Streptococcus mutans activates the AIM2, NLRP3 and NLRC4 inflammasomes in human THP-1 macrophages

Streptococcus mutans(S. mutans), a major aetiologic agent of dental caries, is involved in systemic diseases, such as bacterial endocarditis, if it enters the bloodstream through temporary bacteraemia. Interleukin(IL)-1β, a proinflammatory cytokine, is related to the host defences against pathogens, and its synthesis, maturation, and secretion are tightly regulated by the activation of the inflammasome, an inflammatory signalling complex. This study examined the signalling mechanism of IL-1β secretion and the inflammasome pathway induced by S. mutans to explain the molecular mechanism through which systemic infection by oral streptococci can occur. After infection of THP-1 cells with S. mutans, the expression of inflammasome components was detected using various methods. S. mutans induced IL-1β secretion via caspase-1 activation, and S. mutans-induced IL-1β secretion required absent in melanoma(AIM2), NLR family pyrin domain-containing 3(NLRP3) and NLR family CARD domain-containing 4(NLRC4)inflammasome activation. In particular, the S. mutans-induced NLRP3 inflammasome was mediated by adenosine triphosphate(ATP) release, potassium depletion and lysosomal damage. Our study provides novel insight into the innate immune response against S. mutans infection.

The hypoxia-inducible factor-1α activates ectopic production of fibroblast growth factor 23 in tumor-induced osteomalacia

Tumor-induced osteomalacia （TIO） is a rare paraneoplastic syndrome in which ectopic production of fibroblast growth factor 23 （FGF23） by non-malignant mesenchymal tumors causes phosphate wasting and bone fractures. Recent studies have implicated the hypoxia-inducible factor-la （HIF-la） in other phosphate wasting disorders caused by elevated FGF23, including X-linked hypophosphatemic rickets and autosomal dominant hypophosphatemia. Here we provide evidence that HIF-la mediates aberrant FGF23 in TIO by transcriptionally activating its promoter. Immunohistochemical studies in phosphaturic mesenchymal tumors resected from patients with documented TIO showed that HIF-la and FGF23 were co-localized in spindle- shaped cells adjacent to blood vessels. Cultured tumor tissue produced high levels of intact FGF23 and demonstrated increased expression of HIF-la protein. Transfection of MC3T3-E1 and Saos-2 cells with a HIF-la expression construct induced the activity of a FGF23 reporter construct. Prior treatment of tumor organ cultures with HIF-la inhibitors decreased HIF-la and FGF23 protein accumulation and inhibited HIF-la-induced luciferase reporter activity in transfected cells. Chromatin immunoprecipitation assays confirmed binding to a HIF-la consensus sequence within the proximal FGF23 promoter, which was eliminated by treatment with a HIF-la inhibitor. These results show for the first time that HIF-la is a direct transcriptional activator of FGF23 and suggest that upregulation of HIF-la activity in TIO contributes to the aberrant FGF23 production in these patients.

Novel heat shock protein Hsp70L1 activates dendritic cells and acts as a Th1 polarizing adjuvant

Heat shock proteins (HSPs) are reported to act as effective adjuvants to elicit anti-tumor and anti-infection immunity. Here, we report that Hsp70-like protein 1 (Hsp70L1), a novel HSP derived from human dendritic cells (DCs), has potent adjuvant effects that polarize responses toward Th1. With a calculated molecular weight of 54.8 kDa, Hsp70L1 is smaller in size than Hsp70 but resembles it both structurally and functionally. Hsp70L1 shares common receptors on DCs with Hsp70 and can interact with DCs, promoting DC maturation and stimulating secretion of the proinflammatory cytokines interleukin 12p70 (IL-12p70), IL-1beta, tumor necrosis factor-alpha (TNF-alpha), and the chemokines IP-10, macrophage inflammatory protein-1alpha (MIP-1alpha), MIP-1beta, and normal T cell expressed and secreted (RANTES). The induction of interferon-gamma-inducible protein 10 (IP-10) secretion by Hsp70L1 is not shared by Hsp70, and other functional differences include more potent stimulation of DC IL-12p70, CC-chemokine, and CCR7 and CXCR4 expression by Hsp70L1. Immunization of mice with the hybrid peptide Hsp70L1-ovalbumin(OVA)(257-264) induces an OVA(257-264)-specific Th1 response and cytotoxic T lymphocyte (CTL) that results in significant inhibition of E.G7-OVA tumor growth. The ability of Hsp70L1 to activate DCs indicates its potential as a novel adjuvant for use with peptide immunizations; the Hsp70L1 antigen peptide hybrid may serve as a more effective vaccine for the control of cancer and infectious diseases.

Orthodontic tooth separation activates the hypothalamic area in the human brain

OBJECTIVES： An animal experiment clarified that insertion of an orthodontic apparatus activated the trigeminal neurons of the medulla oblongata. Orthodontic tooth movement is known to be associated with the sympathetic nervous system and controlled by the nucleus of the hypothalamus. However, the transmission of both has not been demonstrated in humans. The purpose of this study were to examine the activated cerebral areas using brain functional magnetic resonance imaging（MRI）, when orthodontic tooth separators were inserted, and to confirm the possibility of the transmission route from the medulla oblongata to the hypothalamus.METHODS： Two types of alternative orthodontic tooth separators（brass contact gauge and floss） were inserted into the right upper premolars of 10 healthy volunteers. Brain functional T2＊-weighted images and anatomical T1-weighted images were taken.RESULTS： The blood oxygenation level dependent（BOLD） signals following insertion of a brass contact gauge and floss significantly increased in the somatosensory association cortex and hypothalamic area.CONCLUSION： Our findings suggest the possibility of a transmission route from the medulla oblongata to the hypothalamus.

Prosaposin ablation inactivates the MAPK and Akt signaling pathways and interferes with the development of the prostate gland

<abstract>The recent development of a prosaposin -/- mouse model has allowed the investigation of the role of prosaposin in the development of the male reproductive organs. A morphometric analysis of the male reproductive system of 37 days old mice revealed that prosaposin ablation produced a 30 % reduction in size and weight of the testes, 37 % of the epididymis, 75 % of the seminal vesicles and 60 % of the prostate glands. Light microscopy (LM) showed that smaller testis size from homozygous mutant mice was associated with reduced spermiogenesis. Both, dorsal and ventral lobules of the prostate glands were underdeveloped in the homozygous mutant. LM analysis also showed that prostatic alveoli were considerably smaller and lined by shorter epithelial cells in the homozygous mutant. Smaller tubular diameter and shorter undifferentiated epithelial cells were also observed in seminal vesicles and epididymis. In the efferent ducts of the homozygous mutant mice, the epithelium was composed exclusively of ciliated cells in contrast to the heterozygotes, which showed the presence of nonciliated cells. Radioimmunoassays demonstrated that testosterone levels were normal or higher in mice with the inactivated prosaposin gene. Immunostaining of prostate sections with an anti-androgen receptor antibody showed that the epithelial cells lining the alveoli express androgen receptor in both the heterozygous and homozygous tissue. Similarly, sections immunostained with antibodies to the phosphorylated MAPKs and Akts strongly reacted with tall prostatic secretory cells in prostate from heterozygous mouse. On the other hand, the epithelial cells in the homozygous prostate remained unstained or weakly stained. These findings demonstrate that inactivation of the prosaposin gene affected the development of the prostate gland and some components of the MAPK pathway. 63 )

Leptin Activates STAT3 and ERK1/2 Pathways and Induces Endometrial Cancer Cell Proliferation

Obesity is an established risk factor for endometrial cancer.Leptin,a secreted protein of the ob gene by white adipose tissue,plays an important role in the regulation of food intake and energy consumption in the brain and acts as a potential growth stimulator in normal and neoplastic cancer cells.However,a direct role for leptin in endometrial cancer has not been demonstrated.In the present study,the effect of leptin on the proliferation of Ishikawa endometrial cancer cells was investigated as well as the possible mechanism（s） underlying this action in endometrial cancers which express both short and long isoforms of leptin receptors.The expression of leptin receptor（ObRb） in Ishikawa cells was detected by RT-PCR and Western blotting.The cells after serum starvation,were treated by leptin with various concentrations（0,10,50,100,150 ng/mL） for different durations（6,12,24 h）.The effect of leptin treatment on cell proliferation was examined by MTT assay.Meanwhile,inhibitory effect of Janus tyrosine kinase 2（JAK2）/signal transducer and activator of transcription 3（STAT3） inhibitor AG490 or extracellular signal-regulated kinase 1/2（ERK1/2） inhibitor PD98059 on the proliferation of Ishikawa cells induced by leptin was also studied.Ishikawa cells were treated with 100 ng/mL leptin for various periods（0,20,40,60 min）,and the levels of STAT3 phosphorylation and ERK1/2 phosphorylation were examined by Western blotting.The results showed that leptin induced the phosphorylation of STAT3 and the activation of ERK1/2 in a time-and dose-dependent manner in the Ishikawa endometrial cancer cells.Blocking STAT3 phosphorylation with the inhibitor AG490,or blocking ERK1/2 activation by the specific ERK1/2 kinase inhibitor,PD98059,abolished leptin-induced proliferation of Ishikawa cells.In addition,leptin was found to potently induce the invasion of endometrial cancer cells in a Matrigel invasion assay.Leptin-stimulated invasion was effectively blocked by pharmacological inhibitors of STAT3（AG490） and ERK1/2 kinase（PD98059）.These results suggested that leptin promotes endometrial cancer growth and invasiveness by activating STAT3 and ERK1/2 signaling pathways and therefore blocking its action at the receptor level can be a rational therapeutic strategy.

Atorvastatin activates autophagy and promotes neurological function recovery after spinal cord injury

Atorvastatin, a lipid-lowering medication, provides neuroprotective effects, although the precise mechanisms of action remain unclear. Our previous studies confirmed activated autophagy following spinal cord injury, which was conducive to recovery of neurological functions. We hypothesized that atorvastatin could also activate autophagy after spinal cord injury, and subsequently improve recovery of neurological functions. A rat model of spinal cord injury was established based on the Allen method. Atorvastatin（5 mg/kg） was intraperitoneally injected at 1 and 2 days after spinal cord injury. At 7 days post-injury, western blot assay, reverse transcription-polymerase chain reaction, and terminal deoxynucleotidyl transferase-mediated dU TP nick-end labeling（TUNEL） staining results showed increased Beclin-1 and light chain 3B gene and protein expressions in the spinal cord injury ＋ atorvastatin group. Additionally, caspase-9 and caspase-3 expression was decreased, and the number of TUNEL-positive cells was reduced. Compared with the spinal cord injury ＋ saline group, Basso, Beattie, and Bresnahan locomotor rating scale scores significantly increased in the spinal cord injury ＋ atorvastatin group at 14–42 days post-injury. These findings suggest that atorvastatin activated autophagy after spinal cord injury, inhibited apoptosis, and promoted recovery of neurological function.

Caprylic Acid Improves Lipid Metabolism, Suppresses the Inflammatory Response and Activates the ABCA1/p-JAK2/pSTAT3 Signaling Pathway in C57BL/6J Mice and RAW264.7 Cells

Objective This study aimed to investigate the effects of caprylic acid(C8:0)on lipid metabolism and inflammation,and examine the mechanisms underlying these effects in mice and cells.Methods Fifty-six 6-week-old male C57BL/6J mice were randomly allocated to four groups fed a highfat diet(HFD)without or with 2%C8:0,palmitic acid(C16:0)or eicosapentaenoic acid(EPA).RAW246.7 cells were randomly divided into five groups:normal,lipopolysaccharide(LPS),LPS+C8:0,LPS+EPA and LPS+cAMP.The serum lipid profiles,inflammatory biomolecules,and ABCA1 and JAK2/STAT3 mRNA and protein expression were measured.Results C8:0 decreased TC and LDL-C,and increased the HDL-C/LDL-C ratio after injection of LPS.Without LPS,it decreased TC in mice(P<0.05).Moreover,C8:0 decreased the inflammatory response after LPS treatment in both mice and cells(P<0.05).Mechanistic investigations in C57BL/6J mouse aortas after injection of LPS indicated that C8:0 resulted in higher ABCA1 and JAK2/STAT3 expression than that with HFD,C16:0 and EPA,and resulted in lower TNF-α,NF-κB mRNA expression than that with HFD(P<0.05).In RAW 264.7 cells,C8:0 resulted in lower expression of pNF-κBP65 than that in the LPS group,and higher protein expression of ABCA1,p-JAK2 and p-STAT3 than that in the LPS and LPS+cAMP groups(P<0.05).Conclusion Our studies demonstrated that C8:0 may play an important role in lipid metabolism and the inflammatory response,and the mechanism may be associated with ABCA1 and the p-JAK2/p-STAT3 signaling pathway.

Magnesium incorporation activates perovskite cobaltites toward efficient and stable electrocatalytic oxygen evolution

Cobalt-rich perovskite oxides play a paramount role in catalyzing oxygen evolution reaction(OER)on account of their acceptable intrinsic activity but are still challenging due to the high costs and undesired stability.In response to the defects,herein,the Mg-incorporated perovskite cobaltite SrCo_(0.6)Fe_(0.3M)g_(0.1)O_(3-δ)(SCFM-0.1)is proposed as a novel earth-abundant and durable OER electrocatalyst.A well-consolidated cubic-symmetry structure and more active oxygen intermediates are enabled upon Mg substitution.Hence,the optimized SCFM-0.1 perovskite oxide achieves prominent OER electrocatalytic performance,that is,a low overpotential of only 320 mV at 10 mA cm^(-2),a small Tafel slope of 65 mV dec^(-1),as well as an outstanding durability within 20 h,substantially outperforming that of the pristine SrCo_(0.7)Fe_(0.3)O_(3-δ)and benchmark Ba_(0.5)Sr_(0.5)Co_(0.8)Fe_(0.2)O_(3-δ)and IrO_(2) catalysts.The strong pHdependent behavior associated with lattice oxygen activation mechanism for SCFM-0.1 catalyst is also confirmed.This work paves a unique avenue to develop cost-effective and robust perovskite cobaltites for efficient OER electrocatalysis.

Makeup Activates Brain Activity in Visually Impaired Persons: Evaluation by Functional Magnetic Resonance Imaging

Cosmetics are used to improve physical appearance, but the benefits may be limited to people without visual impairment. The importance of attractiveness among blind persons has not been assessed. We investigated the influence of makeup on brain activity of blind persons using functional magnetic resonance imaging (fMRI). Participants were 7 blind females (BFs) who learned to fully apply makeup and 9 mostly age-matched normally sighted females (NSFs). Brain activity was measured using fMRI before and after application of makeup and during a makeup image task in each state. In the default mode network at rest, there was no difference between the BFs and NSFs. However, a lateral visual network to the opposite side was observed in the NSFs, whereas no such network was noted in the BFs. A weak network was noted in the BFs in the occipital fusiform gyrus and temporal occipital fusiform cortex, and an extensive visual area network defect was noted. Also, activity after makeup application was significantly higher in the nucleus accumbens, pallidum, and hippocampus. Activity in the right middle cingulate gyrus, right cerebral white matter, and right anterior cingulate gyrus was higher before makeup in both BFs and NSFs, and the activity was significantly higher and more extensive in the BFs. In conclusion, applying makeup is a personally rewarding activity, even for BFs, as it strongly activates the reward system and the reward/memory system network, even in the absence of a visual area network.

Piezoelectricity activates persulfate for water treatment:A perspective

Advanced oxidation processes(AOPs)utilizing persulfate(PS)offer great potential for wastewater treatment.Yet,the dependency on energy and chemical-intensive activation techniques,such as ultraviolet radiation and transition metal ions,constrains their widespread adoption.Recognizing this limitation,researchers are turning towards the piezoelectric effectda novel,energy-efficient method for PS activation that capitalizes on the innate piezoelectric characteristics of materials.Intriguingly,this method taps into weak renewable mechanical forces omnipresent in nature,ranging from wind,tides,water flow,sound,and atmospheric forces.In this perspective,we delve into the burgeoning realm of piezoelectric/PS-AOPs,elucidating its fundamental principles,the refinement of piezoelectric materials,potential mechanical force sources,and pertinent application contexts.This emerging technology harbors significant potential as a pivotal element in wastewater pretreatment and may spearhead innovations in future water pollution control engineering.

PABP-driven secondary condensed phase within RSV inclusion bodies activates viral mRNAs for ribosomal recruitment

Inclusion bodies(IBs)of respiratory syncytial virus(RSV)are formed by liquid-liquid phase separation(LLPS)and contain internal structures termed“IB-associated granules”(IBAGs),where anti-termination factor M2-1 and viral mRNAs are concentrated.However,the mechanism of IBAG formation and the physiological function of IBAGs are unclear.Here,we found that the internal structures of RSV IBs are actual M2-1-free viral messenger ribonucleoprotein(mRNP)condensates formed by secondary LLPS.Mechanistically,the RSV nucleoprotein(N)and M2-1 interact with and recruit PABP to IBs,promoting PABP to bind viral mRNAs transcribed in IBs by RNArecognition motif and drive secondary phase separation.Furthermore,PABP-eIF4G1 interaction regulates viral mRNP condensate composition,thereby recruiting specific translation initiation factors(eIF4G1,eIF4E,eIF4A,eIF4B and eIF4H)into the secondary condensed phase to activate viral mRNAs for ribosomal recruitment.Our study proposes a novel LLPS-regulated translation mechanism during viral infection and a novel antiviral strategy via targeting on secondary condensed phase.

Glutamatergic CYLD deletion leads to aberrant excitatory activity in the basolateral amygdala:association with enhanced cued fear expression

Neuronal activity,synaptic transmission,and molecular changes in the basolateral amygdala play critical roles in fear memory.Cylindromatosis(CYLD)is a deubiquitinase that negatively regulates the nuclear factor kappa-B pathway.CYLD is well studied in non-neuronal cells,yet underinvestigated in the brain,where it is highly expressed.Emerging studies have shown involvement of CYLD in the remodeling of glutamatergic synapses,neuroinflammation,fear memory,and anxiety-and autism-like behaviors.However,the precise role of CYLD in glutamatergic neurons is largely unknown.Here,we first proposed involvement of CYLD in cued fear expression.We next constructed transgenic model mice with specific deletion of Cyld from glutamatergic neurons.Our results show that glutamatergic CYLD deficiency exaggerated the expression of cued fear in only male mice.Further,loss of CYLD in glutamatergic neurons resulted in enhanced neuronal activation,impaired excitatory synaptic transmission,and altered levels of glutamate receptors accompanied by over-activation of microglia in the basolateral amygdala of male mice.Altogether,our study suggests a critical role of glutamatergic CYLD in maintaining normal neuronal,synaptic,and microglial activation.This may contribute,at least in part,to cued fear expression.

Neuroinflammation revisited through the microglial lens

Neuroimmunology is emerging as a pivotal field,shedding light on the intricate dialogues between the central nervous system(CNS)and the immune system.This exploration is particularly significant in understanding microglia,the CNS’s innate immune cells,beyond the conventional conflation of“neuroinflammation”and“microglial activation.”This conflation has clouded the true complexity of these processes,potentially stalling scientific progress and the development of new therapies.We challenge the long-standing perspectives that have oversimplified these interactions,advocating for a deeper exploration of the dynamic relationship between neuroinflammation and microglial activation.By dissecting specific molecular pathways,we aim to illuminate their elaborate roles in neuroinflammatory responses,especially in the context of Alzheimer’s disease(AD).Here,neuroinflammation is not merely a passive observer or a direct antagonist but a complex agent in the disease’s progression.This article calls for a significant paradigm shift towards an integrative,multi-omics approach to neuroimmunology.Adopting such a comprehensive framework is crucial for advancing our understanding of neuroinflammatory conditions and paving the way for targeted therapeutic strategies for brain diseases.

Tuning beneficial calcineurin phosphatase activation to counterα-synuclein toxicity in a yeast model of Parkinson’s disease

Calcineurin(CN)is a calcium-and calmodulindependent serine/threonine that has been studied in many model organisms including yeast,filamentous fungi,plants,and mammals.Its biological functions range from ion homeostasis and virulence in lower eukaryotes to T-cell activation in humans by human nuclear factors of activated T-cells.CN is a heterodimeric protein consisting of a catalytic subunit,calcineurin A(Cna1p),which contains an active site with a dinuclear metal center,and a regulatory Ca^(2+) binding subunit called calcineurin B(Cnb1p)required to activate Cna1p.The calcineurin B subunit has been highly conserved through evolution:For example,the mammalian calcineurin B shows 54%identity with calcineurin B from Saccharomyces cerevisiae.

Lighting the shades of hidden pain:a role for spinal cord neurons and microglia in vestibulodynia

Vulvodynia,a chronic pain disorder affecting the vulvar region,represents a significant challenge in both diagnosis and treatment within the field of women’s health.This condition is characterized by chronic pain that significantly affects the quality of life of afflicted women.The present perspective paper examines the role of spinal sensitization and microglial activation in vulvodynia.

An Efficient Boron Source Activation Strategy for the Low‑Temperature Synthesis of Boron Nitride Nanotubes

Lowering the synthesis temperature of boron nitride nanotubes(BNNTs)is crucial for their development.The primary reason for adopting a high temperature is to enable the effective activation of highmelting-point solid boron.In this study,we developed a novel approach for efficiently activating boron by introducing alkali metal compounds into the conventional MgO–B system.This approach can be adopted to form various low-melting-point AM–Mg–B–O growth systems.These growth systems have improved catalytic capability and reactivity even under low-temperature conditions,facilitating the synthesis of BNNTs at temperatures as low as 850℃.In addition,molecular dynamics simulations based on density functional theory theoretically demonstrate that the systems maintain a liquid state at low temperatures and interact with N atoms to form BN chains.These findings offer novel insights into the design of boron activation and are expected to facilitate research on the low-temperature synthesis of BNNTs.

HPV18 DNA replication inactivates the early promoter P_(55) activity and prevents viral E6 expression

Dear Editor,Human papillomaviruses(HPV)are a large group(>200genotypes)of small double-stranded DNA viruses(https://pave.niaid.nih.gov/).Although infections by most HPV types are asymptomatic,persistent infections in cervical and ano-genital epithelia by high-risk

Decoding molecular mechanisms:brain aging and Alzheimer's disease

The complex morphological,anatomical,physiological,and chemical mechanisms within the aging brain have been the hot topic of research for centuries.The aging process alters the brain structure that affects functions and cognitions,but the worsening of such processes contributes to the pathogenesis of neurodegenerative disorders,such as Alzheimer's disease.Beyond these observable,mild morphological shifts,significant functional modifications in neurotransmission and neuronal activity critically influence the aging brain.Understanding these changes is important for maintaining cognitive health,especially given the increasing prevalence of age-related conditions that affect cognition.This review aims to explore the age-induced changes in brain plasticity and molecular processes,differentiating normal aging from the pathogenesis of Alzheimer's disease,thereby providing insights into predicting the risk of dementia,particularly Alzheimer's disease.

Microglia:a promising therapeutic target in spinal cord injury

Microglia are present throughout the central nervous system and are vital in neural repair,nutrition,phagocytosis,immunological regulation,and maintaining neuronal function.In a healthy spinal cord,microglia are accountable for immune surveillance,however,when a spinal cord injury occurs,the microenvironment drastically changes,leading to glial scars and failed axonal regeneration.In this context,microglia vary their gene and protein expression during activation,and proliferation in reaction to the injury,influencing injury responses both favorably and unfavorably.A dynamic and multifaceted injury response is mediated by microglia,which interact directly with neurons,astrocytes,oligodendrocytes,and neural stem/progenitor cells.Despite a clear understanding of their essential nature and origin,the mechanisms of action and new functions of microglia in spinal cord injury require extensive research.This review summarizes current studies on microglial genesis,physiological function,and pathological state,highlights their crucial roles in spinal cord injury,and proposes microglia as a therapeutic target.