Comparison of the sputum microbiome between patients with stable nontuberculous mycobacterial pulmonary disease and patients requiring treatment.

BACKGROUND: We evaluated whether the sputum bacterial microbiome differs between nontuberculous mycobacteria pulmonary disease (NTM-PD) patients with stable disease not requiring antibiotic treatment and those requiring antibiotics. METHODS: We collected sputum samples from 21 clinically stable NTM-PD patients (stable group) and 14 NTM-PD patients needing antibiotic treatment (treatment group). We also obtained 13 follow-up samples from the stable group. We analyzed the 48 samples using 16S rRNA gene sequencing (V3-V4 region) and compared the groups. RESULTS: In the linear discriminant analysis effect size (LEfSe) analysis, the species Porphyromonas pasteri, Haemophilus parahaemolyticus, Prevotella nanceiensis, and Gemella haemolysans were significantly more prevalent in the sputum of the stable group compared to the treatment group. No taxa showed significant differences in alpha-/beta-diversity or LEfSe between the 21 baseline and 13 follow-up sputum samples in the stable group. In the stable group, the genus Bergeyella and species Prevotella oris were less common in patients who achieved spontaneous culture conversion (n = 9) compared to those with persistent NTM positivity (n = 12) (effect size 3.04, p = 0.039 for Bergeyella; effect size 3.64, p = 0.033 for P. oris). In the treatment group, H. parainfluenzae was more common in patients with treatment success (n = 7) than in treatment-refractory patients (n = 7) (effect size 4.74, p = 0.013). CONCLUSIONS: Our study identified distinct bacterial taxa in the sputum of NTM-PD patients based on disease status. These results suggest the presence of a microbial environment that helps maintain disease stability.

Highly Reliable Performance of Flexible Synaptic Devices Based on PVP-GO QD Nanocomposites Due to the Formation of Directional Filaments.

The metallic conductive filament (CF) model, which serves as an important conduction mechanism for realizing synaptic functions in electronic devices, has gained recognition and is the subject of extensive research. However, the formation of CFs within the active layer is plagued by issues such as uncontrolled and random growth, which severely impacts the stability of the devices. Therefore, controlling the growth of CFs and improving the performance of the devices have become the focus of that research. Herein, a synaptic device based on polyvinylpyrrolidone (PVP)/graphene oxide quantum dot (GO QD) nanocomposites is proposed. Doping GO QDs in the PVP provides a large number of active centers for the reduction of silver ions, which allows, to a certain extent, the growth of CFs to be controlled. Because of this, the proposed device can simulate a variety of synaptic functions, including the transition from long-term potentiation to long-term depression, paired-pulse facilitation, post-tetanic potentiation, transition from short-term memory to long-term memory, and the behavior of the "learning experience". Furthermore, after being bent repeatedly, the devices were still able to simulate multiple synaptic functions accurately. Finally, the devices achieved a high recognition accuracy rate of 89.39% in the learning and inference tests, producing clear digit classification results.

Outcomes of Intermittent Multidrug IV Therapy for Refractory Mycobacterium abscessus Pulmonary Disease.

BACKGROUND: No studies have reported therapies for the treatment of patients with refractory Mycobacterium abscessus pulmonary disease (MAB-PD). We implemented intermittent multidrug IV therapy (IMIT) through repeated hospitalizations for patients with MAB-PD who were refractory to antibiotics for more than 12 months. RESEARCH QUESTION: What are the effects of IMIT on patients with refractory MAB-PD? STUDY DESIGN AND METHODS: The IV antibiotics administered for IMIT included amikacin, imipenem, and tigecycline, and the outcomes for 36 patients who underwent IMIT for refractory MAB-PD were evaluated. Patients were repeatedly hospitalized and administered IMIT on recurrent symptoms or radiographic evidence of deterioration, while maintaining oral/inhaled antibiotics. RESULTS: Of the 36 patients, 26 (72%) had M abscessus subspecies abscessus (herein, M abscessus)-PD, and 10 (28%) had M abscessus subspecies massiliense (herein, M massiliense)-PD. The median number of hospitalizations for IMIT was two (interquartile range, 1-3) for patients with M abscessus-PD and one (interquartile range, 1-2) for patients with M massiliense-PD. At least one negative culture result and culture conversion were observed in 62% and 12% of patients with M abscessus-PD, and in 80% and 60% of patients with M massiliense-PD, respectively. Symptomatic improvement was observed in all patients, and radiologic improvement, including cavity amelioration or no deterioration, was observed in 42% and 70% of patients with M abscessus-PD and with M massiliense-PD, respectively. No resistance to clarithromycin or amikacin was acquired. INTERPRETATION: IMIT with intermittent hospitalization can be a beneficial palliative treatment for patients with refractory MAB-PD. This therapy alleviated symptoms, slowed radiologic progression, and reduced the bacterial burden in some patients. However, radiologic and microbiological responses to IMIT were more apparent in M massiliense-PD than in M abscessus-PD.

Electron Oscillation-Induced Splitting Electroluminescence from Nano-LEDs for Device-Level Encryption.

Data security is a major concern in digital age, which generally relies on algorithm-based mathematical encryption. Recently, encryption techniques based on physical principles are emerging and being developed, leading to the new generation of encryption moving from mathematics to the intersection of mathematics and physics. Here, device-level encryption with ideal security is ingeniously achieved using modulation of the electron-hole radiative recombination in a GaN-light-emitting diode (LED). When a nano-LED is driven in the non-carrier injection mode, the oscillation of confined electrons can split what should be a single light pulse into multiple pulses. The morphology (amplitude, shape, and pulse number) of those history-dependent multiple pulses that act as carriers for transmitted digital information depends highly on the parameters of the driving signals, which makes those signals mathematically uncrackable and can increase the volume and security of transmitted information. Moreover, a hardware and software platform are designed to demonstrate the encrypted data transmission based on the device-level encryption method, enabling recognition of the entire ASCII code table. The device-level encryption based on splitting electroluminescence provides an encryption method during the conversion process of digital signals to optical signals and can improve the security of LED-based communication.

Changes in sputum microbiota during treatment for nontuberculous mycobacterial pulmonary disease.

Limited data exist on longitudinal changes in the sputum bacterial microbiome during treatment in nontuberculous mycobacterial pulmonary disease (NTM-PD) patients. We prospectively collected serial sputum samples from 14 NTM-PD patients during treatment, at the start (n = 14) and at 1 (n = 10), 3 (n = 10), 6 (n = 12), and 12 (n = 7) months. The bacterial microbiome changes were analyzed using 16S rRNA sequences (V3-V4 regions). Subgroup analysis included culture conversion (n = 9) and treatment refractory (n = 5) groups. In all patients, sputum alpha-diversity (ACE, Chao1, and Jackknife) significantly decreased during antibiotic treatment at 1, 3, 6, and 12 months compared to treatment initiation levels. Within the culture conversion group, genus/species-level beta-diversity showed differences at 1, 3, 6, and 12 months compared to treatment initiation (all p < 0.05). However, in the refractory group, there were no differences in beta-diversity at the genus/species levels in the sputum at any time point. In the linear discriminant analysis (LDA) effect sizes (LEfSe) analysis, the culture conversion group exhibited decreasing taxa at various levels (phylum/genus/species), but no significant increase in taxa was observed. LEfSe analysis of the refractory patient group revealed multiple taxa decreased during treatment. However, proportions of Veillonella dispar (LDA = 4.78), Fusobacterium periodonticum (LDA = 4.35), and Pseudomonas aeruginosa (LDA = 2.92) increased as the treatment period progressed in the refractory group. Sputum microbiota diversity decreases during NTM-PD treatment. In the culture conversion group, most taxa decrease, while some increase in the refractory group. These findings suggest that a distinct respiratory microbial community may exist in refractory NTM-PD patients compared to responsive antibiotic-treated patients.

Clinical Characteristics and Treatment Outcomes of Mycobacterium fortuitum Pulmonary Disease.

We evaluated the clinical characteristics and treatment outcomes of 35 patients diagnosed with Mycobacterium fortuitum-pulmonary disease (M. fortuitum-PD). Prior to treatment, all isolates were sensitive to amikacin and 73% and 90% were sensitive to imipenem and moxifloxacin, respectively. Approximately two-thirds of the patients (24 of 35) remained stable without antibiotic treatment. Of 11 patients requiring antibiotic treatment, the majority (81%, 9 of 11) achieved a microbiological cure with susceptible antibiotics. IMPORTANCE Mycobacterium fortuitum (M. fortuitum) is a rapidly growing mycobacterium that causes M. fortuitum-pulmonary disease (PD). It is common among individuals with preexisting lung conditions. Limited data exist regarding treatment and prognosis. Our study examined patients with M. fortuitum-PD. Two-thirds of them remained stable without antibiotics. Among those requiring treatment, 81% achieved a microbiological cure with suitable antibiotics. In many cases, M. fortuitum-PD follows a stable course without antibiotics, and when necessary, a favorable treatment response can be achieved with the appropriate antibiotics.

The lung microbiota in nontuberculous mycobacterial pulmonary disease.

BACKGROUND: The role of bacterial microbiota in the pathogenesis of nontuberculous mycobacterial pulmonary disease (NTM-PD) is unclear. We aimed to compare the bacterial microbiome of disease-invaded lesions and non-invaded lung tissue from NTM-PD patients. METHODS: We analyzed lung tissues from 23 NTM-PD patients who underwent surgical lung resection. Lung tissues were collected in pairs from each patient, with one sample from a disease-involved site and the other from a non-involved site. Lung tissue microbiome libraries were constructed using 16S rRNA gene sequences (V3-V4 regions). RESULTS: Sixteen (70%) patients had Mycobacterium avium complex (MAC)-PD, and the remaining seven (30%) had Mycobacterium abscessus-PD. Compared to non-involved sites, involved sites showed greater species richness (ACE, Chao1, and Jackknife analyses, all p = 0.001); greater diversity on the Shannon index (p = 0.007); and genus-level differences (Jensen-Shannon, PERMANOVA p = 0.001). Analysis of taxonomic biomarkers using linear discriminant analysis (LDA) effect sizes (LEfSe) demonstrated that several genera, including Limnohabitans, Rahnella, Lachnospira, Flavobacterium, Megamonas, Gaiella, Subdoligranulum, Rheinheimera, Dorea, Collinsella, and Phascolarctobacterium, had significantly greater abundance in involved sites (LDA >3.00, p <0.05, and q <0.05). In contrast, Acinetobacter had significantly greater abundance at non-involved sites (LDA = 4.27, p<0.001, and q = 0.002). Several genera were differentially distributed between lung tissues from MAC-PD (n = 16) and M. abscessus-PD (n = 7), and between nodular bronchiectatic form (n = 12) and fibrocavitary form (n = 11) patients. However, there was no genus with a significant q-value. CONCLUSIONS: We identified differential microbial distributions between disease-invaded and normal lung tissues from NTM-PD patients, and microbial diversity was significantly higher in disease-invaded tissues. TRIAL REGISTRATION: Clinical Trial registration number: NCT00970801.

Biocompatible memristive device based on an agarose@gold nanoparticle-nanocomposite layer obtained from nature for neuromorphic computing.

Natural, organic, materials-based artificial synaptic devices have been in the spotlight for wearable/flexible devices due to their lightweight, biocompatibility, and scalability. In this study, an electronic memristive device based on agarose extracted from plants in the Rhodophyceae class was fabricated, and its memory characteristics and analog data processing capabilities were evaluated. The Al/agarose@gold nanoparticle (AuNP) film/indium-tin-oxide (ITO)-structured memristive device exhibited reliable resistive switching characteristics with excellent retention with a large Ron/Roff ratio of 104. Also, analog conductance changes in our device were achieved with power consumption at the pJ level. This notable behavior could be maintained under mechanical deformations from a flat to a 4-mm bent state. In the recognition simulation based on the device's performance, an 91% accuracy and clear digit classification were achieved.

In Vitro Activity of Rifamycin Derivatives against Nontuberculous Mycobacteria, including Macrolide-/Amikacin-Resistant Clinical Isolates.

We evaluated the in vitro activity of rifamycin derivatives, including rifampin, rifapentine, rifaximin, and rifabutin, against clinical nontuberculous mycobacteria (NTM) isolates. Of the rifamycin derivatives, rifabutin showed the lowest MICs against all NTM species, including Mycobacterium avium complex, M. abscessus, and M. kansasii Rifabutin also had effective in vitro activity against macrolide- and aminoglycoside-resistant NTM isolates. Rifabutin could be worth considering as a therapeutic option for NTM disease, particularly drug-resistant disease.

Outcomes of Short-Term Tigecycline-Containing Regimens for Mycobacterium abscessus Pulmonary Disease.

Short-term intravenous tigecycline therapy during a 1-month initial phase may improve early microbiological response in patients with Mycobacterium abscessus pulmonary disease (PD). However, short-term use of tigecycline did not improve the long-term culture conversion rate of M. abscessus PD. Further studies on the efficacy of prolonged intravenous tigecycline-containing regimens are needed.

FBXL17/spastin axis as a novel therapeutic target of hereditary spastic paraplegia.

BACKGROUND: Spastin significantly influences microtubule regulation in neurons and is implicated in the pathogenesis of hereditary spastic paraplegia (HSP). However, post-translational regulation of the spastin protein remains nebulous. The association between E3 ubiquitin ligase and spastin provides a potential therapeutic strategy. RESULTS: As evidenced by protein chip analysis, FBXL17 inversely correlated with SPAST-M1 at the protein level in vitro and, also in vivo during embryonic developmental stage. SPAST-M1 protein interacted with FBXL17 specifically via the BTB domain at the N-terminus of SPAST-M1. The SCFFBXL17 E3 ubiquitin ligase complex degraded SPAST-M1 protein in the nuclear fraction in a proteasome-dependent manner. SPAST phosphorylation occurred only in the cytoplasmic fraction by CK2 and was involved in poly-ubiquitination. Inhibition of SCFFBXL17 E3 ubiquitin ligase by small chemical and FBXL17 shRNA decreased proteasome-dependent degradation of SPAST-M1 and induced axonal extension. The SPAST Y52C mutant, harboring abnormality in BTB domain could not interact with FBXL17, thereby escaping protein regulation by the SCFFBXL17 E3 ubiquitin ligase complex, resulting in loss of functionality with aberrant quantity. Although this mutant showed shortening of axonal outgrowth, low rate proliferation, and poor differentiation capacity in a 3D model, this phenotype was rescued by inhibiting SCFFBXL17 E3 ubiquitin ligase. CONCLUSIONS: We discovered that a novel pathway, FBXL17-SPAST was involved in pathogenicity of HSP by the loss of function and the quantitative regulation. This result suggested that targeting FBXL17 could provide new insight into HSP therapeutics.

The proliferative and multipotent epidermal progenitor cells for human skin reconstruction in vitro and in vivo.

OBJECTIVES: The skin exhibits tremendous regenerative potential, as different types of progenitor and stem cells regulate skin homeostasis and damage. However, in vitro primary keratinocytes present with several drawbacks, such as high donor variability, short lifespan, and limited donor tissue availability. Therefore, more stable primary keratinocytes are needed to generate multiple uniform in vitro and in vivo skin models. RESULTS: We identified epidermal progenitor cells from primary keratinocytes using Integrin beta 1 (ITGB1) an epidermal stem cell marker markedly decreased after senescence in vitro. Epidermal progenitor cells exhibited unlimited proliferation and the potential for multipotent differentiation capacity. Moreover, they could completely differentiate to form an organotypic skin model including conversed mesenchymal cells in the dermis and could mimic the morphologic and biochemical processes of human epidermis. We also discovered that proliferation and the multipotent differentiation capacity of these cells relied on ITGB1 expression. Eventually, we examined the in vitro and in vivo wound healing capacity of these epidermal progenitor cells. CONCLUSIONS: Overall, the findings suggest that these stable and reproducible cells can differentiate into multiple lineages, including human skin models. They are a potentially powerful tool for studying skin regeneration, skin diseases, and are an alternative for in vivo experiments.

Relationship between Resistance to Ethambutol and Rifampin and Clinical Outcomes in Mycobacterium avium Complex Pulmonary Disease.

We evaluated the associations between the in vitro activities of ethambutol and rifampin and clinical outcomes of Mycobacterium avium complex (MAC) pulmonary disease (PD). Among 158 patients with MAC-PD, there was no relationship between high MICs for ethambutol and/or rifampin and treatment failure for MAC-PD. Ethambutol and rifampin resistance was common among MAC isolates (rates of 87% and 59%, respectively), but mutations in embB, rpoB, and rpoC were rare, with detection in only 4% of the drug-resistant MAC isolates.

In Vitro Activity and Clinical Outcomes of Clofazimine for Nontuberculous Mycobacteria Pulmonary Disease.

Limited data are available regarding the in vitro activity of clofazimine against nontuberculous mycobacteria (NTM) or on outcomes of clofazimine-containing regimens in NTM-pulmonary disease (PD). Therefore, we evaluated the in vitro activity of clofazimine and the clinical outcomes of clofazimine-containing regimens. We evaluated clofazimine in vitro activity for 303 NTM isolates from NTM-PD patients. Fifty-seven clarithromycin-resistant and 35 amikacin-resistant isolates were also analyzed. Culture conversion after a 12-month treatment regimen containing clofazimine was evaluated in 58 NTM-PD patients, including 20 patients with drug-resistant isolates. Most of the 303 isolates (238/303) had minimum inhibitory concentrations (MICs) ≤ 0.25 µg/mL for clofazimine (57/63 Mycobacterium avium, 53/57 M. intracellulare, 49/52 M. kansasii, 22/64 M. abscessus, and 57/67 M. massiliense). For the 57 clarithromycin-resistant and 35 amikacin-resistant isolates, most had MICs ≤ 0.25 µg/mL (47/57 and 32/35, respectively). Among the 38 NTM-PD patients without resistance to clarithromycin or amikacin, 47% achieved culture conversion (8/27 M. abscessus, 9/9 M. massiliense, 0/1 M. avium, and 1/1 M. intracellulare). The conversion rate was higher in the MIC ≤ 0.25 µg/mL group than in the MIC = 0.5 µg/mL group (13/18 vs. 5/20, p = 0.004), and an MIC ≤ 0.25 µg/mL remained a significant factor in multivariable analysis. Culture conversion was achieved in 20% of 20 patients with clarithromycin- or amikacin-resistant isolates. However, a clofazimine MIC ≤ 0.25 µg/mL was not significant for culture conversion in the 58 NTM-PD patients, regardless of the drug resistance pattern. Clofazimine was effective in vitro against NTM species. Some patients on clofazimine-containing regimens achieved culture conversion.

In Vitro Activity of Oxazolidinone against Nontuberculous Mycobacteria, Including Macrolide-Resistant Clinical Isolates.

We evaluated the in vitro activities of oxazolidinone antibiotics, including linezolid, sutezolid, and delpazolid, against clinical nontuberculous mycobacteria (NTM) isolates. Regardless of macrolide resistance, for Mycobacterium avium, Mycobacterium intracellulare, and Mycobacterium kansasii, sutezolid showed the lowest MIC and minimal bactericidal concentration (MBC) values among oxazolidinone antibiotics. However, for Mycobacterium abscessus and Mycobacterium massiliense, the MIC and MBC for all oxazolidinone antibiotics showed similar values. Oxazolidinone antibiotics warrant further investigation as potential treatment for NTM.

Association between 16S rRNA gene mutations and susceptibility to amikacin in Mycobacterium avium Complex and Mycobacterium abscessus clinical isolates.

We evaluated the association between 16S rRNA gene (rrs) mutations and susceptibility in clinical isolates of amikacin-resistant nontuberculous mycobacteria (NTM) in NTM-pulmonary disease (PD) patients. Susceptibility was retested for 134 amikacin-resistant isolates (minimum inhibitory concentration [MIC] ≥ 64 µg/ml) from 86 patients. Amikacin resistance was reconfirmed in 102 NTM isolates from 62 patients with either Mycobacterium avium complex-PD (MAC-PD) (n = 54) or M. abscessus-PD (n = 8). MICs and rrs mutations were evaluated for 318 single colonies from these isolates. For the 54 MAC-PD patients, rrs mutations were present in 34 isolates (63%), comprising all 31 isolates with amikacin MICs ≥ 128 µg/ml, but only three of 23 isolates with an MIC = 64 µg/ml. For the eight M. abscessus-PD patients, all amikacin-resistant (MIC ≥ 64 µg/ml) isolates had rrs mutations. In amikacin-resistant isolates, the A1408G mutation (n = 29) was most common. Two novel mutations, C1496T and T1498A, were also identified. The culture conversion rate did not differ by amikacin MIC. Overall, all high-level and 13% (3/23) of low-level amikacin-resistant MAC isolates had rrs mutations whereas mutations were present in all amikacin-resistant M. abscessus isolates. These findings are valuable for managing MAC- and M. abscessus-PD and suggest the importance of phenotypic and genotypic susceptibility testing.

Organic light-emitting devices based on conducting polymer treated with benzoic acid.

We report on the enhanced conductivity of the benzoic-acid-treated poly(3,4-ethlenedioxythiophene):poly(styrene sulfonate) (PEDOT:PSS) electrode for use in highly flexible, organic light-emitting devices (OLEDs). The conductivity of the benzoic-acid-treated PEDOT:PSS electrode increased from 1 to 1583.2 S/cm, in comparison with that of the pristine PEDOT:PSS electrode, due to a complex factor of the H+ mole % and the dielectric constant of the benzoic solution. Among the post-treatment methods of the PEDOT:PSS electrodes, the operating voltage at 1000 cd/m2 of OLEDs fabricated utilizing the PEDOT:PSS electrode with the benzoic acid treatment has the lowest value, and its maximum luminance is 24,400 cd/m2, which are 1.54 and 2.15 times higher than those of OLEDs using PEDOT:PSS electrodes treated with dimethyl sulfoxide and methanol, respectively. The luminance of a flexible OLED with a benzoic-acid-treated PEDOT:PSS electrode after 1400 bending cycles decreased to 83% of the initial luminance, resulting in excellent mechanical stability.

A new experimental model to study human drug responses.

Accurate prediction of pharmacokinetic (PK) and pharmacodynamic (PD) characteristics is critical for drug development. Oral drugs are particularly difficult because they are absorbed by the intestine and metabolized in the liver before systemic metabolism in vivo; this is called the first-pass effect and is a critical factor for predicting oral bioavailability (BA). Here, we fabricated a new networking and circulating cell culture system (NCCS), mimicking the circulatory system and interaction of organs for studying the pharmacokinetic and pharmacodynamics of oral drugs in vitro. NCCS consisted of a micro-pump for circulating fluids, two types of multi-insert culture dishes for culturing different cell types, and an orbital shaker for mixing; flow rate and shaking-speed were controlled by weight-sensors and drivers. A first-pass effect test was performed using functionally differentiated HepaRG and Caco-2 cell lines, using a new modified spheroid forming unit (SFU) protocol. To verify the similarity of PK (first-pass effect) data of NCCS with the data from the human body, 15 reference drugs were chosen and their associated data were obtained by liquid chromatography-mass spectrometry analysis. NCCS generated absorption and metabolism data showed >70% similarity to human data respectively. NCCS can also be used to demonstrate species differences. Animal models are the primary basis for drug discovery, development, and testing. However, the weak correlation between humans and animals, particularly regarding absorption and metabolism, is a substantial limitation for the use of animal models. Here we compare human and mouse acetaminophen (APAP) metabolism using NCCS, and its application can be extended to assess cellular responses, such as efficacy and toxicity, simultaneously.

Meat Composition, Fatty Acid Profile and Sensory Attributes of Meat from Goats Fed Diet Supplemented with Fermented Saccharina japonica and Dendropanax morbifera.

A 90-day feeding trial was conducted to evaluate the effects of diets supplemented with three concentrations (control or 0%, 0.5% and 1.0%) of fermented Saccharina japonica and Dendropanax morbifera (FSJ-DM) on the meat composition, growth performance, oxidative stability and fatty acid profile of Korean native black goat (KNBG) meat. The feed conversion ratio and body weight gain (1st to 2nd month) were improved significantly (p < 0.05) in response to feed supplemented with 1.0% FSJ-DM. Moisture content was increased, whereas ether extract and cholesterol contents were decreased in meat obtained from goats supplemented with 1.0% FSJ-DM dietary feeds (p < 0.05). In the same diet group, the total saturated fatty acids (ΣSFA) were lower, whereas the sum of polyunsaturated fatty acids (ΣPUFA) was higher, along with higher PUFA/SFA ratio and lower n-6/n-3 ratio (p < 0.05). On an average, the dietary supplementation of 1.0% FSJ-DM reduced the thiobarbituric acid reactive substance (TBARS) and pH values of goat meat. Overall, the results of this study suggest that diet supplemented with 1.0% FSJ-DM improves the meat composition, growth performance and fatty acid profile and reduces lipid oxidation of goat meat.

Ginsenoside Rg3 promotes Fc gamma receptor-mediated phagocytosis of bacteria by macrophages via an extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase-dependent mechanism.

Ginsenoside Rg3 is a steroidal saponin abundant in Korean red ginseng that has high anti-inflammatory activity. Rg3 exerts an immunomodulatory effect in acute inflammatory conditions such as bacterial infections. In this study, we determined the effect of Rg3 on bacterial uptake by macrophages and the related intracellular signaling pathways. Rg3 increased macrophage phagocytosis of IgG-opsonized Escherichia coli and IgG-opsonized beads (IgGbeads), but not of non-opsonized beads. Rg3 also enhanced the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 and p38 mitogen-activated protein kinase (p38 MAPK), but not that of Akt. The inclusion of IgGbeads in macrophage cultures also increased the phosphorylation of ERK1/2 and p38, but co-culture of macrophages with non-opsonized beads did not affect the phosphorylation of ERK1/2 and p38. The Rg3-induced promotion of phagocytosis was inhibited by PD98059, an ERK1/2 inhibitor, and SB203580, a p38 inhibitor. PD98059 inhibited Rg3-induced p38 MAPK phosphorylation, but SB203580 did not suppress ERK1/2 phosphorylation. Culture of macrophages with Rg3 increased actin polymerization, and this effect was inhibited by SB203580 and PD98059. The Rg3-induced increase in phagocytosis was also inhibited by NSC23766, a Rac1 inhibitor and CASIN, a Cdc42 inhibitor. Intraperitoneal injection of Rg3 increased the phosphorylation of ERK1/2 and p38 as well as the phagocytosis of bacteria by lung cells. These results demonstrate that ginsenoside Rg3 enhances macrophage phagocytosis of bacteria by activating the ERK1/2 and p38 MAPK pathways.