Lipopolysaccharide-producing Veillonella infantium and Escherichia fergusonii cause vagus nerve-mediated cognitive impairment in mice.

Gut microbiota communicates bidirectionally with the brain through the nervous, immune, and endocrine systems of the gut. In our preliminary study, the fecal microbiota of volunteers with mild cognitive impairment (Fmci) exhibited a higher abundance of Escherichia fergusonii (NK2001), Veillonella infantium (NK2002), and Enterococcus faecium (NK2003) populations compared with those of healthy volunteers. Therefore, we examined the effects of Fmci, NK2001 (gram-negative), NK2002 (gram-negative-like), and NK2003 (gram-positive) on cognitive impairment-like behavior, neuroinflammation, and colitis in mice with or without antibiotics. Fmci transplantation increased cognitive impairment-like behavior, hippocampal tumor necrosis factor (TNF)-α expression, and the size of toll-like receptor (TLR)4+Iba1+, TLR2+Iba1+, and NF-κB+Iba1+ cell populations independent of antibiotic treatment. Oral gavage of NK2001, NK2002, or NK2003, which induced TNF-α expression in Caco-2 cells, significantly increased cognitive impairment-like behavior and hippocampal TNF-α expression and Iba1-positive cell populations and decreased brain-derived neurotrophic factor (BDNF) expression in mice. Celiac vagotomy significantly decreased NK2001- or NK2002-induced cognitive impairment-like behavior and hippocampal Iba1+ cell population and TNF-α expression and increased NK2001- or NK2002-suppressed hippocampal BDNF expression. However, NK2003-induced cognitive impairment-like behavior and hippocampal Iba1+ cell population and TNF-α expression were partially, but not significantly, attenuated by celiac vagotomy. Furthermore, celiac vagotomy did not affect NK2001-, NK2002-, or NK2003-induced lipopolysaccharide (LPS) levels in the blood and feces and TNF-α expression and NF-κB-positive cell population in the colon. In conclusion, LPS-producing NK2001 and NK2002 and LPS-nonproducing NK2003 may induce NF-κB-mediated neuroinflammation through the translocation of byproducts such as LPS and peptidoglycan into the brain through gut-blood/vagus nerve-brain and gut-blood-brain pathways, respectively, resulting in cognitive impairment.

The Role of Cannabidiol in Liver Disease: A Systemic Review.

Cannabidiol (CBD), a non-psychoactive phytocannabinoid abundant in Cannabis sativa, has gained considerable attention for its anti-inflammatory, antioxidant, analgesic, and neuroprotective properties. It exhibits the potential to prevent or slow the progression of various diseases, ranging from malignant tumors and viral infections to neurodegenerative disorders and ischemic diseases. Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease, and viral hepatitis stand as prominent causes of morbidity and mortality in chronic liver diseases globally. The literature has substantiated CBD's potential therapeutic effects across diverse liver diseases in in vivo and in vitro models. However, the precise mechanism of action remains elusive, and an absence of evidence hinders its translation into clinical practice. This comprehensive review emphasizes the wealth of data linking CBD to liver diseases. Importantly, we delve into a detailed discussion of the receptors through which CBD might exert its effects, including cannabinoid receptors, CB1 and CB2, peroxisome proliferator-activated receptors (PPARs), G protein-coupled receptor 55 (GPR55), transient receptor potential channels (TRPs), and their intricate connections with liver diseases. In conclusion, we address new questions that warrant further investigation in this evolving field.

Enhanced bioleaching of spent Li-ion batteries using A. ferrooxidans by application of external magnetic field.

Recycling spent batteries is increasingly important for the sustainable use of Li-ion batteries (LIBs) and for countering the supply uncertainty of critical raw minerals (Li, Co, and Ni). Bioleaching, which uses microorganisms to extract valuable metals, is both economical and environmentally safe compared to other recycling methods, but its practical application is impaired by slow kinetics. Accelerating the process is a key for bioleaching spent LIBs on an industrial scale. Acidithiobacillus ferrooxidans (A. ferrooxidans), which thrives in extremely low pH conditions, has long been explored for bioleaching of spent LIBs. Metabolism of A. ferrooxidans involves the oxidation of magnetic Fe2+ and produces intracellular magnetic nanoparticles. The possibility of accelerating the leaching kinetics of A. ferrooxidans by the application of an external magnetic field is explored in this work. A weak static magnetic field is applied during the bioleaching of spent LIBs to recover Li, Ni, and Co using A. ferrooxidans. It is determined that 3 mT is the optimal field strength which allows the leaching efficiency of Li to reach 100% after only 2 days of leaching at a pulp density of 3 w/v % while without the external magnetic field, the leaching efficiency is limited to 57% even after 4 days. The leaching efficiency of Ni and Co also increases by nearly three-fold to >80% after 4 days of leaching. The proposed magnetic field-assisted bioleaching of spent LIBs using A. ferrooxidans substantially improves the leaching kinetics and thus the cost-effectiveness of the bioleaching process with minimal environmental impact, hence enabling environment-friendly recycling of raw materials that are increasingly becoming scarce. The positive effect of an external magnetic field on the metabolism of A. ferrooxidans demonstrated in this work provide a new set of tools to engineer the bioleaching process and the possibility for genetic modification of acidophile bacteria, especially targeted for magnetic enhancement.

Effects of Non-Pharmacological Interventions on Respiratory Viruses Other Than SARS-CoV-2: Analysis of Laboratory Surveillance and Literature Review From 2018 to 2021.

BACKGROUND: Since the global coronavirus disease 2019 (COVID-19) pandemic, non-pharmacological interventions (NPIs) such as extensive and comprehensive hand hygiene, mask-wearing, and social distancing have been implemented globally. This study aimed to investigate changes in respiratory viruses other than severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) that occurred following the implementation of these NPIs. METHODS: From January 2018 to December 2021, influenza-like illness patient specimens and specimens from the Korea Influenza and Respiratory Viruses Surveillance System were analyzed at the Incheon Metropolitan City Institute of Public Health and Environment. Oropharyngeal or nasopharyngeal swab samples from respiratory infection patients were transferred in a virus transport medium at 4°C. After RNA or DNA extraction, respiratory virus-specific genes for human influenza virus (IFV), adenovirus (ADV), parainfluenza virus (PIV), respiratory syncytial virus (RSV), human rhinovirus (hRV), human coronavirus, human bocavirus, and human metapneumovirus were detected by individual real-time reverse transcription polymerase chain reaction. RESULTS: A total 3,334 samples were collected. After NPI was implemented, the detection of respiratory viruses other than SARS-CoV-2 decreased overall. The yearly detection rate of respiratory viruses was decreased from 69.5% (399/574) in 2018 and 73.3% (505/689) in 2019 to 19.8% (206/1,043) in 2020 and 34.9% (365/1,028) in 2021. The epidemic was more prominent in respiratory viruses such as IFV and RSV, which were considered dominant viruses, especially those with viral envelopes. Among viruses that were not considered dominant, hRV showed no clear change before and after NPI, while PIV showed a rapid increase compared to the existing dominant viruses between October-December 2021, after the increase in the number of gatherings started at the end of September and the "Relaxing COVID19 and mitigation policy," which was implemented on November 1. CONCLUSION: NPI seems to have influenced the isolation and transmission of respiratory viruses in South Korea. In the future, additional studies focusing on the isolation and transmission patterns of respiratory viruses following NPI are needed.

Second-look arthroscopic findings and clinical outcomes after management of intra-articular lesions in acute ankle fractures with arthroscopy.

BACKGROUND: Anatomically surgical reduction of ankle fractures does not always result in a clinically favorable outcome. Arthroscopic examination combined with treatment of intra-articular lesion may related to clinical outcomes OBJECTIVES: The purpose of the present study was to review initial and second look arthroscopic finding of acute ankle fracture and to evaluate clinical outcomes. RESULTS: Lauge-Hansen classification system of ankle fractures included supination-external rotation type (n = 24), supination-adduction type (n = 3), pronation-external rotation type (n = 7), and pronation-abduction type (n = 6), total 40 ankles. Osteochondral lesions were found in 25 ankles (62%) with an initial arthroscopic finding of acute ankle fracture. Newly discovered chondral lesions in secondary arthroscopy were found in 17 cases. According to the Ferkel and Cheng staging at secondary arthroscopy, 4 of 25 ankles with osteochondral lesions of the talus were deteriorating (more than stage D). In terms of ICRS overall repair grades, 5 ankles (20%) were abnormal (grade III). Diffuse synovitis and arthrofibrosis were found in 12 and 7 ankles, respectively, in secondary arthroscopy, and correlations were found between AOFAS scores, VAS and intra-articular lesions. CONCLUSION: Second-look arthroscopic examination combined with treatment of intra-articular lesion such as arthrofibrosis and osteochondral lesion arising from ankle fracture surgery may consider to improve clinical outcomes.

Monitoring Culicine Mosquitoes (Diptera: Culicidae) as a Vector of Flavivirus in Incheon Metropolitan City and Hwaseong-Si, Gyeonggi-Do, Korea, during 2019.

The flaviviruses are small single-stranded RNA viruses that are typically transmitted by mosquitoes or tick vectors and are etiological agents of acute zoonotic infections. The viruses are found around the world and account for significant cases of human diseases. We investigated population of culicine mosquitoes in central region of Korean Peninsula, Incheon Metropolitan City and Hwaseong-si. Aedes vexans nipponii was the most frequently collected mosquitoes (56.5%), followed by Ochlerotatus dorsalis (23.6%), Anopheles spp. (10.9%), and Culex pipiens complex (5.9%). In rural regions of Hwaseong, Aedes vexans nipponii was the highest population (62.9%), followed by Ochlerotatus dorsalis (23.9%) and Anopheles spp. (12.0%). In another rural region of Incheon (habitat of migratory birds), Culex pipiens complex was the highest population (31.4%), followed by Ochlerotatus dorsalis (30.5%), and Aedes vexans vexans (27.5%). Culex pipiens complex was the predominant species in the urban region (84.7%). Culicine mosquitoes were identified at the species level, pooled up to 30 mosquitoes each, and tested for flaviviral RNA using the SYBR Green-based RT-PCR and confirmed by cDNA sequencing. Three of the assayed 2,683 pools (989 pools without Anopheles spp.) were positive for Culex flaviviruses, an insect-specific virus, from Culex pipiens pallens collected at the habitats for migratory birds in Incheon. The maximum likelihood estimation (the estimated number) for Culex pipiens pallens positive for Culex flavivirus was 25. Although viruses responsible for mosquito-borne diseases were not identified, we encourage intensified monitoring and long-term surveillance of both vector and viruses in the interest of global public health.

Surveillance of Chigger Mite Vectors for Tsutsugamushi Disease in the Hwaseong Area, Gyeonggi-do, Republic of Korea, 2015.

Owing to global climate change, the global resurgence of vector-borne infectious diseases and their potential to inflict widespread casualties among human populations has emerged as a pivotal burden on public health systems. Tsutsugamushi disease (scrub typhus) in the Republic of Korea is steadily increasing and was designated as a legal communicable disease in 1994. The disease is a mite-borne acute febrile disease most commonly contracted from October to December. In this study, we tried to determine the prevalence of tsutsugamushi disease transmitted by chigger mites living on rodents and investigated their target vector diversity, abundance, and distribution to enable the mapping of hotspots for this disease in 2015. A total of 5 species belonging to 4 genera (109 mites): Leptotrombidium scutellare 60.6%, L. pallidum 28.4% Neotrombicula tamiyai 9.2%, Euschoengastia koreaensis/0.9%), and Neoschoengastia asakawa 0.9% were collected using chigger mite collecting traps mimicking human skin odor and sticky chigger traps from April to November 2015. Chigger mites causing tsutsugamushi disease in wild rodents were also collected in Hwaseong for the zoonotic surveillance of the vector. A total of 77 rodents belonging to 3 genera: Apodemus agrarius (93.5%), Crocidura lasiura (5.2%), and Micromys minutus (1.3%) were collected in April, October, and November 2015. The most common mite was L. pallidum (46.9%), followed by L. scutellare (18.6%), and L. orientale (18.0%). However, any of the chigger mite pools collected from rodent hosts was tested positive for Orientia tsutsugamushi, the pathogen of tsutsugamushi disease, in this survey.

Four Year Surveillance of the Vector Hard Ticks for SFTS, Ganghwa-do, Republic of Korea.

The seasonal abundance of hard ticks that transmit severe fever with thrombocytopenia syndrome virus was monitored with a collection trap method every April to November during 2015-2018 and with a flagging method every July and August during 2015-2018 in Ganghwa-do (island) of Incheon Metropolitan City, Republic of Korea. This monitoring was performed in a copse, a short grass field, coniferous forest and broad-leaved forest. A total of 17,457 ticks (8,277 larvae, 4,137 nymphs, 3,389 females, and 1,654 males) of the ixodid ticks comprising 3 species (Haemaphysalis longicornis, H. flava, and Ixodes nipponensis) were collected with collection traps. Of the identified ticks, H. longicornis was the most frequently collected ticks (except larval ticks) (94.26%, 8,653/9,180 ticks (nymphs and adults)), followed by H. flava (5.71%, 524/9,180) and Ix. nipponensis (less than 0.04%, 3/9,180). The ticks collected with collecting traps were pooled and assayed for the presence of SFTS virus with negative results. In addition, for monitoring the prevalence of hard ticks, a total of 7,461 ticks (5,529 larvae, 1,272 nymphs, 469 females, and 191 males) of the ixodid ticks comprising 3 species (H. longicornis, H. flava, and Ix. nipponensis) were collected with flagging method. H. longicornis was the highest collected ticks (except larval ticks) (99.53%, 1,908/1,917 ticks (nymphs and adults)), followed by H. flava (1.15%, 22/1,917).

Effect of Probiotics on Pharmacokinetics of Orally Administered Acetaminophen in Mice.

Orally administered probiotics change gut microbiota composition and enzyme activities. Thus, coadministration of probiotics with drugs may lead to changes in the pharmacokinetic parameters of the drugs. In this study, we investigated the pharmacokinetics of acetaminophen in mice treated with probiotics. Oral administration of probiotics changed the gut microbiota composition in the mice. Of these probiotics, Lactobacillus reuteri K8 increased the numbers of clostridia, bifidobacteria, and enterococci, and Lactobacillus rhamnosus K9 decreased the number of bifidobacteria, determined by culturing in selective media. Next, we performed a pharmacokinetic study of acetaminophen in mice orally treated with K8 and K9 for 3 days. Treatment with K8 reduced the area under the curve (AUC) of orally administered acetaminophen to 68.4% compared with normal control mice, whereas K9 did not affect the AUC of acetaminophen. Oral administration to mice of K8, which degraded acetaminophen, increased the degradation of acetaminophen by gut microbiota, whereas K9 treatment did not affect it. Treatment with K8 increased the number of L. reuteri adhered in the upper small intestine, whereas the number of L. rhamnosus was not affected by treatment with K8 or K9. K8 increased the number of cyanobacteria, whereas K9 increased the number of deferribacteres. These results suggest that the intake of probiotics may make the absorption of orally administered drugs fluctuate through the disturbance of gut microbiota-mediated drug metabolism and that the subsequent impact on microbiota metabolism could result in altered systemic concentrations of the intact drug.

Radiologic Factors Affecting Ankle Pain Before and After Total Knee Arthroplasty for the Varus Osteoarthritic Knee.

The aim of the present study was to evaluate the radiologic factors related to ankle pain before and after total knee arthroplasty (TKA) among patients with a varus osteoarthritic knee. Fifty-five patients (65 ankles) with a varus osteoarthritic knee who had undergone TKA and were followed up for >24 months were enrolled. For clinical assessment, the visual analog scale for pain and the American Orthopaedic Foot and Ankle Society ankle-hindfoot scale were used. For radiologic assessment, the mechanical axis deviation angle, talar tilt, tibial anterior surface angle, distal medial clear space, medial tibiotalar joint space, frontal tibial ground angle, and hindfoot alignment view angle were measured. The patients with ankle pain before TKA (11 ankles) had a larger hindfoot alignment view angle (9.2° ± 2.6°) than that of patients without ankle pain before TKA (54 ankles; 5.5° ± 4.8°; p = .007). The patients with newly developed ankle pain or experienced an aggravation of existing pain after TKA (8 ankles) had a significantly larger degree of residual varus (5.1° ± 2.1°) than did the patients without ankle pain before and after TKA or those with ankle pain before surgery. However, the severity of the pain was not different during the follow-up period (52 ankles; 1.6° ± 2.5°; p = .001). The results of the present study showed that residual varus deformity was associated with ankle pain after TKA. Surgeons should perform evaluations of the ankles of patients who complain of pain before and after TKA and should give careful attention to the correction of alignment during TKA.

Comparison of histologic healing and biomechanical characteristics between repair techniques for a delaminated rotator cuff tear in rabbits.

BACKGROUND: The purpose of this study was to compare histologic healing and biomechanical characteristics between 2 repair techniques (layer by layer, repair of each layer to bone separately; and whole layer, repair of each layer to the bone en masse) for delaminated rotator cuff tear. MATERIALS AND METHODS: Rabbits were used as subjects and classified into 2 groups: group A, right side, the layer-by-layer repair group; and group B, left side, the whole-layer repair group. Histologic evaluations were done at 3 weeks (n = 7) and 6 weeks (n = 4) after operation. Biomechanical tests to evaluate the tensile property were done at time 0 (n = 5) and 3 weeks (n = 5) after operation. RESULTS: Histologic healing improved in all groups. A smaller cleft was found between layers in group B compared with the cleft in group A at 3 weeks after operation. At time 0, group A showed a higher yield load and ultimate failure load (67 ± 10.5 N and 80 ± 7.8 N, respectively). However, at 3 weeks after operation, group B showed a higher yield load (48 ± 7.6 N). CONCLUSIONS: In the delaminated rotator cuff tear model in the rabbit, the whole-layer repair showed a narrow gap between layers and a higher yield load at 3 weeks after operation. Surgical techniques that unite the cleft in a delaminated tear could improve biomechanical strength after operation.

Arthroscopic Deltoid Repair: A Technical Tip.

Deltoid ligament repair can be challenging, and implementation of an arthroscopic method can be useful in terms of minimizing morbidity associated with open dissection, as long as the repair is effective and durable. In this brief report, we describe a method of arthroscopic deltoid ligament repair that we have found to be useful.

A Comparison of Screw Fixation and Suture-Button Fixation in a Syndesmosis Injury in an Ankle Fracture.

The present study compared the quality of reduction and the clinical assessment between screw fixation and suture-button fixation with an ankle fracture accompanied by syndesmosis injury. We studied the clinical and radiologic findings 1 year postoperatively through retrospective examination of 24 patients who had undergone screw fixation from January 2011 to December 2012 and prospective examination of 20 patients who had undergone suture button fixation from January 2013 to May 2014. Regarding the tibiofibular clear space, tibiofibular overlap, and medial clear space, the screw fixation group had improvement from a preoperative mean of 6.97 (range 2.79 to 15.81) mm, 4.43 (range 0 to 7.87) mm, 7.90 (range 4.24 to 19.50) mm to a postoperative mean of 4.95 (range 2.72 to 9.08) mm, 6.29 (range 0 to 10.37) mm, and 4.32 (range 1.98 to 6.57) mm, respectively. The corresponding improvement for the suture-button fixation group was from a preoperative mean of 6.65 (range 3.94 to 13.73) mm, 5.39 (range 0 to 9.44) mm, 7.27 (range 4.04 to 16.00) mm to a postoperative mean of 5.15 (range 2.93 to 7.30) mm, 7.21 (range 2.15 to 10.30) mm, and 4.25 (range 2.97 to 5.71) mm. No statistically significant difference was found between the 2 techniques. Both suture-button and metal screw fixation are effective treatment methods for an ankle fracture accompanied by syndesmosis injury. However, a long-term and prospective analysis is needed.

AMPK Alchemy: Therapeutic Potentials in Allergy, Aging, and Cancer.

All cells are equipped with intricate signaling networks to meet the energy demands and respond to the nutrient availability in the body. AMP-activated protein kinase (AMPK) is among the most potent regulators of cellular energy balance. Under ATP -deprived conditions, AMPK phosphorylates substrates and affects various biological processes, such as lipid/glucose metabolism and protein synthesis. These actions further affect the cell growth, death, and functions, altering the cellular outcomes in energy-restricted environments. AMPK plays vital roles in maintaining good health. AMPK dysfunction is observed in various chronic diseases, making it a promising target for preventing and alleviating such diseases. Herein, we highlight the different AMPK functions, especially in allergy, aging, and cancer, to facilitate the development of new therapeutic approaches in the future.

Long-term taxonomic and functional stability of the gut microbiome from human fecal samples.

Appropriate storage of fecal samples is a critical step for unbiased analysis in human microbiome studies. The purpose of this study was to evaluate the stability of the fecal microbial community for up to 18 months. Ten healthy volunteers provided fecal samples at the Jeonbuk National University Hospital. Stool samples were stored under the following six conditions: four different storage temperatures (- 70 °C, - 20 °C, 4 °C, and room temperature [20-25 °C]) and two different collection tubes (OMNIgene-Gut and DNA/RNA shield-fecal collection tubes). The gut microbiome was analyzed with 16S rRNA sequencing. We compared the taxonomic composition, alpha diversity, beta diversity and inferred pathway abundance between the baseline and 18 months after storage. Samples collected in the DNA/RNA Shield-fecal collection tubes showed the best performance in preservation of the taxonomic composition at 18 months. Pairwise differences in alpha diversity metrics showed the least deviation from zero. The PERMANOVA test showed non-significant change of beta diversity metrics (Unweighted Unifrac: q-value 0.268; Weighted Unifrac: q-value 0.848). The functional stability was significantly well preserved in the DNA/RNA Shield-fecal collection tubes (adjusted p value < 0.05). Our results demonstrate the use of the DNA/RNA Shield-fecal collection tube as an alternative storage method for fecal samples to preserve the taxonomic and functional stability of the microbiome over a long term.

Alleviation of Cognitive Impairment-like Behaviors, Neuroinflammation, Colitis, and Gut Dysbiosis in 5xFAD Transgenic and Aged Mice by Lactobacillus mucosae and Bifidobacterium longum.

Neuropsychiatric disorders including Alzheimer's disease (AD) may cause gut inflammation and dysbiosis. Gut inflammation-suppressing probiotics alleviate neuropsychiatric disorders. Herein, to understand whether anti-inflammatory probiotics Lactobacillus mucosae NK41 and Bifidobacterium longum NK46, which suppressed tumor necrosis factor (TNF)-α expression in lipopolysaccharide (LPS)-stimulated macrophages, could alleviate cognitive impairment, we first examined their effects on cognitive function, gut inflammation, and gut microbiota composition in 5xFAD-transgenic mice. Oral administration of NK41 or NK46 decreased cognitive impairment-like behaviors, hippocampal amyloid-ß (Aß), TNF-α and interleukin (IL)-1ß expression, hippocampal NF-κB+Iba1+ cell population, and Aß accumulation, while hippocampal brain-derived neurotropic factor (BDNF) and IL-10 expression and BDNF+NeuN+ cell population increased. They also decreased TNF-α and IL-1ß expression and NF-κB+CD11c+ cell population in the colon. They also reduced fecal and blood LPS levels and gut Proteobacteria and Verrucomicrobia populations (including Akkkermansiaceae), which are positively associated with hippocampal TNF-α and fecal LPS levels and negatively correlated with hippocampal BDNF level. However, they increased Odoribactericeae, which positively correlated with BDNF expression level and TNF-α to IL-10 expression ratio. The combination of NK41 and NK46 (4:1, NKc), which potently inhibited TNF-α expression in LPS-stimulated macrophages, additively alleviated cognitive impairment-like behaviors in 5xFAD-transgenic or aged mice. NKc increased hippocampal BDNF+NeuN+ cell population and BDNF expression in 5xFAD-transgenic or aged mice, while hippocampal TNF-α and IL-1ß expression decreased. NKc also decreased TNF-α and IL-1ß expression in the colon and LPS levels in the blood and feces. These findings suggest that gut bacteria and its product LPS may be closely connected with occurrence of cognitive impairment and neuroinflammation and the combination of NK41 and NK46 can additively alleviate cognitive impairment and neuroinflammation by inducing NF-κB-suppressed BDNF expression and suppressing LPS-producing gut bacteria.

Pharmacokinetic Profiling of Ginsenosides, Rb1, Rd, and Rg3, in Mice with Antibiotic-Induced Gut Microbiota Alterations: Implications for Variability in the Therapeutic Efficacy of Red Ginseng Extracts.

Ginsenoside Rg3 is reported to contribute to the traditionally known diverse effects of red ginseng extracts. Significant individual variations in the therapeutic efficacy of red ginseng extracts have been reported. This study aimed to investigate the effect of amoxicillin on the pharmacokinetics of ginsenosides Rb1, Rd, and Rg3 in mice following the oral administration of red ginseng extracts. We examined the α-diversity and ß-diversity of gut microbiota and conducted pharmacokinetic studies to measure systemic exposure to ginsenoside Rg3. We also analyzed the microbiome abundance and microbial metabolic activity involved in the biotransformation of ginsenoside Rb1. Amoxicillin treatment reduced both the α-diversity and ß-diversity of the gut microbiota and decreased systemic exposure to ginsenoside Rg3 in mice. The area under the curve (AUC) values for Rg3 in control and amoxicillin-treated groups were 247.7 ± 96.6 ng·h/mL and 139.2 ± 32.9 ng·h/mL, respectively. The microbiome abundance and microbial metabolic activity involved in the biotransformation of ginsenoside Rb1 were also altered by amoxicillin treatment. The metabolizing activity was reduced from 0.13 to 0.05 pmol/min/mg on average. Our findings indicate that amoxicillin treatment potentially reduces the gut-microbiota-mediated metabolism of ginsenoside Rg3 in mice given red ginseng extracts, altering its pharmacokinetics. Gut microbiome variations may thus influence individual ginsenoside pharmacokinetics, impacting red ginseng extract's efficacy. Our results suggest that modulating the microbiome could enhance the efficacy of red ginseng.

The Intake of Coffee Increases the Absorption of Aspirin in Mice by Modifying Gut Microbiome.

The absorption of orally administered aspirin into the blood was affected by gastrointestinal environmental factors such as gut pH, digestive enzymes, and microbiota. The intake of coffee affects the pharmacological effects of aspirin. Therefore, we examined the gut microbiota-mediated effect of coffee bean extract (CBE) intake on the pharmacokinetics of aspirin in mice. The intake of CBE modified the gut microbiota composition and their α- and ß-diversities: It decreased the Proteobacteria, Helicobacteriaceae, and Bacteroidaceae populations in the fecal microbiota composition, while the S24-7_f (Muribaculaceae) and Lactobacillaceae populations increased. The fecal aspirin-hydrolyzing activities of humans and mice to salicylic acid were 0.045 ± 0.036 µmole/h/g and 0.032 ± 0.003 µmole/h/g, respectively. However, CBE treatment significantly suppressed the aspirin-hydrolyzing activity in mice. Furthermore, the area under the serum concentration-time curves (AUCs) of aspirin and salicylic acid were 0.265 ± 0.050 µg·h/mL and 16.224 ± 5.578 µg·h/mL in CBE-treated mice, respectively, and 0.248 ± 0.042 µg·h/mL and 10.756 ± 2.071 µg·h/mL in control mice, respectively. Moreover, CBE treatment suppressed the multidrug resistance protein 4 (Mrp4) expression in the intestines of mice, while the P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) expression was not affected. Furthermore, the CBE-treated mouse fecal lysate suppressed Mrp4 expression in Caco-2 cells compared to that of vehicle-treated mice, while CBE treatment did not affect Mrp4 expression. Oral gavage of caffeine also suppressed the Mrp4 expression in the intestines of mice. These findings suggest that intake of coffee can increase the absorption of aspirin by modifying the gut microbiome.

Case report: Toceranib as adjuvant chemotherapy in a dog with incompletely resected combined hepatocellular-cholangiocarcinoma.

An 11-year-old intact female mixed breed dog was presented with abdominal distention and elevated hepatic enzyme levels. Computed tomography revealed a multicystic hepatic mass at the left medial lobe adjacent to the diaphragm and caudal vena cava. The mass was surgically removed with partial hepatectomy, but it could not be removed completely because of adhesion to the diaphragm. The tissue was submitted for histopathologic evaluation, and the patient was diagnosed with stage IIIA combined hepatocellular-cholangiocarcinoma (cHCC-CC). Considering the residual tumor tissue from incomplete surgical excision, adjuvant chemotherapy was recommended. Tumor tissue obtained from the patient was assessed using an anticancer drug response prediction test, and the results showed that toceranib phosphate was the most effective chemotherapeutic agent for this patient. Toceranib was initiated (3.1 mg/kg, PO, q48 h), and routine adverse effect assessment, including systemic blood pressure measurement, complete blood count, serum biochemical evaluations, and urinalysis were performed at two-week intervals for the first 2 months and every 2 months thereafter. Radiography and ultrasonography were conducted at one-month intervals for the first two months and then every 2 months subsequently. Concurrent hyperadrenocorticism was managed with trilostane (1 to 5 mg/kg, PO, q12h). The patient showed no critical adverse effects of chemotherapy, obvious recurrence, or metastasis. The response to toceranib was assessed as a partial response, and the patient is still alive over 23 months after tumor excision. This is the first case report describing chemotherapy for a dog with cHCC-CC.

Enterococcus faecium and Pediococcus acidilactici deteriorate Enterobacteriaceae-induced depression and colitis in mice.

Gut dysbiosis is closely associated with the outbreak of inflammatory bowel disease (IBD) and psychiatric disorder. The Enterobacteriaceae population was higher in the feces of patients with inflammatory bowel disease (IBD-F) than in those of healthy control volunteers (HC-F). The Enterococcaceae and Lactobacillaceae populations were higher in the feces of IBD patients with depression (IBD/D+-F) vs. the feces of IBD patients without depression (IBD/D--F). Therefore, we examined the effects of Klebsiella oxytoca, Escherichia coli, Cronobacter sakazakii, Enterococcus faecium, and Pediococcus acidolactici overpopulated in IBD/D+-F and their byproducts LPS and exopolysaccharide (EPS) on the occurrence of depression and colitis in mice. Oral gavages of Klebsiella oxytoca, Escherichia coli, and Cronobacter sakazakii belonging to Enterobacteriaceae, singly or together, caused dose-dependently colitis and depression-like behaviors in germ-free and specific-pathogen-free mice. Although Enterococcus faecium and Pediococcus acidolactici did not significantly cause colitis and depression-like behaviors, they significantly deteriorated Klebsiella oxytoca- or Escherichia coli-induced colitis, neuroinflammation, and anxiety/depression-like behaviors and increased blood LPS, corticosterone, and IL-6 levels. The EPSs from Enterococcus faecium and Pediococcus acidolactici also worsened Klebsiella oxytoca LPS-induced colitis, neuroinflammation, and depression-like behaviors in mice and increased the translocation of fluorescein isothiocyanate-conjugated LPS into the hippocampus. However, Bifidobacterium longum, which was lower in IBD/D+-F vs. IBD/D--F, or its EPS suppressed them. In conclusion, Enterococcus faecium and Pediococcus acidolactici, known as a probiotic strain, and their EPSs may be a risk factor for the outbreak of depression and IBD.