A case report of Pseudomonas citronellolis and Escherichia coli isolated from acute suppurative appendicitis: reveals the potential intestinal colonization and pathogenicity of Pseudomonas citronellolis.

Human infections caused by Pseudomonas citronellolis, an environmental bacterium, are infrequent, with only two cases related to uncommon urinary tract infections and bacteremia reported in recent years. All these cases typically occurred in elderly patients with compromised or decreased immune function. Simultaneously, the epithelial barrier disruption induced by invasive biopsy procedures or gastrointestinal disorders such as gastroenteritis provided a pathway for Pseudomonas citronellolis to infiltrate the organism. In this study, we present the first report of a case where Pseudomonas citronellolis and Escherichia coli were isolated from the inflamed appendix of a patient without underlying conditions. Compared to the Escherichia coli, Pseudomonas citronellolis has never been isolated in patients with appendicitis. We identified the species using MALDI-TOF MS and genetic sequencing. Based on our findings, we highlight the perspective that Pseudomonas citronellolis can colonize the intestines of healthy individuals and may trigger infections like appendicitis.

Bifidobacterium animalis subsp. lactis boosts neonatal immunity: unravelling systemic defences against Salmonella.

Bifidobacterium animalis subsp. lactis may be a useful probiotic intervention for regulating neonatal intestinal immune responses and counteracting Salmonella infection. However, recent research has focused on intestinal immunity, leaving uncertainties regarding the central, peripheral, and neural immune responses in neonates. Therefore, this study investigated the role and mechanisms of B. animalis subsp. lactis in the systemic immune responses of neonatal rats following Salmonella infection. Through extremely early pretreatment with B. animalis subsp. lactis (6 hours postnatal), the neonatal rat gut microbiota was effectively reshaped, especially the Bifidobacterium community. In the rats pretreated with B. animalis subsp. lactis, Salmonella was less prevalent in the blood, liver, spleen, and intestines following infection. The intervention promoted T lymphocyte subset balance in the spleen and thymus and fostered neurodevelopment and neuroimmune balance in the brain. Furthermore, metabolic profiling showed a strong correlation between the metabolites in the serum and colon, supporting the view that B. animalis subsp. lactis pretreatment influences the systemic immune response by modifying the composition and metabolism of the gut microbiota. Overall, the results imply that B. animalis subsp. lactis pretreatment, through the coordinated regulation of colonic and serum metabolites, influences the systemic immune responses of neonatal rats against Salmonella infection.

Caenorhabditis elegans as an in vivo model for the identification of natural antioxidants with anti-aging actions.

Natural antioxidants have recently emerged as a highly exciting and significant topic in anti-aging research. Diverse organism models present a viable protocol for future research. Notably, many breakthroughs on natural antioxidants have been achieved in the nematode Caenorhabditis elegans, an animal model frequently utilized for the study of aging research and anti-aging drugs in vivo. Due to the conservation of signaling pathways on oxidative stress resistance, lifespan regulation, and aging disease between C. elegans and multiple high-level organisms (humans), as well as the low and controllable cost of time and labor, it gradually develops into a trustworthy in vivo model for high-throughput screening and validation of natural antioxidants with anti-aging actions. First, information and models on free radicals and aging are presented in this review. We also describe indexes, detection methods, and molecular mechanisms for studying the in vivo antioxidant and anti-aging effects of natural antioxidants using C. elegans. It includes lifespan, physiological aging processes, oxidative stress levels, antioxidant enzyme activation, and anti-aging pathways. Furthermore, oxidative stress and healthspan improvement induced by natural antioxidants in humans and C. elegans are compared, to understand the potential and limitations of the screening model in preclinical studies. Finally, we emphasize that C. elegans is a useful model for exploring more natural antioxidant resources and uncovering the mechanisms underlying aging-related risk factors and diseases.

Therapeutic targeting of DNA damage repair pathways guided by homologous recombination deficiency scoring in ovarian cancers.

The susceptibility of cells to DNA damage and their DNA repair ability are crucial for cancer therapy. Homologous recombination is one of the major repairing mechanisms for DNA double-strand breaks. Approximately half of ovarian cancer (OvCa) cells harbor homologous recombination deficiency (HRD). Considering that HRD is a major hallmark of OvCas, scholars proposed HRD scoring to evaluate the HRD degree and guide the choice of therapeutic strategies for OvCas. In the last decade, synthetic lethal strategy by targeting poly (ADP-ribose) polymerase (PARP) in HR-deficient OvCas has attracted considerable attention in view of its favorable clinical effort. We therefore suggested that the uses of other DNA damage/repair-targeted drugs in HR-deficient OvCas might also offer better clinical outcome. Here, we reviewed the current small molecule compounds that targeted DNA damage/repair pathways and discussed the HRD scoring system to guide their clinical uses.

Differential reinforcement of intestinal barrier function by various Lactobacillus reuteri strains in mice with DSS-induced acute colitis.

AIMS: Inflammatory bowel disease is a complex, refractory disorder characterised by chronic gastrointestinal inflammation. Studies have reported that Lactobacillus reuteri alleviates gastrointestinal inflammation and strengthens the intestinal barrier. However, further biochemical and genetic studies are required to correctly understand the therapeutic potential of L. reuteri. MATERIALS AND METHODS: This study sought to further understand the anti-colitis effect of L. reuteri isolated from faecal samples of healthy locals by focusing on biochemical (immunological, mechanical, chemical and biological barriers) and genetic studies. KEY FINDINGS: In this study, we assessed and compared the benefits and efficacy of L. reuteri FYNDL13 and FCQHC8L in the treatment of colitis and found strain FYNDL13 to be superior to FCQHC8L in this regard. Compared with FCQHC8L, FYNDL13 was associated with more diverse and powerful regulatory pathways. Meanwhile, it encouraged butyric acid formation, upregulated antimicrobial peptide-coding gene transcription and prevented hyperimmune reactions on the intestinal periphery and within the intestine. Moreover, it enhanced the abundance of beneficial bacteria (Bifidobacterium, Akkermansia, Blautia and Oscillospira), thereby limiting the relative abundance of harmful bacteria (Bacteroides and Sutterella). Furthermore, the advantage might be attributed to metabolism- and defence system-related genomic characteristics. SIGNIFICANCE: Taken together, our study compares and summarizes a pathway paradigm of these two L. reuteri strains in reinforcing the intestinal barrier against colitis and identifies candidate genes responsible for microbiota-immune axis balance.

Litchi flower essential oil balanced lipid metabolism through the regulation of DAF-2/IIS, MDT-15/SBP-1, and MDT-15/NHR-49 pathway.

Many litchi flowers are discarded in China every year. The litchi flower is rich in volatile compounds and exhibits strong anti-obesity activity. Litchi flower essential oil (LFEO) was extracted by the continuous phase transformation device (CPTD) independently developed by our research group to recycle the precious material resources in litchi flowers. However, its fat-reducing effect and mechanism remain unclear. Employing Caenorhabditis elegans as a model, we found that LFEO significantly reduced fat storage and triglyceride (TG) content in normal, glucose-feeding, and high-fat conditions. LFEO significantly reduced body width in worms and significantly decreased both the size and number of lipid droplets in ZXW618. LFEO treatment did not affect energy intake but increased energy consumption by enhancing the average speed of worms. Further, LFEO might balance the fat metabolism in worms by regulating the DAF-2/IIS, sbp-1/mdt-15, and nhr-49/mdt-15 pathways. Moreover, LFEO might inhibit the expression of the acs-2 gene through nhr-49 and reduce ß-oxidation activity. Our study presents new insights into the role of LFEO in alleviating fat accumulation and provides references for the large-scale production of LFEO to promote the development of the litchi circular economy.

RAD54B mutations enhance the sensitivity of ovarian cancer cells to poly(ADP-ribose) polymerase (PARP) inhibitors.

Synthetic lethal targeting of homologous recombination (HR)-deficient ovarian cancers (OvCas) with poly(ADP-ribose) polymerase inhibitors (PARPis) has attracted considerable attention. Olaparib was the first PARPi approved by the Food and Drug Administration, offering significant clinical benefits in BRCA1/2-deficient OvCas. However, only approximately 20% of OvCa patients harbor BRCA1/2 mutations. Given the shared roles that BRCA1/2 have with other HR regulators, alterations in HR genes may also contribute to "BRCAness profiles" in OvCas. RAD54B has been considered a key player in HR repair, although its roles and therapeutic potential in cancers need further investigation. Here, we identified 22 frequently mutated HR genes by whole-exome sequencing of OvCa tissues from 82 patients. To our surprise, 7.3% of patients were found to harbor mutations of RAD54B, the third-highest mutated gene among patients. We determined that RAD54B-mutated tumor tissues harbored more DNA double-strand breaks than normal tissues. Additionally, we found that RAD54B knockdown inhibited HR repair, enhanced sensitivities of OvCa cells with increased DNA double-strand breaks to olaparib, and induced apoptosis. Enhanced inhibitory effects of olaparib on the growth of ES2 xenograft tumors were further demonstrated by RAD54B knockdown. Finally, we show that restoration with wildtype RAD54B rather than RAD54BN593S and RAD54BH219Y, identified in patients, abolished the effects of RAD54B knockdown, indicating these RAD54B mutants probably malfunctioned in HR repair. Our investigations may offer insight into the contributions of RAD54B mutations to synthetic lethality with olaparib treatment in OvCas, enrich the gene list for "HR deficiency scoring," and expand the applications of PARPis.

Intestinal 'Infant-Type' Bifidobacteria Mediate Immune System Development in the First 1000 Days of Life.

Immune system maturation begins early in life, but few studies have examined how early-life gut microbiota colonization educates the neonatal immune system. Bifidobacteria predominate in the intestines of breastfed infants and metabolize human milk oligosaccharides. This glycolytic activity alters the intestinal microenvironment and consequently stimulates immune system maturation at the neonatal stage. However, few studies have provided mechanistic insights into the contribution of 'infant-type' Bifidobacterium species, especially via metabolites such as short-chain fatty acids. In this review, we highlight the first 1000 days of life, which provide a window of opportunity for infant-type bifidobacteria to educate the neonatal immune system. Furthermore, we discuss the instrumental role of infant-type bifidobacteria in the education of the neonatal immune system by inducing immune tolerance and suppressing intestinal inflammation, and the potential underlying mechanism of this immune effect in the first 1000 days of life. We also summarize recent research that suggests the administration of infant-type bifidobacteria helps to modify the intestinal microecology and prevent the progress of immune-mediated disorders.

Effect of Momordica saponin- and Cyclocarya paliurus polysaccharide-enriched beverages on oxidative stress and fat accumulation in Caenorhabditis elegans.

BACKGROUND: As an edible and medicinal herb in Chinese folk medicine, Cyclocarya paliurus (Batal.) Iljinskaja leaves are traditionally widely used in the treatment of metabolic disorders. The vegetable Momordica charantia L. has been consumed worldwide for thousands of years as a traditional drug due to its activities against obesity and diabetes. In view of the therapeutic value of Momordica saponins (MSs) and C. paliurus polysaccharides (CPPs), an independently developed MSs- and CPPs-containing beverage (MC) was evaluated for its efficacy in controlling oxidative stress and obesity in Caenorhabditis elegans. RESULTS: First, we found that MC could promote the nuclear localization of DAF-16 and the translation of SOD-3. Further exploring its antioxidant properties, the oxidative stress by-products reactive oxygen species, malondialdehyde, and nonesterified fatty acids were significantly inhibited in C. elegans. Moreover, damage due to diseases related to oxidative stress (age pigments and neurodegenerative diseases) was alleviated. Furthermore, fat accumulation was significantly reduced in normal and high-fat models. Finally, the lipid-lowering effects of MC might involve reductions in the size and number of lipid droplets without impairing basic physiological functions in C. elegans. CONCLUSION: These results provide promising data indicating MC as an innovative health beverage for the pharmacological management of oxidative stress and obesity. © 2020 Society of Chemical Industry.

Antistress and anti-aging activities of Caenorhabditis elegans were enhanced by Momordica saponin extract.

BACKGROUND: Momordica saponin extract (MSE) was found to not only improve longevity and neuroprotection but also alleviate fat accumulation in Caenorhabditis elegans in our previous study. However, the lipid-lowering activity of MSE alone could not fully explain its ability to improve health, so the antistress effects of MSE were further studied. METHODS: Using C. elegans as an in vivo animal, the lifespan of MSE-treated C. elegans under various stressors (H2O2, paraquat and heat) and normal conditions was studied. Furthermore, the antioxidant activities of MSE were discussed. To study the underlying mechanisms, the expression of stress resistance genes and the resistance of related mutants to H2O2 stress were tested. RESULTS: MSE significantly improved the lifespan of C. elegans under stress and normal conditions. Meanwhile, the mobility of C. elegans was also improved. Moreover, the activities of SOD and CAT and the ratio of GSH/GSSG were elevated. Consistently, the levels of ROS and lipid oxidation (the NEFA and MDA content) were reduced. Furthermore, MSE treatment upregulated the expression of the sod-3, sod-5, clt-1, clt-2, hsp-16.1 and hsp-16.2 genes. All biomarkers indicated that the antistress and anti-aging activities of MSE were due to its strong antioxidant activities. Finally, MSE induced nuclear DAF-16::GFP localization. Studies with mutants revealed that skn-1 and hsf-1 were involved in the activity of MSE, which might upregulate the expression of downstream stress-responsive genes. CONCLUSIONS: Therefore, in addition to its lipid-lowering property, the ability of MSE to improve healthspan was also attributed to the stress resistance effect. Together, MSE might serve as a lead nutraceutical in geriatric research.

Anti-fat effect and mechanism of polysaccharide-enriched extract from Cyclocarya paliurus (Batal.) Iljinskaja in Caenorhabditis elegans.

Obesity is a global epidemic. Recent studies have shown that Cyclocarya paliurus (C. paliurus) leaves have the potential to alleviate fat deposits. However, the fat-reducing mechanism of it remains unclear. Using Caenorhabditis elegans (C. elegans) as a model, we found that C. paliurus polysaccharide (CPP) significantly decreased fat storage in both normal and high-fat worms without affecting the movement. Moreover, the size and number of lipid droplets were reduced in CPP-treated ZXW618 worms. In energy metabolism, CPP decreased Escherichia coli (E. coli) OP50 growth and pharyngeal pumping and increased the expression of vit-2. In lipid metabolism, CPP down-regulated the expression of the sbp-1 and nhr-49 genes by modulating mdt-15 to prevent the expression of the Δ9-desaturase genes (fat-5, fat-6 and fat-7). Meanwhile, the expression of the acs-2 genes, the downstream of nhr-49, was suppressed by CPP. These findings provided insights into the CPP-induced anti-fat mechanisms, which contributed to the application of CPP in anti-obesity drugs.

Healthspan Improvements in Caenorhabditis elegans with Traditional Chinese Herbal Tea.

Searching for natural and safe herbal tea with health benefits has attracted more and more attention, which is of great significance for reducing disease risk. A Chinese traditional herbal tea (HT) is rich in active ingredients extracted from natural plants. Numerous pharmacological studies showed that HT had the potential to improve health, including antidepression and antioxidant effects. In this study, we proposed a strategy to explore the role and underlying mechanism of HT in improving healthspan of a Caenorhabditis elegans model. First, we found that HT significantly prolonged the lifespan without reducing fertility in worms. Second, stress resistance (oxidative stress and heat stress) was enhanced and Aß- and polyQ-induced toxicity was relieved significantly by HT treatment. Both fat deposition and age pigment accumulation were found to be significantly reduced in HT-treated worms. The locomotion in mid-late stages was improved, indicating that behavioral mobility was also significantly enhanced. Furthermore, the main components of HT were eighteen polyphenols and two terpenoids. Finally, it was found that this protective mechanism was positively correlated with the insulin/insulin-like growth factor signaling- (IIS-) dependent manner, which went through promoting the nuclear localization of DAF-16 and its downstream SOD-3 expression. These results suggested that HT had an important role in improving health, which might serve as a promising healthy tea.

Polysaccharide extracted from the leaves of Cyclocarya paliurus (Batal.) Iljinskaja enhanced stress resistance in Caenorhabditis elegans via skn-1 and hsf-1.

Cyclocarya paliurus polysaccharide (CPP) has many beneficial biological activities. Although the antioxidant activity of CPP is well-known, the stress tolerance and underlying mechanism of the activities of CPP have not been determined in vivo. In this study, we applied the emerging model of Caenorhabditis elegans (C. elegans) to observe that CPP imparted stronger resistance to stress than the positive control Astragalus polysaccharide (H2O2- and paraquat-induced oxidative stress, as well as heat stress) without threatening the growth and reproduction of worms. Further studies found that CPP-treated worms had a strong antioxidant defense system that downregulated peroxidation products (ROS, MDA, NEFAs and GSSG) and upregulated antioxidant enzymes and nonenzymatic activities (SOD, CAT, GSH-Px and GSH). The CPP-treated worms also exhibited improved physiological functions, such as inhibition of age pigment and improvement of lifespan, mobility and neuroprotection. Further exploration of the mechanism of action of CPP treatment suggested that increased resistance to CPP might activate stress-inducible genes (sod-3, sod-5, ctl-1, ctl-2, hsp-16.1 and hsp-16.2) via skn-1 and hsf-1, rather than daf-16. These findings suggest that CPP may have health benefits for humans.

Mechanism of Pentagalloyl Glucose in Alleviating Fat Accumulation in Caenorhabditis elegans.

Pentagalloyl glucose (PGG) has been studied for its valuable biological activities. However, the functional role of PGG in lipid metabolism in vivo is unclear. Here, we investigated the effects of PGG on lipid metabolism and its underlying mechanism in Caenorhabditis elegans. PGG decreased the accumulation of reactive oxygen species at 800 µM and remarkably increased the activities of antioxidant enzymes. PGG decreased significantly fat accumulation in wild-type worms (39.7 ± 5.7% in the normal group and 19.9 ± 4.5% in the high-fat group by Oil red O; 21.2 ± 2.7% in the high-fat group by Nile red; p < 0.001), but fat reduction by PGG was eliminated in the skn-1 mutant. The amount and size of lipid droplets in the ZXW618 mutant were decreased by PGG. The proportions of unsaturated fatty acids in both conditions were increased by PGG. In addition, the expression levels of fat metabolism genes were significantly changed in both conditions by PGG, which include mdt-15, pod-2, elo-2, fat-6, and fat-7 genes modulated fat synthesis; aak-2 and nhr-49 genes participated in fat consumption; and tub-1 gene regulated fat storage. However, fat-5 and acs-2 were downregulated in high-fat worms only, and vit-2 and lipl-4 were downregulated in normal worms only. Our study provided new insights into the role of PGG in alleviating fat accumulation and its underlying mechanism of action in C. elegans.

Carnosol Improved Lifespan and Healthspan by Promoting Antioxidant Capacity in Caenorhabditis elegans.

Carnosol, a phenolic diterpene, is one of the main constituents of Rosmarinus. It is known to possess a range of bioactivities, including antioxidant, anticancer, antimicrobial, and anti-inflammatory properties. Nevertheless, the antiaging effects of carnosol have received little attention. This study first indicated that carnosol increased the healthspan of Caenorhabditis elegans (C. elegans). First, compared with the control condition, carnosol treatment effectively decreased ROS accumulation under normal or oxidative stress condition, significantly increased several key antioxidant enzyme activities, and significantly decreased MDA content. Second, carnosol effectively prolonged lifespan under normal and stress conditions and slowed aging-related declines, including mobility, age pigmentation, and neurodegenerative disease, but had no effect on fertility and fat deposition. Finally, carnosol-mediated longevity required the upregulated expression of sod-3, sod-5, hsf-1, hsp-16.1, and hsp-16.2 and was dependent on the hsf-1 gene. Increased DAF-16 translocation was observed, but daf-16 was independent of the effects on lifespan induced by carnosol. These results suggested that carnosol might serve as a good source of natural antioxidants, and in particular, carnosol could be explored as a potential dietary supplement to slow aging.

Rosmarinic acid improved antioxidant properties and healthspan via the IIS and MAPK pathways in Caenorhabditis elegans.

Rosmarinic acid (RA) has a wide range of biological effects, including the antioxidation and antiaging. However, the detailed mechanisms remain unclear but highly attractive. Herein, RA promoted lifespan and motoricity in a dose-dependent manner, and reduced fat store without threatening fertility in Caenorhabditis elegans. In term of antioxidant efficacy, catalase activity, glutathione peroxidas activity, reduced glutathione content, and reduced glutathione/oxidized glutathione ratio were enhanced. And malondialdehyde content was diminished significantly. Moreover, RA increased survival under acute oxidative and thermal stress, and suppressed intestinal lipofuscin accumulation. So the improvement of lifespan mediated by RA could be related with its strong antioxidant properties. Furthermore, RA was absorbed by worms. Further research in pursuit of the mechanism showed that longevity induced by RA was involved with the genes sod-3, sod-5, ctl-1, daf-16, ins-18, skn-1, and sek-1, but was independent of subcellular localization of DAF-16. These findings indicated that RA had a potential for promoting healthy lifespan.

Effects of Momordica saponin extract on alleviating fat accumulation in Caenorhabditis elegans.

Momordica saponins have diverse biological activities and are widely used to improve obesity. Here, we investigated the alleviation of fat accumulation and mechanism of action of the saponin-enriched ethanol extract from Momordica charantia (MSE) in Caenorhabditis elegans (C. elegans). First, MSE had a strong fat-reduction capacity in normal and high-fat worms. Second, MSE significantly increased the proportion of small lipid droplets and reduced the average particle size in ZXW618. Meanwhile, it improved lifespan and healthspan and physiological functions, such as age pigmentation and neuroprotection. Furthermore, MSE mediated fat reduction gets involved neither in energy intake nor in energy expenditure. Finally, MSE might down-regulate sbp-1 and nhr-49 via mdt-15, and up regulate age-1 via daf-2. And these targets genes together down-regulated the expression of fat-5, fat-6 and fat-7 to decrease fat accumulation. Our results provided new insights into the inhibition of fat accumulation and underlying mechanisms of Momordica saponins in C. elegans, which might be developed into a nutraceutical to ameliorate obesity.

Effects on longevity extension and mechanism of action of carnosic acid in Caenorhabditis elegans.

The beneficial effects of carnosic acid (CA) on health in terms of antioxidative, anti-inflammatory, antibacterial, anti-cancer and neuroprotective properties have long been recognized. However, the role of CA in aging remains unknown. In the present study, we examined the effects on longevity extension, as well as the mechanism of action, of CA in Caenorhabditis elegans (C. elegans). The results suggest that CA increased the lifespan of C. elegans. Meanwhile, CA was absorbed by the worms and promoted the healthspan of C. elegans by improving the mobility, reducing the accumulation of age pigment, delaying Aß-induced and polyQ-dependent paralysis and increasing the resistance to heat and oxidative stress. In terms of the mechanism underlying the longevity extension induced by CA, the beneficial effects were associated with the increased expression of SOD-3 but not with ROS scavenging activity. The CA-mediated longevity extension involved the upregulating of the expression of the skn-1, sek-1, sod-5, hsf-1, hsp-16.1 and hsp-16.2 genes but acted independently of the insulin/insulin-like growth factor signaling (IIS) pathway. Furthermore, CA treatment had no impact on the lifespan of skn-1 and hsf-1 mutants, confirming that mitogen-activated protein kinase (MAPK) and heat-shock transcription factor-1 (HSF-1) pathways were associated with the longevity mechanism of CA. These findings contribute to our knowledge of the lifespan extension and underlying mechanism of action of CA in C. elegans.