Butyrate's (a short-chain fatty acid) microbial synthesis, absorption, and preventive roles against colorectal and lung cancer.

Butyrate, a short-chain fatty acid (SCFA) produced by bacterial fermentation of fiber in the colon, is a source of energy for colonocytes. Butyrate is essential for improving gastrointestinal (GI) health since it helps colonocyte function, reduces inflammation, preserves the gut barrier, and fosters a balanced microbiome. Human colonic butyrate producers are Gram-positive firmicutes, which are phylogenetically varied. The two most prevalent subgroups are associated with Eubacterium rectale/Roseburia spp. and Faecalibacterium prausnitzii. Now, the mechanism for the production of butyrate from microbes is a very vital topic to know. In the present study, we discuss the genes encoding the core of the butyrate synthesis pathway and also discuss the butyryl-CoA:acetate CoA-transferase, instead of butyrate kinase, which usually appears to be the enzyme that completes the process. Recently, butyrate-producing microbes have been genetically modified by researchers to increase butyrate synthesis from microbes. The activity of butyrate as a histone deacetylase inhibitor (HDACi) has led to several clinical trials to assess its effectiveness as a potential cancer treatment. Among various significant roles, butyrate is the main energy source for intestinal epithelial cells, which helps maintain colonic homeostasis. Moreover, people with non-small-cell lung cancer (NSCLC) have distinct gut microbiota from healthy adults and frequently have dysbiosis of the butyrate-producing bacteria in their guts. So, with an emphasis on colon and lung cancer, this review also discusses how the microbiome is crucial in preventing the progression of certain cancers through butyrate production. Further studies should be performed to investigate the underlying mechanisms of how these specific butyrate-producing bacteria can control both colon and lung cancer progression and prognosis.

Graphene Hybrid Inner Ear Organoid with Enhanced Maturity.

Inner ear organoids (IEOs) are 3D structures grown in vitro, which can mimic the complex cellular structure and function of the inner ear. IEOs are potential solutions to problems related to inner ear development, disease modeling, and drug delivery. However, current approaches in generating IEOs using chemical factors have a few limitations, resulting in unpredictable outcomes. In this study, we propose the use of nanomaterial-based approaches, specifically by using graphene oxide (GO). GO's unique properties promote cell-extracellular matrix interactions and cell-cell gap junctions, thereby enhancing hair cell formation, which is an essential part of IEO development. We also investigated the potential applications for drug testing. Our findings suggest that GO is a promising candidate for enhancing the functionality of IEOs and advancing our understanding of the problems underlying inner ear development. The use of nanomaterial-based approaches may provide a more reliable and effective method for building better IEOs in the future.

Comparative anti-inflammatory effect of extract from novel Korean strawberry cultivars (Fragaria × ananassa) on lipopolysaccharide-induced RAW264.7 macrophages and mouse model.

BACKGROUND: Dietary interventions are crucial in modulating inflammation in humans. Strawberries are enjoyed by people of different ages as a result of their attractive phenotype and taste. In addition, the active compounds in strawberries may contribute to the reduction of inflammation. When developing new strawberry cultivars to address agricultural and environmental threats, the bioactivity of strawberries must be improved to maintain their health benefits. RESULTS: We determined the phytochemical contents of extracts from a new Korean strawberry cultivar, with the CN7 cultivar extract possessing the highest total polyphenol and flavonoid contents compared to the CN5 and Seolhyang cultivar extracts. The new Korean strawberry cultivars reduced the expression of inflammatory-related genes in lipopolysaccharide (LPS)-induced RAW264.7 cells via the nuclear factor-kappa B signaling pathway, indicating an anti-inflammatory effect. The CN7 cultivar showed greater bioactivity potential and the highest ellagic acid content; hence, we assessed the effect of the CN7 cultivar in an LPS-stimulated mouse model. The CN7 cultivar treatment demonstrated its effectiveness in reducing inflammation via the downregulation of inflammatory cytokines secretion and gene expression. CONCLUSION: The results obtained in the present study have revealed the observable differences of the newly developed strawberry cultivars with Seolhyang in mitigating inflammation induced by LPS. The enhanced phytochemical content of the CN7 cultivar extract may contribute to its improved anti-inflammatory effect. Therefore, it is crucial to maintain the nutritive benefits of strawberry during the development of new cultivation. © 2023 Society of Chemical Industry.

Evaluating the Clinical Utility of Brachial Plexus Block for Reducing Opioid Exposure in Pediatric Elbow Fracture Surgery: A Retrospective Cohort Study.

Background and Objectives: Reducing opioid exposure in common pediatric surgeries is of paramount importance. This study aimed to assess the efficacy of regional nerve blocks in reducing opioid exposure while preserving high success rates. Materials and Methods: We conducted a retrospective matched cohort study (1:1) including patients with elbow fractures < 12 years old who underwent treatment with percutaneous pinning. Patients were divided into general-anesthesia (GA) and GA-followed-by-supraclavicular-brachial-plexus-block (GA-SCB) groups. The primary outcome was the number of patients administered postoperative rescue opioids. The secondary outcomes included intraoperative and postoperative opioid administration, the time to first request for rescue analgesia, pain scores, block success rate, block performing time, and block-related complications. Results: In a total of 478 patients, 363 underwent percutaneous pinning, and 86 were cohort-matched (GA: n = 43, GA-SCB: n = 43). On the first postoperative day, 34 (79.0%) patients in the GA group were administered postoperative rescue opioids, compared with 12 (27.9%) in the GA-SCB group (p < 0.001). All the patients in the GA-SCB group were opioid-free during the intraoperative period. No SCB-associated complications were observed. Total opioid consumption was significantly lower in the GA-SCB group than in the GA group until the first postoperative day (GA vs. GA-SCB, 3.2 ± 3.0 mg vs. 0.9 ± 1.8 mg, p < 0.001). Conclusions: SCB application in pediatric patients who underwent elbow fracture surgery significantly reduced opioid exposure and had a high success rate when performed using ultrasound guidance by an expert. Furthermore, the complication risk and surgical delay were minimal.

Comparison of the Analgesic Efficacy between Arthroscopically Placed Continuous Suprascapular Nerve Block and Ultrasound-guided Continuous Superior Trunk Block: A Double-blinded Randomized Controlled Trial.

BACKGROUND: Single-shot suprascapular nerve block and superior trunk block have been reported to provide a noninferior analgesic effect after shoulder surgery with a lesser incidence of hemidiaphragmatic paresis compared with interscalene brachial plexus block. This study hypothesized that continuous suprascapular nerve block provides noninferior analgesia with minimal effects on diaphragmatic movement compared with continuous superior trunk block in patients undergoing arthroscopic shoulder surgery. METHODS: 100 patients were randomized undergoing arthroscopic shoulder surgery between December 2020 and October 2021 into continuous suprascapular nerve block and continuous superior trunk block groups. Before the surgery, patients received either a single-shot superior trunk block or subomohyoid suprascapular nerve block. Thereafter, a superior trunk catheter was inserted by anesthesiologists in patients in the continuous superior trunk block group, and a posterior suprascapular nerve catheter was inserted with arthroscopic assistance during the surgery by surgeon in the continuous suprascapular nerve block group. The primary outcome was the postoperative pain score at postoperative 24 h, and the incidence of hemidiaphragmatic paresis was also compared. RESULTS: Overall, 98 patients were included in the final analysis. The worst and resting pain scores at postoperative 24 h in the continuous suprascapular nerve block group were inferior compared with those in the continuous superior trunk block group in the test with a noninferiority margin of 1 (worst pain score: mean difference, 0.9; 95% CI, 0.1 to 1.7; resting pain score: mean difference, 0.5; 95% CI, 0.0 to 1.0). However, the continuous suprascapular nerve block group had a significantly lower incidence of hemidiaphragmatic paresis at postoperative 24 h than the continuous superior trunk block group. CONCLUSIONS: Continuous suprascapular nerve block provides statistically inferior analgesia compared to the continuous superior trunk block; however, the continuous suprascapular nerve block had a minimal effect on the phrenic nerve function.

8-paradol from ginger exacerbates PINK1/Parkin mediated mitophagy to induce apoptosis in human gastric adenocarcinoma.

Gastric cancer (GC) occurs in the gastric mucosa, and its high morbidity and mortality make it an international health crisis. Therefore, novel drugs are needed for its treatment. The use of natural products and their components in cancer treatments has shown promise. Therefore, this study aimed to evaluate the effect of 8-paradol, a phenolic compound isolated from ginger (Zingiber officinale Roscoe), on GC and determine its underlying mechanisms of action. In this study, repeated column chromatography was conducted on ginger EtOH extract to isolate gingerol and its derivatives. The cytotoxicity of the eight ginger compounds underwent a (3-(4,5-dimethylthiazol-2-yl)- 2,5-diphenyltetrazolium bromide) tetrazolium reduction (MTT) assay. 8-paradol showed the most potent cytotoxicity effect among the isolated ginger compounds. The underlying mechanism by which 8-paradol regulated specific proteins in AGS cells was evaluated by proteomic analysis. To validate the predicted mechanisms, AGS cells and thymus-deficient nude mice bearing AGS xenografts were used as in vitro and in vivo models of GC, respectively. The results showed that the 8-paradol promoted PINK1/Parkin-associated mitophagy, mediating cell apoptosis. Additionally, the inhibition of mitophagy by chloroquine (CQ) ameliorated 8-paradol-induced mitochondrial dysfunction and apoptosis, supporting a causative role for mitophagy in the 8-paradol-induced anticancer effect. Molecular docking results revealed the molecular interactions between 8-paradol and mitophagy-/ apoptosis-related proteins at the atomic level. Our study provides strong evidence that 8-paradol could act as a novel potential therapeutic agent to suppress the progression of GC by targeting mitophagy pathway.

Repurposing of conformationally-restricted cyclopentane-based AKT-inhibitors leads to discovery of potential and more selective antileishmanial agents than miltefosine.

Conformational restriction was addressed towards the development of more selective and effective antileishmanial agents than currently used drugs for treatment of Leishmania donovani; the causative parasite of the fatal visceral leishmaniasis. Five types of cyclopentane-based conformationally restricted miltefosine analogs that were previously explored in literature as anticancer AKT-inhibitors were reprepared and repurposed as antileishmanial agents. Amongst, positions-1 and 2 cis-conformationally-restricted compound 1a and positions-2 and 3 trans-conformationally-restricted compound 3b were highly potent eliciting sub-micromolar IC50 values for inhibition of infection and inhibition of parasite number compared with the currently used miltefosine drug that showed low micromolar IC50 values for inhibition of infection and inhibition of parasite number. Compounds 1a and 3b eradicated the parasite without triggering host cells cytotoxicity over more than one log concentration interval which is a superior performance compared to miltefosine. In silico studies suggested that conformational restriction conserved the conformer capable of binding LdAKT-like kinase while it might be possible that it excludes other conformers mediating undesirable effects and/or toxicity of miltefosine. Together, this study presents compounds 1a and 3b as antileishmanial agents with superior performance over the currently used miltefosine drug.

Complications and Technical Consideration of Ultrasound-Guided Rectus Sheath Blocks: A Retrospective Analysis of 4033 Patients.

BACKGROUND: Although the ultrasound-guided rectus sheath block (RSB) is usually regarded as an easy and safe procedure in clinical settings, there is currently no report on complications incidence. Therefore, the present study investigated complications in a large cohort and described the technical considerations to minimize complications of real-time ultrasound-guided RSBs. METHODS: This was a retrospective cohort study of patients who underwent real-time ultrasound-guided RSBs for perioperative pain control in laparoscopic surgery with an umbilical port between February 1, 2017, and February 28, 2021, at the Asan Medical Center in South Korea. All RSBs were performed bilaterally using a 23-gauge Quincke needle, and a bilateral 2-block placement was regarded as 1 RSB. Patient data, including demographics, preoperative laboratory data, preoperative antiplatelet or anticoagulant medication with the duration of discontinuation, and type of surgery, were collected to show the study population characteristics and explore potential factors associated with adverse events such as hematoma. Ultrasound images of patients and adverse events of RSBs, including extrarectus sheath injections, vascular injuries, bowel injury, or local anesthetic systemic toxicity, were also analyzed accordingly. RESULTS: A total of 4033 procedures were analyzed. The mean body mass index of the patients was 24.1 (21.8-26.5) kg/m2. The preoperative laboratory data were within normal range in 4028 (99.9%) patients. Preoperative antiplatelets or anticoagulants were administered in 17.3% of the patients. Overall, 96 complications (2.4%) were observed. Among them, extrarectus sheath injection occurred in 88 cases (2.2%), which included preperitoneal injection (0.9%) and intraperitoneal injection (1.3%). Vascular injuries constituted 8 cases (0.2%) and all vascular injuries resulted in hematoma: 7 cases of inferior epigastric artery injury with rectus sheath hematoma and 1 of inferior mesenteric artery injury with retroperitoneal hematoma. Bowel injury or local anesthetic systemic toxicity was not reported. CONCLUSIONS: In this study of RSBs performed on 4033 patients using a 23-gauge Quincke needle in patients with low body mass index, there were 8 cases (0.2%) of vascular injury, all of which accompanied hematoma.

Design, synthesis, and study of novel phenethyl-based antitumor phospholipids downregulating p38 mitogen-activated protein kinase.

Phenethyl-based edelfosine-analogs with saturated, monounsaturated, or polyunsaturated alkoxy substituents on phenyl ring were designed as novel antitumor lipids modulating p38 MAPK. Evaluation of the synthesised compounds against nine panels of diverse cancer cells presented saturated and monounsaturated alkoxy-substituted derivatives as the most active than other derivatives. In addition, ortho-substituted compounds were more active than meta- or ortho-substituted compounds. They were potential anticancer agents against blood, lung, colon, CNS, ovary, renal, and prostate cancers but not against skin nor breast cancers. Compounds, 1b and 1a emerged as the most potential anticancer agents. Assessment of compound 1b impact on p38 MAPK and AKT confirmed it as an inhibitor of p38 MAPK but not AKT. In silico study suggested compounds 1b and 1a as possible binders to the lipid binding pocket of p38 MAPK. Overall, compounds 1b and 1a as novel broad spectrum antitumor lipids modulating activity of p38 MAPK for further development.

Rational repurposing, synthesis, in vitro and in silico studies of chromone-peptidyl hybrids as potential agents against Leishmania donovani.

A chromone-peptidyl hybrids series was synthesised and rationally repurposed towards identification of potential antileishmanial hits against visceral leishmaniasis. Three hybrids 7c, 7n, and 7h showed potential IC50 values (9.8, 10, and 12 µM, respectively) which were comparable to erufosine IC50 (9.8 µM) but lower potency than miltefosine IC50 (3.5 µM). Preliminary assessment of cytotoxicity using human THP-1 cells presented chromone-peptidyl hybrids 7c and 7n as non-cytotoxic up to 100 µM while erufosine and miltefosine had CC50 of 19.4 µM and >40 µM, respectively. In silico studies pinpointed the N-p-methoxyphenethyl substituent at the peptidyl moiety together with the oxygen-based substituted functions of the phenyl ring of the chromone moiety as crucial players in binding to LdCALP. Together, these findings present chromone-peptidyl hybrids 7c and 7n as potential and anticipated non-cytotoxic antileishmanial hit compounds for possible development of potential antileishmanial agents against visceral leishmaniasis.

A comparison of the continuous supraclavicular brachial plexus block using the proximal longitudinal oblique approach and the interscalene brachial plexus block for arthroscopic shoulder surgery: A randomised, controlled, double-blind trial.

BACKGROUND: Continuous interscalene brachial plexus block (ISB) is widely used for arthroscopic shoulder surgery, but the incidence of hemidiaphragmatic paresis (HDP) has been reported to reach 100%. Several methods, including injections distal to the C5-C6 nerve roots, have been attempted to reduce the HDP incidence. However, catheter placement distal to the C5-C6 nerve roots interferes with the surgical site. OBJECTIVE: Our primary objective was to describe a new technique, the supraclavicular brachial plexus block (SCB), using the proximal longitudinal oblique approach (PLO-SCB), which can facilitate catheter placement and, when compared with ISB, to test whether this would provide noninferior analgesia and spare the phrenic nerve. DESIGN: Prospective, randomised, double-blind study. SETTING: Operating rooms, postanaesthesia care unit, and wards. PATIENTS: Seventy-six patients aged 20 to 80 years scheduled for arthroscopic shoulder surgery. INTERVENTIONS: Patients were randomly assigned to the continuous PLO-SCB (n = 40) or the continuous ISB (n = 40) groups. All patients received an initial low-volume single-injection (5 ml 0.75% ropivacaine) followed by a patient-controlled infusion of 0.15% ropivacaine. MAIN OUTCOME MEASURES: The primary outcomes were the incidence of HDP and pain scores. Secondary outcomes were respiratory function, postoperative analgesic consumption, sensory and motor function, and complications. RESULTS: The HDP incidence was significantly lower in the PLO-SCB group than in the ISB group at 30 min after block injection: 0% (0 of 38 patients) and 73.7% (28 of 38 patients), respectively (P < 0.001). Similarly, at 24 h after surgery, the incidences were 23.7% (9 of 38 patients) and 47.4% (18 of 38 patients) in the PLO-SCB and ISB groups, respectively (P = 0.002). Median [IQR] NRS pain scores at rest measured after surgery in the ISB and PLO-SCB groups were similar: immediately after surgery, 1 [0 to 2] vs. 1 [0 to 1], P = 0.06); at 30 min, 2 [0.25 to 2] vs. 1 [0 to 2], P = 0.065); and at 24 h 2 [0.25 to 3] vs. 1 [0 to 3], P = 0.47, respectively. CONCLUSION: For major shoulder surgery, compared with continuous ISB, continuous PLO-SCB was more sparing of diaphragmatic and respiratory function while providing noninferior analgesia. Catheter placement via the PLO approach is feasible without interfering with the surgical field. TRIAL REGISTRATION: Registered by the Clinical Trial Registry of Korea (Seoul, Korea; KCT0004759, http: cris.nih.go.kr, principal investigator: Hyungtae Kim).

Probe-Free Identification of RNA Virus Variants with Point Mutations by Surface-Enhanced Raman Spectroscopy.

As observed in the COVID-19 pandemic, RNA viruses continue to rapidly evolve through mutations. In the absence of effective therapeutics, early detection of new severely pathogenic viruses and quarantine of infected people are critical for reducing the spread of the viral infections. However, conventional detection methods require a substantial amount of time to develop probes specific to new viruses, thereby impeding immediate response to the emergence of viral pathogens. In this study, we identified multiple types of viruses by obtaining the spectral fingerprint of their surface proteins with probe-free surface-enhanced Raman scattering (SERS). In addition, the SERS-based method can remarkably distinguish influenza virus variants with several surface protein point mutations from their parental strain. Principal component analysis (PCA) of the SERS spectra systematically captured the key Raman bands to distinguish the variants. Our results show that the combination of SERS and PCA can be a promising tool for rapid detection of newly emerging mutant viruses without a virus-specific probe.

The association between the type of anesthesia and hemodynamic instability during pheochromocytoma surgery: a retrospective cohort study.

BACKGROUND: Pheochromocytoma often carries a risk for perioperative hemodynamic instability (HDI). The aim of this study is to evaluate the risk factors of intraoperative HDI during minimally invasive posterior retroperitoneal adrenalectomy (PRA) for pheochromocytoma. MATERIALS AND METHODS: This retrospective study analyzed the prospectively collected data of 172 patients who underwent laparoscopic PRA or robotic PRA for pheochromocytoma between January 2014 and December 2020 at a single tertiary center. The patients were divided into two groups according to the intraoperative hypertensive event of systolic blood pressure (> 160 mmHg). The clinical manifestations and perioperative hemodynamic conditions were analysed. RESULTS: In the multivariate logistic regression analysis, the tumor size (> 3.4 cm) [OR 3.14, 95% confidence intervals (CI) (1.48-6.64), p = 0.003], type of preoperative alpha-blocker (selective type) [OR 3.9, 95% CI (1.52-10.02), p = 0.005], preoperative use of beta-blockers [OR 3.94, 95% CI (1.07-14.49), p = 0.039] and type of anesthesia [total intravenous anesthesia (TIVA) vs. balanced anesthesia (BA)] [OR 2.57, 95% CI (1.23-5.38), p = 0.012] were determined as independent risk factors of intraoperative hypertensive events during minimally invasive adrenalectomy. CONCLUSIONS: The type of anesthesia was independently associated with intraoperative HDI along with larger tumor size, type of preoperative alpha-blocker and the use of preoperative beta-blockers. TIVA increased the risk of intraoperative hypertensive events compared with BA. Thus, the consideration of the type of anesthesia prior to adrenal surgery for pheochromocytoma along with the use of preoperative non-selective alpha-blockers may be beneficial in minimizing the risk of intraoperative HDI.

Biologically synthesized black ginger-selenium nanoparticle induces apoptosis and autophagy of AGS gastric cancer cells by suppressing the PI3K/Akt/mTOR signaling pathway.

BACKGROUND: Despite being a promising strategy, current chemotherapy for gastric cancer (GC) is limited due to adverse side effects and poor survival rates. Therefore, new drug-delivery platforms with good biocompatibility are needed. Recent studies have shown that nanoparticle-based drug delivery can be safe, eco-friendly, and nontoxic making them attractive candidates. Here, we develop a novel selenium-nanoparticle based drug-delivery agent for cancer treatment from plant extracts and selenium salts. RESULTS: Selenium cations were reduced to selenium nanoparticles using Kaempferia parviflora (black ginger) root extract and named KP-SeNP. Transmission electron microscopy, selected area electron diffraction, X-ray diffraction, energy dispersive X-ray, dynamic light scattering, and Fourier-transform infrared spectrum were utilized to confirm the physicochemical features of the nanoparticles. The KP-SeNPs showed significant cytotoxicity in human gastric adenocarcinoma cell (AGS cells) but not in normal cells. We determined that the intracellular signaling pathway mechanisms associated with the anticancer effects of KP-SeNPs involve the upregulation of intrinsic apoptotic signaling markers, such as B-cell lymphoma 2, Bcl-associated X protein, and caspase 3 in AGS cells. KP-SeNPs also caused autophagy of AGS by increasing the autophagic flux-marker protein, LC3B-II, whilst inhibiting autophagic cargo protein, p62. Additionally, phosphorylation of PI3K/Akt/mTOR pathway markers and downstream targets was decreased in KP-SeNP-treated AGS cells. AGS-cell xenograft model results further validated our in vitro findings, showing that KP-SeNPs are biologically safe and exert anticancer effects via autophagy and apoptosis. CONCLUSIONS: These results show that KP-SeNPs treatment of AGS cells induces apoptosis and autophagic cell death through the PI3K/Akt/mTOR pathway, suppressing GC progression. Thus, our research strongly suggests that KP-SeNPs could act as a novel potential therapeutic agent for GC.

Correction: Rethineswaran et al. CHIR99021 Augmented the Function of Late Endothelial Progenitor Cells by Preventing Replicative Senescence. Int. J. Mol. Sci. 2021, 22, 4796.

There was an error in representative images of the tube formation in Figure 4b in the original publication [...].

Inhibitory Effect of Etravirine, a Non-Nucleoside Reverse Transcriptase Inhibitor, via Anterior Gradient Protein 2 Homolog Degradation against Ovarian Cancer Metastasis.

Anterior gradient protein 2 homolog (AGR2), an endoplasmic reticulum protein, is secreted in the tumor microenvironment. AGR2 is a member of the disulfide isomerase family, is highly expressed in multiple cancers, and promotes cancer metastasis. In this study, we found that etravirine, which is a non-nucleoside reverse transcriptase inhibitor, could induce AGR2 degradation via autophagy. Moreover, etravirine diminished proliferation, migration, and invasion in vitro. Moreover, in an orthotopic xenograft mouse model, the combination of etravirine and paclitaxel significantly suppressed cancer progression and metastasis. This drug may be a promising therapeutic agent for the treatment of ovarian cancer.

Rhamnogalacturonan I-rich polysaccharide isolated from fermented persimmon fruit increases macrophage-stimulatory activity by activating MAPK and NF-κB signaling.

BACKGROUND: Persimmon (Diospyros kaki) is a familiar and widespread fruit, cultivated worldwide. To date, physiological and chemical changes in fermented persimmon fruit and its active compounds have been rarely investigated. Moreover, comparative studies on the pharmacological activities of fermented persimmon fruit-derived compounds have not been reported. RESULTS: To investigate the effect of traditional fermented foods on immunostimulatory activity, non-fermented persimmon fruit (D. kaki, DK) and fermented persimmon fruit (fermented D. kaki, FDK) were prepared and further fractionated into low- and high-molecular weight fractions. FDK exhibited significantly higher activity toward the production of macrophage-stimulatory mediators compared with that of DK, and the high-molecular weight fraction (FDK-H) isolated from FDK was shown to have more potent activity than FDK. FDK-H not only increased the expression of immunostimulatory genes (TNF-α, IL-6, IL-12, and iNOS), but also stimulated the phosphorylation of both MAPK (ERK, JNK, and p38) and NF-κB (p65 and IκB) signaling molecules underlying macrophage activation. The putative chemical characteristic of FDK-H was identified as a pectic rhamnogalacturonan (RG) I-rich polysaccharide with a high molecular weight of 304 kDa containing galacturonic acid, arabinose, rhamnose, and galactose as the major monosaccharide units. CONCLUSION: The present study reveals that traditional fermentation is a useful method for increasing the macrophage-immunostimulatory activity of persimmon fruit, and the increased activity may be associated with structural modification of persimmon polysaccharides. This study may serve to identify a functional ingredient as an immunostimulatory agent, and our results may be applied to develop a new immunostimulatory product using FDK-H. © 2021 Society of Chemical Industry.

Interaction between Dexamethasone, Ropivacaine, and Contrast Media Used in Interventional Pain Treatment: Considerations in Safety.

Background and Objectives: Although epidural steroid injections are used as an effective treatment, this technique is associated with rare but serious ischemic complications, especially when particulate steroids are used. However, recent studies have reported that even if non-particulate steroids are used, particulates are formed by the interaction with some local anesthetics (LA), causing ischemic complications. This observational study evaluated commonly used combinations of non-particulate steroids and LA with contrast media via microscopic analysis and analyzed the chemical properties of each mixture to identify the correlation of particulate formation. Materials and Methods: Commonly used clinical non-particulate and particulate steroids, contrast media, and LA agent combinations were evaluated macroscopically and microscopically. The pH values were also measured at both room temperature (26 °C) and body temperature (36 °C). Where particulates were observed, the particulate size was measured. Results: Macroscopically, the mixture of non-particulate steroid and ropivacaine had a slightly cloudy appearance at all concentrations, but there was no visible particulate. However, when observed under a microscope, the pH-dependent particulate formation was observed at all concentration combinations tested. (0.1% ropivacaine: from 19 µm to 70 µm, and 0.2% ropivacaine: from 37 µm to 108 µm at room temperature (26 °C)). When contrast media was mixed or the temperature was raised to body temperature (36 °C), the number and size of the particulates decreased or dissolved. Conclusions: The combination of ropivacaine and dexamethasone, a non-particulate steroid, mainly used in epidural injections, forms particulates. However, when mixed with contrast media, particulates are dissolved because of changes in pH and factors affecting particulate formation. In fluoroscopy-guided injections, the use of contrast media could resolve particulate formation.

Gap Junction-Mediated Intercellular Communication of cAMP Prevents CDDP-Induced Ototoxicity via cAMP/PKA/CREB Pathway.

In the cochlea, non-sensory supporting cells are directly connected to adjacent supporting cells via gap junctions that allow the exchange of small molecules. We have previously shown that the pharmacological regulation of gap junctions alleviates cisplatin (CDDP)-induced ototoxicity in animal models. In this study, we aimed to identify specific small molecules that pass through gap junctions in the process of CDDP-induced auditory cell death and suggest new mechanisms to prevent hearing loss. We found that the cyclic adenosine monophosphate (cAMP) inducer forskolin (FSK) significantly attenuated CDDP-induced auditory cell death in vitro and ex vivo. The activation of cAMP/PKA/CREB signaling was observed in organ of Corti primary cells treated with FSK, especially in supporting cells. Co-treatment with gap junction enhancers such as all-trans retinoic acid (ATRA) and quinoline showed potentiating effects with FSK on cell survival via activation of cAMP/PKA/CREB. In vivo, the combination of FSK and ATRA was more effective for preventing ototoxicity compared to either single treatment. Our study provides the new insight that gap junction-mediated intercellular communication of cAMP may prevent CDDP-induced ototoxicity.

CHIR99021 Augmented the Function of Late Endothelial Progenitor Cells by Preventing Replicative Senescence.

Endothelial progenitor cells (EPCs) are specialized cells in circulating blood, well known for their ability to form new vascular structures. Aging and various ailments such as diabetes, atherosclerosis and cardiovascular disease make EPCs vulnerable to decreasing in number, which affects their migration, proliferation and angiogenesis. Myocardial ischemia is also linked to a reduced number of EPCs and their endothelial functional role, which hinders proper blood circulation to the myocardium. The current study shows that an aminopyrimidine derivative compound (CHIR99021) induces the inhibition of GSK-3ß in cultured late EPCs. GSK-3ß inhibition subsequently inhibits mTOR by blocking the phosphorylation of TSC2 and lysosomal localization of mTOR. Furthermore, suppression of GSK-3ß activity considerably increased lysosomal activation and autophagy. The activation of lysosomes and autophagy by GSK-3ß inhibition not only prevented replicative senescence of the late EPCs but also directed their migration, proliferation and angiogenesis. To conclude, our results demonstrate that lysosome activation and autophagy play a crucial role in blocking the replicative senescence of EPCs and in increasing their endothelial function. Thus, the findings provide an insight towards the treatment of ischemia-associated cardiovascular diseases based on the role of late EPCs.