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Cell Death and Differentiation Jul 2023Curcumin, a natural phytochemical isolated from tumeric roots, represents a candidate for prevention and therapy of colorectal cancer/CRC. However, the exact mechanism...
Curcumin, a natural phytochemical isolated from tumeric roots, represents a candidate for prevention and therapy of colorectal cancer/CRC. However, the exact mechanism of action and the downstream mediators of curcumin's tumor suppressive effects have remained largely unknown. Here we used a genetic approach to determine the role of the p53/miR-34 pathway as mediator of the effects of curcumin. Three isogenic CRC cell lines rendered deficient for the p53, miR-34a and/or miR-34b/c genes were exposed to curcumin and subjected to cell biological analyses. siRNA-mediated inhibition and ectopic expression of NRF2, as well as Western blot, qPCR and qChIP analyses of its target genes were performed. CRC cells were i.v. injected into NOD/SCID mice and lung-metastases formation was determined by longitudinal, non-invasive imaging. In CRC cells curcumin induced apoptosis and senescence, and suppressed migration and invasion in a p53-independent manner. Curcumin activated the KEAP1/NRF2/ARE pathway by inducing ROS. Notably, curcumin induced miR-34a and miR-34b/c expression in a ROS/NRF2-dependent and p53-independent manner. NRF2 directly induced miR-34a and miR-34b/c via occupying multiple ARE motifs in their promoter regions. Curcumin reverted repression of miR-34a and miR-34b/c induced by IL6 and hypoxia. Deletion of miR-34a and miR-34b/c significantly reduced curcumin-induced apoptosis and senescence, and prevented the inhibition of migration and invasion by curcumin or ectopic NRF2. In CRC cells curcumin induced MET and prevented the formation of lung-metastases in mice in a miR-34a-dependent manner. In addition, we found that curcumin may enhance the therapeutic effects of 5-FU on CRC cells deficient for p53 and miR-34a/b/c. Activation of the KEAP1/NRF2/miR-34a/b/c axis mediates the tumor suppressive activity of curcumin and suggests a new approach for activating miR-34 genes in tumors for therapeutic purposes.
Topics: Animals; Mice; Cell Line, Tumor; Colorectal Neoplasms; Curcumin; Gene Expression Regulation, Neoplastic; Kelch-Like ECH-Associated Protein 1; Lung Neoplasms; Mice, Inbred NOD; Mice, SCID; MicroRNAs; NF-E2-Related Factor 2; Reactive Oxygen Species; Tumor Suppressor Protein p53
PubMed: 37210578
DOI: 10.1038/s41418-023-01178-1 -
Cell Feb 2024Behavior relies on activity in structured neural circuits that are distributed across the brain, but most experiments probe neurons in a single area at a time. Using...
Behavior relies on activity in structured neural circuits that are distributed across the brain, but most experiments probe neurons in a single area at a time. Using multiple Neuropixels probes, we recorded from multi-regional loops connected to the anterior lateral motor cortex (ALM), a circuit node mediating memory-guided directional licking. Neurons encoding sensory stimuli, choices, and actions were distributed across the brain. However, choice coding was concentrated in the ALM and subcortical areas receiving input from the ALM in an ALM-dependent manner. Diverse orofacial movements were encoded in the hindbrain; midbrain; and, to a lesser extent, forebrain. Choice signals were first detected in the ALM and the midbrain, followed by the thalamus and other brain areas. At movement initiation, choice-selective activity collapsed across the brain, followed by new activity patterns driving specific actions. Our experiments provide the foundation for neural circuit models of decision-making and movement initiation.
Topics: Brain; Movement; Neurons; Thalamus; Memory
PubMed: 38306983
DOI: 10.1016/j.cell.2023.12.035 -
Sports Medicine (Auckland, N.Z.) Jul 2023The use of dynamic stretching as a replacement for static stretching in the warm-up is widespread based on the reports of static stretching-induced performance... (Review)
Review
The use of dynamic stretching as a replacement for static stretching in the warm-up is widespread based on the reports of static stretching-induced performance impairments. While acute and chronic static stretching has been reported to reduce musculotendinous injuries, especially with explosive and change of direction actions, the influence of dynamic stretching on injury incidence lacks a similar volume of literature for acute and chronic responses. It was the objective of this narrative review to examine the acute and training effects of dynamic stretching on injury incidence and possible moderating variables such as dynamic stretching effects on range of motion, strength, balance, proprioception, muscle morphology, and psycho-physiological responses. One study demonstrated no significant difference regarding injury incidence when comparing a dynamic stretching-only group versus a combined dynamic stretching plus static stretching group. The only other study examined functional dynamic stretching training with injured dancers and reported improved ankle joint stability. However, several studies have shown that dynamic activity with some dynamic stretching exercises within a warm-up consistently demonstrates positive effects on injury incidence. Regarding moderating variables, while there is evidence that an acute bout of dynamic stretching can enhance range of motion, the acute and training effects of dynamic stretching on strength, balance, proprioception, and musculotendinous stiffness/compliance are less clear. The acute effects of dynamic stretching on thixotropic effects and psycho-physiological responses could be beneficial for injury reduction. However, the overall conflicting studies and a lack of substantial literature compared with SS effects points to a need for more extensive studies in this area.
Topics: Humans; Muscle Stretching Exercises; Incidence; Athletic Performance; Range of Motion, Articular; Athletes; Risk Factors; Muscle, Skeletal
PubMed: 37162736
DOI: 10.1007/s40279-023-01847-8 -
Cellular & Molecular Biology Letters Nov 2023To investigate the mechanism of action of Srg3 in acute lung injury caused by sepsis.
OBJECTIVE
To investigate the mechanism of action of Srg3 in acute lung injury caused by sepsis.
METHODS
First, a sepsis-induced acute lung injury rat model was established using cecal ligation and puncture (CLP). RNA sequencing (RNA-seq) was used to screen for highly expressed genes in sepsis-induced acute lung injury (ALI), and the results showed that Srg3 was significantly upregulated. Then, SWI3-related gene 3 (Srg3) was knocked down using AAV9 vector in vivo, and changes in ALI symptoms in rats were analyzed. In vitro experiments were conducted by establishing a cell model using lipopolysaccharide (LPS)-induced BEAS-2B cells and coculturing them with phorbol 12-myristate 13-acetate (PMA)-treated THP-1 cells to analyze macrophage polarization. Next, downstream signaling pathways regulated by Srg3 and transcription factors involved in regulating Srg3 expression were analyzed using the KEGG database. Finally, gain-of-loss functional validation experiments were performed to analyze the role of downstream signaling pathways regulated by Srg3 and transcription factors involved in regulating Srg3 expression in sepsis-induced acute lung injury.
RESULTS
Srg3 was significantly upregulated in sepsis-induced acute lung injury, and knocking down Srg3 significantly improved the symptoms of ALI in rats. Furthermore, in vitro experiments showed that knocking down Srg3 significantly weakened the inhibitory effect of LPS on the viability of BEAS-2B cells and promoted alternative activation phenotype (M2) macrophage polarization. Subsequent experiments showed that Srg3 can regulate the activation of the NF-κB signaling pathway and promote ferroptosis. Specific activation of the NF-κB signaling pathway or ferroptosis significantly weakened the effect of Srg3 knockdown. It was then found that Srg3 can be transcriptionally activated by interferon regulatory factor 7 (Irf7), and specific inhibition of Irf7 significantly improved the symptoms of ALI.
CONCLUSIONS
Irf7 transcriptionally activates the expression of Srg3, which can promote ferroptosis and activate classical activation phenotype (M1) macrophage polarization by regulating the NF-κB signaling pathway, thereby exacerbating the symptoms of septic lung injury.
Topics: Animals; Rats; Acute Lung Injury; Ferroptosis; Interferon Regulatory Factor-7; Lipopolysaccharides; NF-kappa B; Sepsis; Transcription Factors
PubMed: 37946128
DOI: 10.1186/s11658-023-00495-0 -
Pharmacological Reports : PR Dec 2023Psychedelics are compounds acting by serotonin 5-hydroxytryptamine (5-HT) receptor activation and induce several behavioral responses. They are of special interest... (Review)
Review
Psychedelics are compounds acting by serotonin 5-hydroxytryptamine (5-HT) receptor activation and induce several behavioral responses. They are of special interest because of their positive effects on neuropsychiatric disorders (depression and posttraumatic stress disorder). However, several findings revealed that some psychedelic actions are similar to symptoms observed in schizophrenia (psychosis, sensorimotor gating impairments, attention, and working memory deficits) which might limit their clinical applications. Psychedelics activate some neurotransmitters, i.e., serotonergic, and glutamatergic, that are also impaired in schizophrenia. Therefore, the neurobiological background of psychedelics and schizophrenia is partially similar. Another important aspect to discuss is the perspective of using psychedelics in schizophrenia therapy. Postmortem studies showed a loss of synapses in schizophrenia, and the positive effects of psychedelics on neuroplasticity (synaptogenesis, neurogenesis, and neuritogenesis) might be essential in the context of schizophrenia therapy. However, because of psychedelics' psychotic action, the recommended doses of psychedelics in schizophrenia treatment are not established, and subpsychedelic dosing or microdosing are considered. Exploratory studies are needed to determine the tolerability of treatment and appropriate dosing regimen. Another therapeutic option is using non-hallucinogenic psychedelic analogs that also induce neuroplastic outcomes but do not have psychotogenic effects. Further preclinical and clinical studies are needed to recognize the potential effectiveness of 5-HT agonists in schizophrenia therapy.
Topics: Humans; Hallucinogens; Schizophrenia; Serotonin; Psychotic Disorders; Memory, Short-Term
PubMed: 37899392
DOI: 10.1007/s43440-023-00546-5 -
Redox Biology Jul 2023Exercise physiology has gained increasing interest due to its wide effects to promote health. Recent years have seen a growth in this research field also due to the... (Review)
Review
Exercise physiology has gained increasing interest due to its wide effects to promote health. Recent years have seen a growth in this research field also due to the finding of several circulating factors that mediate the effects of exercise. These factors, termed exerkines, are metabolites, growth factors, and cytokines secreted by main metabolic organs during exercise to regulate exercise systemic and tissue-specific effects. The metabolic effects of exerkines have been broadly explored and entail a promising target to modulate beneficial effects of exercise in health and disease. However, exerkines also have broad effects to modulate redox signaling and homeostasis in several cellular processes to improve stress response. Since redox biology is central to exercise physiology, this review summarizes current evidence for the cross-talk between redox biology and exerkines actions. The role of exerkines in redox biology entails a response to oxidative stress-induced pathological cues to improve health outcomes and to modulate exercise adaptations that integrate redox signaling.
Topics: Health Promotion; Oxidation-Reduction; Oxidative Stress; Exercise; Homeostasis
PubMed: 37247469
DOI: 10.1016/j.redox.2023.102748 -
BMC Geriatrics Oct 2023Dementia is a growing health concern that affects millions of people worldwide. Gait and mobility disorders are often present and represent a major risk factor for... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Dementia is a growing health concern that affects millions of people worldwide. Gait and mobility disorders are often present and represent a major risk factor for falls. The purpose of this study was to investigate the effectiveness of tango-therapy in gait speed, functional mobility, balance, falls, ability to perform activities of daily living and quality of life.
METHODS
A randomised controlled trial with 31 participants living in a specialised dementia unit, aged 65 to 93 years old, who were randomly assigned to tango group (IG) or physical exercise group (CG). The primary outcome was gait speed and Timed Up and Go test. The secondary outcomes include the Short Physical Performance Battery, the ability to perform activities of daily living (Katz Index) and quality of life (Quality of life in Alzheimer Disease). Measurements were performed at baseline, and after one and three months of training.
RESULTS
After 3 months, IG improved gait speed (p = 0.016), implying a statistically significant difference between groups in favour of IG (p = 0.003). CG significantly worsened the time to complete the TUG (p = 0.039). Both groups declined in their ability to perform activities of daily living, being statistically significant only in the CG (p < 0.001).
CONCLUSION
Tango interventions showed efficacy in improving gait speed and in mitigating the decline in functional mobility and ADL skill capacities. Allowing older people with dementia access to non-pharmacological interventions may be a successful strategy to prevent functional decline.
TRIAL REGISTRATION
Registered at ClinicalTrials.gov (ID: NCT05744011).
Topics: Humans; Aged; Aged, 80 and over; Activities of Daily Living; Postural Balance; Quality of Life; Time and Motion Studies; Exercise; Gait; Alzheimer Disease; Exercise Therapy
PubMed: 37875856
DOI: 10.1186/s12877-023-04342-x