Associations Between Brain-Gut Axis and Psychological Distress in Fibromyalgia: A Microbiota and Magnetic Resonance Imaging Study.

An altered brain-gut axis is suspected to be one of the pathomechanisms in fibromyalgia (FM). This cross-sectional study investigated the associations among altered microbiota, psychological distress, and brain functional connectivity (FC) in FM. We recruited 25 FM patients and 25 healthy people in the present study. Psychological distress was measured using standardized questionnaires. Microbiota analysis was performed on the participants' stools. Functional magnetic resonance imaging data were acquired, and seed-based resting-state FC (rs-FC) analysis was conducted with the salience network nodes as seeds. Linear regression and mediation analyses evaluated microbiota, symptoms, and rs-FCs associations. We found altered microbiota diversity in FM, of which Phascolarctobacterium and Lachnoclostridium taxa increased the most and Faecalibacterium taxon decreased the most compared to controls. The Phascolarctobacterium abundance significantly predicted Beck depression inventory (BDI-II) scores in FM (ß = 6.83; P = .033). Rs-FCs from salience network nodes were reduced in FM, of which rs-FCs from the right lateral rostral prefrontal cortex (RPFC) to the lateral occipital cortex, superior division right (RPFC-sLOC) could be predicted by BDI-II scores in patients (ß = -.0064; P = .0054). In addition, the BDI-II score was a mediator in the association between Phascolarctobacterium abundance and rs-FCs of RPFC-sLOC (ab = -.06; 95% CI: -.16 to -9.10-3). In conclusion, microbial dysbiosis might be associated with altered neural networks mediated by psychological distress in FM, emphasizing the critical role of the brain-gut axis in FM's non-pain symptoms and supporting further analysis of mechanism-targeted therapies to reduce FM symptoms. PERSPECTIVE: Our study suggests microbial dysbiosis might be associated with psychological distress and the altered salience network, supporting the role of brain-gut axis dysfunction in fibromyalgia pathomechanisms. Further targeting therapies for microbial dysbiosis should be investigated to manage fibromyalgia patients in the future.

Integrins and Actions of Androgen in Breast Cancer.

Androgen has been shown to regulate male physiological activities and cancer proliferation. It is used to antagonize estrogen-induced proliferative effects in breast cancer cells. However, evidence indicates that androgen can stimulate cancer cell growth in estrogen receptor (ER)-positive and ER-negative breast cancer cells via different types of receptors and different mechanisms. Androgen-induced cancer growth and metastasis link with different types of integrins. Integrin αvß3 is predominantly expressed and activated in cancer cells and rapidly dividing endothelial cells. Programmed death-ligand 1 (PD-L1) also plays a vital role in cancer growth. The part of integrins in action with androgen in cancer cells is not fully mechanically understood. To clarify the interactions between androgen and integrin αvß3, we carried out molecular modeling to explain the potential interactions of androgen with integrin αvß3. The androgen-regulated mechanisms on PD-L1 and its effects were also addressed.

Intranasal administration of Lactobacillus johnsonii attenuates hyperoxia-induced lung injury by modulating gut microbiota in neonatal mice.

BACKGROUND: Supplemental oxygen impairs lung development in newborn infants with respiratory distress. Lactobacillus johnsonii supplementation attenuates respiratory viral infection in mice and exhibits anti-inflammatory effects. This study investigated the protective effects of intranasal administration of L. johnsonii on lung development in hyperoxia-exposed neonatal mice. METHODS: Neonatal C57BL/6N mice were reared in either room air (RA) or hyperoxia condition (85% O2). From postnatal days 0 to 6, they were administered intranasal 10 µL L. johnsonii at a dose of 1 × 105 colony-forming units. Control mice received an equal volume of normal saline (NS). We evaluated the following four study groups: RA + NS, RA + probiotic, O2 + NS, and O2 + probiotic. On postnatal day 7, lung and intestinal microbiota were sampled from the left lung and lower gastrointestinal tract, respectively. The right lung of each mouse was harvested for Western blot, cytokine, and histology analyses. RESULTS: The O2 + NS group exhibited significantly lower body weight and vascular density and significantly higher mean linear intercept (MLI) and lung cytokine levels compared with the RA + NS and RA + probiotic groups. At the genus level of the gut microbiota, the O2 + NS group exhibited significantly higher Staphylococcus and Enterobacter abundance and significantly lower Lactobacillus abundance compared with the RA + NS and RA + probiotic groups. Intranasal L. johnsonii treatment increased the vascular density, decreased the MLI and cytokine levels, and restored the gut microbiota in hyperoxia-exposed neonatal mice. CONCLUSIONS: Intranasal administration of L. johnsonii protects against hyperoxia-induced lung injury and modulates the gut microbiota.

Plasmon-activated water as a therapeutic strategy in Alzheimer's disease by altering gut microbiota.

Gut microbiota (GM) are involved in the pathophysiology of Alzheimer's disease (AD) and might correlate to the machinery of the gut-brain axis. Alteration of the GM profiles becomes a potential therapy strategy in AD. Here, we found that plasmon-activated water (PAW) therapy altered GM profile and reduced AD symptoms in APPswe/PS1dE9 transgenic mice (AD mice). GM profile showed the difference between AD and WT mice. PAW therapy in AD mice altered GM profile and fecal microbiota transplantation (FMT) reproduced GM profile in AD mice. PAW therapy and FMT in AD mice reduced cognitive decline and amyloid accumulation by novel object recognition (NOR) test and amyloid PET imaging. Immunofluorescent staining and western blot analysis of ß-amyloid (Aß) and phosphorylated (p)-tau in the brain of AD mice were reduced in PAW therapy and FMT. The inflammatory markers, interleukin (IL)-6, IL-1ß, and tumor necrosis factor (TNF)-α and pro-inflammatory indicator of arginase-1/CD86 ratio were also reduced. Furthermore, immunohistochemistry (IHC) analysis of occludin and claudin-5 in the intestine and AXL in the brain were increased to correlate with the abundant GM in PAW therapy and FMT. Our results showed the machinery of gut-brain axis, and PAW might be a potential therapeutic strategy in AD.

Exploration of anti-leukemic effect of soft coral-derived 13-acetoxysarcocrassolide: Induction of apoptosis via oxidative stress as a potent inhibitor of heat shock protein 90 and topoisomerase II.

13-Acetoxysarcocrassolide (13-AC) is a marine cembranoid derived from the aquaculture soft coral of Lobophytum crassum. The cytotoxic effect of 13-AC against leukemia cells was previously reported but its mechanism of action is still unexplored. In the current study, we showed that 13-AC induced apoptosis of human acute lymphoblastic leukemia Molt4 cells, as evidenced by the cleavage of PARP and caspases, phosphatidylserine externalization, as well as the disruption of mitochondrial membrane potential. The use of N-acetylcysteine (NAC), a reactive oxygen species (ROS) scavenger, attenuated the cytotoxic effect induced by 13-AC. Molecular docking and thermal shift assay indicated that the cytotoxic mechanism of action of 13-AC involved the inhibition of heat shock protein 90 (Hsp 90) activity by eliciting the level of Hsp 70 and topoisomerase IIα in Molt4 cells. 13-AC also exhibited potent antitumor activity by reducing the tumor volume (48.3%) and weight (72.5%) in the in vivo Molt4 xenograft mice model. Our findings suggested that the marine cembranoid, 13-AC, acted as a dual inhibitor of Hsp 90 and topoisomerase IIα, exerting more potent apoptotic activity via the enhancement of ROS generation.

Modulatory Effects of Heat-Inactivated Streptococcus Thermophilus Strain 7 on the Inflammatory Response: A Study on an Animal Model with TLR3-Induced Intestinal Injury.

Rotavirus infections result in severe gastroenteritis with a detrimental inflammatory response in the intestine. Because probiotics have an anti-inflammatory effect and can modulate the gut microbiota profile, they can be used as a biotherapy for inflammatory intestinal diseases. In this study, we isolated Streptococcus thermophilus strain 7 (ST7) from cow milk and examined the effect of heat-inactivated ST7 on the intestinal histopathological score, inflammatory cytokine levels, T-cell activation and effector function, and microbiome profile in a mouse model with intestinal injury induced by polyinosinic-polycytidylic acid (poly I:C), a Toll-like receptor 3 agonist. The results indicated that ST7 treatment prevented weight loss and intestinal injury and prevented the upregulation of serum interleukin-6 (IL-6), tumor necrosis factor-α, and IL-15 levels in intestinal epithelial cells; prevented the upregulation of inflammation-associated Gammaproteobacteria and Alistipes; and increased the levels of Firmicutes in fecal microbiota after poly I:C stimulation. ST7 treatment also increased the serum interferon-γ (IFN-γ) level and promoted the expression of IFN-γ in both CD8 and CD4 T cells. In summary, ST7 prevented the inflammatory response, promoted the T-cell effector function, and modulated the microbiota profile of mice with poly I:C-induced small intestine injury.

Acute sleep deprivation exacerbates systemic inflammation and psychiatry disorders through gut microbiota dysbiosis and disruption of circadian rhythms.

Acute sleep deprivation (ASD) is often observed in shift workers and characterized by drowsiness and unrelenting exhaustion. The physiological and psychological effects of ASD include anxiety, depression, cognitive impairment, systemic inflammation, stress responses, and disruptions of gut microbiota. However, the mechanisms involved in the ASD-associated circadian dysregulations with regard to gut dysbiosis, systemic inflammation, physiological modulation, and psychiatry disorders remain unclear. The aim of this study was to investigate whether central nervous system disorders induced by ASD are related to inflammation, barrier dysfunction, and circadian dysregulation. We also assessed impacts on microbiota succession. Male C57BL/6 mice were randomly allocated to the control and sleep deprivation (SD) groups. Mice in the SD group were subjected to 72 h of paradoxical SD using the modified multiple-platform method for ASD induction (72 h rapid eye movement-SD). The effects of ASD on dietary consumption, behaviors, cytokines, microbiota, and functional genes were determined. The appetite of the SD group was significantly higher than that of the control group, but the body weight was significantly lower than that of the control group. The anxiety-like behaviors were found in the SD group. Alpha and beta diversity of microbiota showed significant decrease after ASD induction; the relative abundance of Candidatus_Arthromitus and Enterobacter was increased, whereas that abundance of Lactobacillus, Muribaculum, Monoglobus, Parasutterella, and others was decreased in the SD group. These effects were accompanied by reduction in fecal propionic acid. In the proximal colon, the SD group exhibited significantly higher inflammation (tumor necrosis factor-α [TNF-α]) and dysregulation of the circadian rhythms (brain and muscle ARNT-like 1 [BMAL1] and cryptochrome circadian regulator 1 [CRY1]) and tight junction genes (occludin [OCLN]) than the control group. Gut barrier dysfunction slightly increased the plasma concentration of lipopolysaccharide and significantly elevated TNF-α. Inflammatory signals might be transduced through the brain via TNF receptor superfamily member 1 A (TNFRSF1A), which significantly increased the levels of microglia activation marker (ionized calcium-binding adapter molecule 1 [IBA1]) and chemokine (intercellular adhesion molecule 1 [ICAM1]) in the cerebral cortex. The serotonin receptor (5-hydroxytryptamine 1A receptor [5-HT1AR]) was significantly downregulated in the hippocampus. In summary, 72 h of rapid eye movement-SD induced physiological and psychological stress, which led to disruption of the circadian rhythms and gut microbiota dysbiosis; these effects were related to decrement of short chain fatty acids, gut inflammation, and hyperpermeability. The microbiota may be utilized as preventive and therapeutic strategies for ASD from the perspectives of medicine and nutrition.

Rifaximin Modifies Gut Microbiota and Attenuates Inflammation in Parkinson's Disease: Preclinical and Clinical Studies.

Patients with Parkinson's disease (PD) exhibit distinct gut microbiota, which may promote gut-derived inflammation. Rifaximin is a nonabsorbable antibiotic that can modify gut microbiota. The present study investigated the effect of rifaximin on gut microbiota and inflammation status in PD. The study examined the effect of long-term rifaximin treatment on in vivo transgenic PD mice (MitoPark) and short-term rifaximin treatment on patients with PD. Rifaximin treatment caused a significant change in gut microbiota in the transgenic PD mice; in particular, it reduced the relative abundance of Prevotellaceae UCG-001 and increased the relative abundance of Bacteroides, Muribaculum, and Lachnospiraceae UCG-001. Rifaximin treatment attenuated serum interleukin-1ß, interleukin-6 and tumor necrosis factor-α, claudin-5 and occludin, which indicated the reduction of systemic inflammation and the protection of the blood-brain barrier integrity. The rifaximin-treated MitoPark mice exhibited better motor and memory performance than did the control mice, with lower microglial activation and increased neuronal survival in the hippocampus. In the patients with PD, 7-day rifaximin treatment caused an increase in the relative abundance of Flavonifractor 6 months after treatment, and the change in plasma proinflammatory cytokine levels was negatively associated with the baseline plasma interleukin-1α level. In conclusion, the present study demonstrated that rifaximin exerted a neuroprotective effect on the transgenic PD mice by modulating gut microbiota. We observed that patients with higher baseline inflammation possibly benefited from rifaximin treatment. With consideration for the tolerability and safety of rifaximin, randomized controlled trials should investigate the disease-modification effect of long-term treatment on select patients with PD.

Thyroid Hormone Induces Oral Cancer Growth via the PD-L1-Dependent Signaling Pathway.

Oral cancer is a fatal disease, and its incidence in Taiwan is increasing. Thyroid hormone as L-thyroxine (T4) stimulates cancer cell proliferation via a receptor on integrin αvß3 of plasma membranes. It also induces the expression of programmed death-ligand 1 (PD-L1) and cell proliferation in cancer cells. Thyroid hormone also activates ß-catenin-dependent cell proliferation in cancer cells. However, the relationship between PD-L1 and cancer proliferation is not fully understood. In the current study, we investigated the role of inducible thyroid hormone-induced PD-L1-regulated gene expression and proliferation in oral cancer cells. Thyroxine bound to integrin αvß3 to induce PD-L1 expressions via activation of ERK1/2 and signal transducer and activator of transcription 3 (STAT3). Inactivated STAT3 inhibited PD-L1 expression and nuclear PD-L1 accumulation. Inhibition of PD-L1 expression reduced ß-catenin accumulation. Furthermore, nuclear PD-L1 formed a complex with nuclear proteins such as p300. Suppression PD-L1 expression by shRNA blocked not only expression of PD-L1 and ß-catenin but also signal transduction, proliferative gene expressions, and cancer cell growth. In summary, thyroxine via integrin αvß3 activated ERK1/2 and STAT3 to stimulate the PD-L1-dependent and ß-catenin-related growth in oral cancer cells.

Uteroplacental Insufficiency Causes Microbiota Disruption and Lung Development Impairment in Growth-Restricted Newborn Rats.

Preclinical studies have demonstrated that intrauterine growth retardation (IUGR) is associated with reduced lung development during the neonatal period and infancy. Uteroplacental insufficiency (UPI), affecting approximately 10% of human pregnancies, is the most common cause of IUGR. This study investigated the effects of UPI on lung development and the intestinal microbiota and correlations in newborn rats with IUGR, using bilateral uterine artery ligation to induce UPI. Maternal fecal samples were collected on postnatal day 0. On postnatal days 0 and 7, lung and intestinal microbiota samples were collected from the left lung and the lower gastrointestinal tract. The right lung was harvested for histological assessment and Western blot analysis. Results showed that UPI through bilateral uterine artery ligation did not alter the maternal gut microbiota. IUGR impaired lung development and angiogenesis in newborn rats. Moreover, on postnatal day 0, the presence of Acinetobacter and Delftia in the lungs and Acinetobacter and Nevskia in the gastrointestinal tract was negatively correlated with lung development. Bacteroides in the lungs and Rodentibacter and Romboutsia in the gastrointestinal tract were negatively correlated with lung development on day 7. UPI may have regulated lung development and angiogenesis through the modulation of the newborn rats' intestinal and lung microbiota.

2,3,5,4'-Tetrahydroxystilbene-2-O-ß-D-Glucoside improves female ovarian aging.

Reduced fertility associated with normal aging may reflect the over-maturity of oocytes. It is increasingly important to reduce aging-induced infertility since recent trends show people marrying at later ages. 2,3,5,4'-Tetrahydroxystilbene-2-O-ß-D-glucoside (THSG), a polyphenol extracted from Polygonum multiflorum, has been reported to have anti-inflammatory and anti-aging properties. To evaluate whether THSG can reduce aging-related ovarian damage in a female mouse model of aging, THSG was administered by gavage at a dose of 10 mg/kg twice weekly, starting at 4 weeks of age in a group of young mice. In addition, the effect of THSG in a group of aged mice was also studied in mice starting at 24 weeks of age. The number of oocytes in the THSG-fed group was higher than in the untreated control group. Although the percentage of secondary polar bodies (PB2) decreased during aging in the THSG-fed group, it decreased much more slowly than in the age-matched control group. THSG administration increased the quality of ovaries in young mice becoming aged. Western blotting analyses also indicated that CYP19, PR-B, and ER-ß expressions were significantly increased in 36-week-old mice. THSG also increased oocyte numbers in aged mice compared to mice without THSG fed. Studies of qPCR and immunohistochemistry (IHC) analyses of ovaries in the aged mice groups were conducted. THSG increased gene expression of anti-Müllerian hormone (AMH), a biomarker of oocyte number, and protein accumulation in 40-week-old mice. THSG increased the expression of pgc1α and atp6, mitochondrial biogenesis-related genes, and their protein expression. THSG also attenuated the fading rate of CYP11a and CYP19 associated with sex hormone synthesis. And THSG maintains a high level of ER-ß expression, thereby enhancing the sensitivity of estrogen. Our findings indicated that THSG increased or extended gene expression involved in ovarian maintenance and rejuvenation in young and aged mice. On the other hand, THSG treatments significantly maintained oocyte quantity and quality in both groups of young and aged mice compared to each age-matched control group. In conclusion, THSG can delay aging-related menopause, and the antioxidant properties of THSG may make it suitable for preventing aging-induced infertility.

KI Essence extract (a spleen-tonifying formula) promotes neurite outgrowth, alleviates oxidative stress and hypomyelination, and modulates microbiome in maternal immune activation offspring.

Mushrooms and Chinese traditional herbs have bioactive nutraceuticals with multiple therapeutic functions, including antioxidant and antibacterial activities and microbiome modulation properties. Mushroom-derived bioactive compounds are used in medicines for the treatment of neurological disorders with abnormal brain-gut-microbiome axis. This study examined the effects of KI Essence extract, a spleen-tonifying formula, on neurite growth, antioxidant activity, hypomyelination modulation, and the microbiome profile in lipopolysaccharide (LPS)-induced maternal immune activation (MIA) offspring. The KI Essence extract induced PC12 cell neurite growth by increasing extracellular signal-regulated kinase (ERK) phosphorylation, promoting 2,2'-diphenyl-1-picrylhydrazyl radical scavenging activity, reducing the level of tert-butylhydroperoxide-induced lipid peroxidation in brain homogenates, protecting PC12 cells from H2O2-induced cell death (through the inhibition of ERK phosphorylation), alleviating hypomyelination, and downregulating interleukin-1ß through LPS-activated microglia production; moreover, the numbers of Enterobacteriaceae, Actinobacteria, Peptostreptococcaceae, Erysipelotrichaceae, and Bifidobacterium bacteria in MIA offspring increased. In summary, the KI Essence extract promotes neurite outgrowth, alleviates oxidative stress and hypomyelination, and modulates microbiota dysbiosis in MIA offspring.

The power of heteronemin in cancers.

Heteronemin (Haimian jing) is a sesterterpenoid-type natural marine product that is isolated from sponges and has anticancer properties. It inhibits cancer cell proliferation via different mechanisms, such as reactive oxygen species (ROS) production, cell cycle arrest, apoptosis as well as proliferative gene changes in various types of cancers. Recently, the novel structure and bioactivity evaluation of heteronemin has received extensive attention. Hormones control physiological activities regularly, however, they may also affect several abnormalities such as cancer. L-Thyroxine (T4), steroid hormones, and epidermal growth factor (EGF) up-regulate the accumulation of checkpoint programmed death-ligand 1 (PD-L1) and promote inflammation in cancer cells. Heteronemin suppresses PD-L1 expression and reduces the PD-L1-induced proliferative effect. In the current review, we evaluated research and evidence regarding the antitumor effects of heteronemin and the antagonizing effects of non-peptide hormones and growth factors on heteronemin-induced anti-cancer properties and utilized computational molecular modeling to explain how these ligands interacted with the integrin αvß3 receptors. On the other hand, thyroid hormone deaminated analogue, tetraiodothyroacetic acid (tetrac), modulates signal pathways and inhibits cancer growth and metastasis. The combination of heteronemin and tetrac derivatives has been demonstrated to compensate for anti-proliferation in cancer cells under different circumstances. Overall, this review outlines the potential of heteronemin in managing different types of cancers that may lead to its clinical development as an anticancer agent.

Clinical significance and intestinal microbiota composition in immunocompromised children with norovirus gastroenteritis.

BACKGROUND: Norovirus (NoV) infection is common in pediatric patients with immunodeficiency and is more likely to cause severe disease. Objective Our study aims to figure out the clinical differences and distribution of intestinal microbiota in immunocompromised children with NoV gastroenteritis. METHODS: Pediatric patients admitted to Shang-Ho Hospital with diagnosis of acute gastroenteritis including different immune status were enrolled and their medical records were reviewed. NoV gastroenteritis was validated using RT-PCR molecular methods. Viral shedding period was determined by real-time RT-PCR assays. Intestinal microbiota enrichment analysis was carried out by next generation sequencing after fecal DNA extraction and subsequent Linear Discriminant Analysis (LDA) Effect Size (LEfSe) method. RESULTS: Significantly higher frequency of diarrhea [mean, (IQR), 3.8 (3-5) /day] and longer viral shedding time [mean, IQR, 8.5 (5-13) days] was found in immunocompromised NoV infections than in immunocompetent patients without NoV infections (p = 0.013*) and immunocompetent patients with NoV infections (p = 0.030**). The fever prevalence was significantly lower in immunocompromised NoV infections than in different immune or infection status. Intestinal microbiota metagenomics analysis showed no significant community richness difference while the LEfSe analysis showed a significant difference in commensal richness at the phylum level, the family level, and the genus level in patients under different immune status. CONCLUSION: We evaluated the clinical significances and microbiota composition in immunocompromised children with norovirus gastroenteritis. This will further facilitate studies of the interaction between the intestinal microbiota in such patients with precise determination of their bacterial infection control and probiotic supplements strategy.

Endurance exercise ameliorates Western diet-induced atherosclerosis through modulation of microbiota and its metabolites.

The World Health Organization determined cardiovascular disease to be the leading cause of death globally; atherosclerosis is the primary cause of the high morbidity and mortality rates. Regular physical activity is an effective strategy for maintaining endothelial health and function to prevent the development of atherosclerosis. Obesity is also a crucial risk factor for atherosclerotic progression in combination with various complications and systemic inflammation. Physiological homeostasis is modulated by the intestinal microbiota, but the mechanisms through which exercise attenuates atherosclerosis through the microbiota have not been elucidated. Therefore, we investigated the effects of endurance exercise on atherosclerosis induced by a Western diet (WD) and apolipoprotein E (ApoE) knockout in terms of microbiota parameters and metabolites. Genetically modified ApoE knockout mice (C57BL/6-Apoeem1Narl/Narl, ApoEKO) and wild-type mice (C57BL6/J) were divided into the following four groups (n = 6), namely, wild-type mice fed a chow diet (WT CD), ApoEKO mice fed a chow diet (ApoE CD), ApoEKO mice fed a WD (ApoE WD), and ApoEKO mice fed a WD and performing endurance exercise (ApoE WD EX), for a 12-week intervention. The WD significantly induced obesity and atherosclerotic syndrome in the ApoE WD group. Severe atherosclerotic lesions and arterial thickness were significantly elevated and accompanied by increases in VCAM-1, MCP-1, TNF-α, and IL-1ß for immune cell chemotaxis and inflammation during atherosclerotic pathogenesis in the ApoE WD group. In addition, dysbiosis in the ApoE WD group resulted in the lowest short-chain fatty acid (SCFA) production. Endurance exercise intervention (ApoE WD EX) significantly alleviated atherosclerotic syndrome by reducing obesity, significantly inhibiting VCAM-1, MCP-1, TNF-α, and IL-1ß expression, and increasing the production of SCFAs. Modulation of the microbiota associated with inflammation, such as Desulfovibrio, Tyzzerella, and Lachnospiraceae_ge, and increased SCFA production, particularly through an abundance of Rikenellaceae and Dubosiella, were also observed after exercise intervention. Endurance exercise can alleviate WD-induced atherosclerosis through the amelioration of obesity, inflammation, and chemotaxis signaling, which are modulated by the microbiota and derived SCFAs.

Role of Integrin αvß3 in Doxycycline-Induced Anti-Proliferation in Breast Cancer Cells.

Doxycycline, an antibiotic, displays the inhibition of different signal transduction pathways, such as anti-inflammation and anti-proliferation, in different types of cancers. However, the anti-cancer mechanisms of doxycycline via integrin αvß3 are incompletely understood. Integrin αvß3 is a cell-surface anchor protein. It is the target for estrogen, androgen, and thyroid hormone and plays a pivotal role in the proliferation, migration, and angiogenic process in cancer cells. In our previous study, thyroxine hormones can interact with integrin αvß3 to activate the extracellular signal-regulated kinase 1/2 (ERK1/2), and upregulate programmed death-ligand 1 (PD-L1) expression. In the current study, we investigated the inhibitory effects of doxycycline on proliferation in two breast cancer cell lines, MCF-7 and MDA-MB-231 cells. Doxycycline induces concentration-dependent anti-proliferation in both breast cancer cell lines. It regulates gene expressions involved in proliferation, pro-apoptosis, and angiogenesis. Doxycycline suppresses cell cyclin D1 (CCND1) and c-Myc which play crucial roles in proliferation. It also inhibits PD-L1 gene expression. Our findings show that modulation on integrin αvß3 binding activities changed both thyroxine- and doxycycline-induced signal transductions by an integrin αvß3 inhibitor (HSDVHK-NH2). Doxycycline activates phosphorylation of focal adhesion kinase (FAK), a downstream of integrin, but inhibits the ERK1/2 phosphorylation. Regardless, doxycycline-induced FAK phosphorylation is blocked by HSDVHK-NH2. In addition, the specific mechanism of action associated with pERK1/2 inhibition via integrin αvß3 is unknown for doxycycline treatment. On the other hand, our findings indicated that inhibiting ERK1/2 activation leads to suppression of PD-L1 expression by doxycycline treatment. Furthermore, doxycycline-induced gene expressions are disturbed by a specific integrin αvß3 inhibitor (HSDVHK-NH2) or a mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinases (ERK) kinase (MAPK/ERK, MEK) inhibitor (PD98059). The results imply that doxycycline may interact with integrin αvß3 and inhibits ERK1/2 activation, thereby regulating cell proliferation and downregulating PD-L1 gene expression in estrogen receptor (ER)-negative breast cancer MDA-MB-231 cells.

Heteronemin and tetrac derivatives suppress non-small cell lung cancer growth via ERK1/2 inhibition.

The most common cancer, lung cancer, causes deaths worldwide. Most lung cancer patients have non-small cell lung carcinomas (NSCLCs) with a poor prognosis. The chemotherapies frequently cause resistance therefore search for new effective drugs for NSCLC patients is an urgent and essential issue. Deaminated thyroxine, tetraiodothyroacetic acid (tetrac), and its nano-analogue (NDAT) exhibit antiproliferative properties in several types of cancers. On the other hand, the most abundant secondary metabolite in the sponge Hippospongia sp., heteronemin, shows effective cytotoxic activity against different types of cancer cells. In the current study, we investigated the anticancer effects of heteronemin against two NSCLC cell lines, A549 and H1299 cells in vitro. Combined treatment with heteronemin and tetrac derivatives synergistically inhibited cancer cell growth and significantly modulated the ERK1/2 and STAT3 pathways in A549 cells but only ERK1/2 in H1299 cells. The combination treatments induce apoptosis via the caspases pathway in A549 cells but promote cell cycle arrest via CCND1 and PCNA inhibition in H1299 cells. In summary, these results suggest that combined treatment with heteronemin and tetrac derivatives could suppress signal transduction pathways essential for NSCLC cell growth. The synergetic effects can be used potentially as a therapeutic procedure for NSCLC patients.

The Anti-Proliferative Activity of Secondary Metabolite from the Marine Streptomyces sp. against Prostate Cancer Cells.

Many active substances from marine organisms are produced by symbiotic microorganisms such as bacteria, fungi, and algae. Secondary metabolites from marine actinomycetes exhibited several biological activities and provided interesting drug leads. This study reported the isolation of Lu01-M, a secondary metabolite from the marine actinomycetes Streptomyces sp., with potent anti-proliferative activity against prostate cancers. Lu01-M blocked cell proliferation with IC50 values of 1.03 ± 0.31, 2.12 ± 0.38, 1.27 ± 0.25 µg/mL in human prostate cancer PC3, DU145, and LNCaP cells, respectively. Lu01-M induced cytotoxic activity through multiple mechanisms including cell apoptosis, necroptosis, autophagy, ER stress, and inhibiting colony formation and cell migration. Lu01-M induced cell cycle arrest at the G2/M phase and DNA damage. However, the activity of autophagy induced survival response in cancer cells. Our findings suggested that Lu01-M holds the potential to be developed as an anti-cancer agent against prostate cancers.

The Antileukemic Effect of Xestoquinone, A Marine-Derived Polycyclic Quinone-Type Metabolite, Is Mediated through ROS-Induced Inhibition of HSP-90.

Xestoquinone is a polycyclic quinone-type metabolite with a reported antitumor effect. We tested the cytotoxic activity of xestoquinone on a series of hematological cancer cell lines. The antileukemic effect of xestoquinone was evaluated in vitro and in vivo. This marine metabolite suppressed the proliferation of Molt-4, K562, and Sup-T1 cells with IC50 values of 2.95 ± 0.21, 6.22 ± 0.21, and 8.58 ± 0.60 µM, respectively, as demonstrated by MTT assay. In the cell-free system, it inhibited the activity of topoisomerase I (Topo I) and II (Topo II) by 50% after treatment with 0.235 and 0.094 µM, respectively. The flow cytometric analysis indicated that the cytotoxic effect of xestoquinone was mediated through the induction of multiple apoptotic pathways in Molt-4 cells. The pretreatment of Molt-4 cells with N-acetyl cysteine (NAC) diminished the disruption of the mitochondrial membrane potential (MMP) and apoptosis, as well as retaining the expression of both Topo I and II. In the nude mice xenograft model, the administration of xestoquinone (1 µg/g) significantly attenuated tumor growth by 31.2% compared with the solvent control. Molecular docking, Western blotting, and thermal shift assay verified the catalytic inhibitory activity of xestoquinone by high binding affinity to HSP-90 and Topo I/II. Our findings indicated that xestoquinone targeted leukemia cancer cells through multiple pathways, suggesting its potential application as an antileukemic drug lead.

Maternal Immune Activation Causes Social Behavior Deficits and Hypomyelination in Male Rat Offspring with an Autism-Like Microbiota Profile.

Maternal immune activation (MIA) increases the risk of autism spectrum disorder (ASD) in offspring. Microbial dysbiosis is associated with ASD symptoms. However, the alterations in the brain-gut-microbiota axis in lipopolysaccharide (LPS)-induced MIA offspring remain unclear. Here, we examined the social behavior, anxiety-like and repetitive behavior, microbiota profile, and myelination levels in LPS-induced MIA rat offspring. Compared with control offspring, MIA male rat offspring spent less time in an active social interaction with stranger rats, displayed more anxiety-like and repetitive behavior, and had more hypomyelination in the prefrontal cortex and thalamic nucleus. A fecal microbiota analysis revealed that MIA offspring had a higher abundance of Alistipes, Fusobacterium, and Ruminococcus and a lower abundance of Coprococcus, Erysipelotrichaies, and Actinobacteria than control offspring, which is consistent with that of humans with ASD. The least absolute shrinkage and selection operator (LASSO) method was applied to determine the relative importance of the microbiota, which indicated that the abundance of Alistipes and Actinobacteria was the most relevant for the profile of defective social behavior, whereas Fusobacterium and Coprococcus was associated with anxiety-like and repetitive behavior. In summary, LPS-induced MIA offspring showed an abnormal brain-gut-microbiota axis with social behavior deficits, anxiety-like and repetitive behavior, hypomyelination, and an ASD-like microbiota profile.