SAH had worse functional outcomes and survival rates than those with infarction. CONCLUSION: An aggressive approach to elucidate the etiology of stroke is indicated because structural vasculopathy-induced ICH and other determined infarction are distinctively prevalent in young adults, particularly those aged 16-30.