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BACKGROUND AND PURPOSE:We hypothesized that admission insular infarcts could be associated with early neurological deterioration (END) in acute minor stroke with large vessel occlusion. METHODS:Using acute and follow-up diffusion-weighted imaging (DWI), we assessed insular involvement including the percent insular ribbon infarction (PIRI) scores and follow-up lesion patterns in acute minor stroke (NIHSS ≤5) with MCA/ICA occlusion. Follow-up lesion patterns were classified as swelling, new lesions, or infarct growth. END was defined as any increase in the NIHSS score. RESULTS:Among 166 patients (age: 66±12 y, 60.8% male), 82 (49.4%) had insular lesions on baseline DWI, and 64 (38.6%) had PIRI scores ≥2. On follow-up DWI, infarct growths, new lesions, and swelling were observed in 34.9%, 69.9%, and 29.5% of patients. Infarct growths were significantly more frequent in patients with insular infarcts (43.9%), especially those with a PIRI score of 2 (54.8%), than in patients without insular infarcts (p = 0.02). While END was not significantly different in patients with and without insular lesions, insular lesions were independently associated with infarct growths (OR 2.18, 95% CI 1.12-4.26, p = 0.02) and END due to infarct growth (OR 2.54, 95% CI 1.12-5.76, p = 0.03), particularly in those with PIRI scores ≥2. CONCLUSION:In acute minor stroke with MCA/ICA occlusion, insular lesions on admission DWI, especially in patients with PIRI scores ≥2, were more likely to exhibit infarct growth and END due to infarct growth. This finding may help identify patients with higher risks of clinical worsening following acute minor stroke with large vessel occlusion.

Inducing programmed cell death in tumors is a fundamental approach in cancer therapy, prompting extensive efforts to discover bioactive compounds with anticancer properties. Peucedanum japonicum, a plant used in traditional medicine across East Asia, has been reported to exhibit various biological activities, including anticancer effects. This study aimed to evaluate the apoptosis-inducing effects of methanol/dichloromethane (MeOH/CH2Cl2) extracts of P. japonicum roots and their components in HL-60 human leukemia cells. Compounds were isolated using solvent extraction and reverse-phase column chromatography, and their structures were confirmed by nuclear magnetic resonance (NMR) spectroscopy. The cytotoxicity effect of the compounds was tested on various cancer cell lines (HL-60, A549, and MCF-7). Two coumarins, (−)-isosamidin (1) and 3′S,4′S-disenecioylkhellactone (2), were isolated through bioactivity-guided fractionation. Compound 2 significantly induced apoptosis in HL-60 cells, as evidenced by an increase in the sub-G1 cell population and the initiation of both early and late apoptosis. Additional apoptotic markers, including reduced mitochondrial membrane potential (MMP) and increased cleavage of caspase-3, -8, and -9, were observed. These findings suggest that compound 2 shows potential as a candidate for leukemia treatment, providing a promising natural-product-based approach to cancer therapy. [ABSTRACT FROM AUTHOR]

Mycobacterium avium complex (MAC) infection is a growing public health concern worldwide, particularly affecting the elderly and immunocompromised population. The treatment of MAC lung disease relies on a combination of antibiotics in a three‐drug regimen that includes macrolides, rifamycins, and ethambutol. Therefore, the investigation of antimicrobial susceptibility is crucial for successful treatment. This study aimed to assess the antibiotic susceptibility of the most prevalent MAC species causing MAC lung disease, Mycobacterium intracellulare, in the Southwestern Gyeongsang province of South Korea using a resazurin‐based microtiter assay. A total of 97 strains of M. intracellulare were isolated and tested for antimicrobial susceptibility. The results demonstrated high susceptibility rates for two aminoglycosides (amikacin and streptomycin, 94.9% and 99%), rifampicin (90.9%), clarithromycin (98%), linezolid (100%), and moxifloxacin (94.9%) against M. intracellulare. However, notably high resistance rates were observed for ethambutol (97%) and clofazimine (98%) against M. intracellulare. In conclusion, our findings indicate relatively high susceptibility rates for these six antibiotics and significantly elevated resistance rates for clofazimine and ethambutol compared to other regions in South Korea and foreign countries. The investigated MIC data can offer valuable insights for developing an effective treatment regimen for MAC lung infection in this area. [ABSTRACT FROM AUTHOR]

The WNT pathway has become an attractive target for skeletal therapies. High-bone-mass phenotypes in patients with loss-of-function mutations in the LRP5/6 inhibitor Sost (sclerosteosis), or in its downstream enhancer region (van Buchem disease), highlight the utility of targeting Sost/sclerostin to improve bone properties. Sclerostin-neutralizing antibody is highly osteoanabolic in animal models and in human clinical trials, but antibody-based inhibition of another potent LRP5/6 antagonist, Dkk1, is largely inefficacious for building bone in the unperturbed adult skeleton. Here, we show that conditional deletion of Dkk1 from bone also has negligible effects on bone mass. Dkk1 inhibition increases Sost expression, suggesting a potential compensatory mechanism that might explain why Dkk1 suppression lacks anabolic action. To test this concept, we deleted Sost from osteocytes in, or administered sclerostin neutralizing antibody to, mice with a Dkk1-deficient skeleton. A robust anabolic response to Dkk1 deletion was manifest only when Sost/sclerostin was impaired. Whole-body DXA scans, μCT measurements of the femur and spine, histomorphometric measures of femoral bone formation rates, and biomechanical properties of whole bones confirmed the anabolic potential of Dkk1 inhibition in the absence of sclerostin. Further, combined administration of sclerostin and Dkk1 antibody in WT mice produced a synergistic effect on bone gain that greatly exceeded individual or additive effects of the therapies, confirming the therapeutic potential of inhibiting multiple WNT antagonists for skeletal health. In conclusion, the osteoanabolic effects of Dkk1 inhibition can be realized if sclerostin upregulation is prevented. Anabolic therapies for patients with low bone mass might benefit from a strategy that accounts for the compensatory milieu of WNT inhibitors in bone tissue.

Grainyhead-Like 2 (GRHL2) is an epithelial-specific transcription factor that regulates epithelial morphogenesis and differentiation. Prior studies suggested inverse regulation between GRHL2 and TGF-β in epithelial plasticity and potential carcinogenesis. Here, we report the role of GRHL2 in oral carcinogenesis in vivo using a novel Grhl2 knockout (KO) mouse model and the underlying mechanism involving its functional interaction with TGF-β signaling. We developed epithelial-specific Grhl2 conditional KO mice by crossing Grhl2 floxed mice with those expressing CreER driven by the K14 promoter. After induction of Grhl2 KO, we confirmed the loss of GRHL2 and its target proteins, while Grhl2 KO strongly induced TGF-β signaling molecules. When exposed to 4-nitroquinoline 1-oxide (4-NQO), a strong chemical carcinogen, Grhl2 wild-type (WT) mice developed rampant oral tongue tumors, while Grhl2 KO mice completely abolished tumor development. In cultured oral squamous cell carcinoma (OSCC) cell lines, TGF-β signaling was notably induced by GRHL2 knockdown while being suppressed by GRHL2 overexpression. GRHL2 knockdown or KO in vitro and in vivo, respectively, led to loss of active p-Erk1/2 and p-JNK MAP kinase levels; moreover, ectopic overexpression of GRHL2 strongly induced the MAP kinase activation. Furthermore, the suppressive effect of GRHL2 on TGF-β signaling was diminished in cells exposed to Erk and JNK inhibitors. These data indicate that GRHL2 activates the Erk and JNK MAP kinases, which in turn suppresses the TGF -β signaling. This novel signaling represents an alternative pathway by which GRHL2 regulates carcinogenesis, and is distinct from the direct transcriptional regulation by GRHL2 binding at its target gene promoters, e.g., E-cadherin, hTERT, p63, and miR-200 family genes. Taken together, the current study provides the first genetic evidence to support the role of GRHL2 in carcinogenesis and the underlying novel mechanism that involves the functional interaction between GRHL2 and TGF-β signaling through the MAPK pathways.

Intensive study of the organic extract of the marine-derived bacterium Saccharomonospora sp. CNQ-490 has yielded three new α-pyrones, saccharomonopyrones A-C (1-3). The chemical structures of these compounds were assigned from the interpretation of 1D, 2D NMR and mass spectrometry data. Saccharomonopyrone A (1) is the first α-pyrone microbial natural product bearing the ethyl-butyl ether chain in the molecule, while saccharomonopyrones B and C possess unusual 3-methyl and a 6-alkyl side-chain within a 3,4,5,6-tetrasubstituted α-pyrone moiety. Saccharomonopyrone A exhibited weak antioxidant activity using a cation radical scavenging activity assay with an IC50 value of 140 μM.