Preterm birth (PTB) remains a global health challenge, with atmospheric particulate matter (PM) exposure implicated as a modifiable risk factor. As major chemical components of PM, sulfate, nitrate, and ammonium (SNA) have been linked to PTB. However, discrepancies between epidemiological and toxicological evidence hinder understanding of SNA's health effects, therefore requiring a potential modulating factor to explain its biological impact. In this study, we propose aerosol acidity as a key modulator of PM bioactivity. In a Beijing birth cohort (2520 singleton pregnancies, November 1, 2022, and October 31, 2023), we assessed trimester-specific exposure to SNA and aerosol acidity. In addition, distributed lag models (DLMs) were applied to identify critical exposure windows and estimate odds ratios (ORs) for PTB risk. Our findings demonstrated significant trimester-specific effects of aerosol acidity on PTB risk. A 1-unit decrease in aerosol pH during the second-trimester exposure significantly increased PTB risk (adjusted OR = 1.54, 95% CI: 1.02-2.07). Weekly-specific analysis identified the 21st to 27th gestational weeks as the most susceptible window for aerosol acidity exposure, with elevated PTB risk observed in the late second trimester. These identified critical windows coincided with peak placental vascular remodeling. By bridging epidemiological-toxicological discrepancies, our findings establish aerosol acidity as a novel, actionable target for PTB prevention. We advocate integrating aerosol acidity metrics into air quality assessment and prioritizing SNA emission controls-the dominant acidity drivers in northern China-to protect vulnerable pregnancy windows.

Obstructive sleep apnea-hypopnea syndrome (OSAHS) is a common sleep disorder, but cognitive impairment occurs only in a subset of patients, indicating individual susceptibility. This study aimed to identify oral fluid-derived protein biomarkers potentially related to neurobehavioral vulnerability in OSAHS by integrating clinical and animal model data. Nineteen participants (13 OSAHS, 6 controls) provided gingival crevicular fluid; age, body mass index (BMI), and weight showed no significant differences, while OSAHS patients exhibited significantly higher Epworth Sleepiness Scale (ESS) scores, reflecting increased daytime sleepiness. Fourteen C57BL/6J mice were randomly assigned to chronic intermittent hypoxia or normoxia conditions for 12 weeks; behavioral performance was evaluated using open field and Y-maze tests, and oral fluid was collected for proteomic analysis. 4D-DIA profiling identified 225 human and 105 mouse differentially expressed proteins; enrichment analysis highlighted humoral immunity and complement pathways. Notably, FN1 and JCHAIN were consistently upregulated across species, with expression changes accompanied by behavioral alterations in CIH mice. This clinic-driven, cross-species experimental study revealed FN1 and JCHAIN as shared, upregulated proteins potentially linked to hypoxia-associated neurobehavioral vulnerability in OSAHS. Rather than broadly focusing on differential expression, the study highlights these two proteins as candidates for further mechanistic investigation and future biomarker validation in cognitively vulnerable OSAHS patients.

BackgroundBackgroundAlzheimer's disease (AD) is characterized by progressive cognitive decline and neuropsychiatric symptoms, including chronic neuropathic pain. However, the molecular mechanisms linking pain sensitivity to early AD pathology remain poorly understood.MethodsIn the present study, 4- to 5-month-old APP/PS1 mice were used to identify molecular signatures of the early pathological stage. Transcriptomic analysis, quantitative real-time RT-PCR (qRT-PCR), immunoblot, and ELISA analyses were performed to assess region-specific gene expression, neuroinflammation, and synaptic protein levels in pain-related regions.ResultsAlthough memory behaviors remained unchanged in 4–5-month-old APP/PS1 mice, these mice showed an increase in whole-brain Aβ plaque burden. Transcriptomic analysis and qRT-PCR revealed distinct region-specific gene expression changes. Plin4 was downregulated in the DRG, spinal cord, thalamus, and hippocampus of APP/PS1 mice. Rps3a3 and Prnp were significantly upregulated in both the spinal cord and thalamus, whereas Hif3a and Serpina3f were significantly upregulated in the thalamus and hippocampus. These gene alterations were closely involved in inflammatory responses and synaptic plasticity. Immunoblot and ELISA analyses in these pain-related regions demonstrated increased TNF-α and IL-1β levels, as well as reduced expression of synaptic proteins, indicating enhanced neuroinflammation and synaptic loss in the early stages of APP/PS1 mice.ConclusionThese findings support the presence of neuroinflammation and synaptic dysfunction in pain-processing circuits as early molecular events in APP/PS1 mice, suggesting that nociceptive alterations may represent an early feature of the pathological stage of AD.

Cognitive disorders and psychiatric pathologies, particularly Alzheimer’s disease (AD) and Major depressive disorder (MDD), represent a considerable health burden, impacting millions of people in the United States and worldwide. Notably, comorbidities of MDD and anxiety are prevalent in the early stages of mild cognitive impairment (MCI), which is the preceding phase of Alzheimer’s disease and related dementia (ADRD). The symptoms of MDD and anxiety affect up to 80% of individuals in the advanced stages of the neurodegenerative conditions. Despite overlapping clinical manifestations, the pathogenesis of AD/ADRD and MDD remains inadequately elucidated. Until now, dozens of drugs for treating AD/ADRD have failed in clinical trials because they have not proven beneficial in reversing or preventing the progression of these neuropsychiatric indications. This underscores the need to identify new drug targets that could reverse neuropsychiatric symptoms and delay the progress of AD/ADRD. In this context, phosphodiesterase 4 (PDE4) arises as a primary enzyme in the modulation of cognition and mood disorders, particularly through its enzymatic action on cyclic adenosine monophosphate (cAMP) and its downstream anti-inflammatory pathways. Despite the considerable cognitive and antidepressant potential of PDE4 inhibitors, their translation into clinical practice is hampered by profound side effects. Recent studies have focused on the effects of PDE4 and its subtype-selective isoform inhibitors, aiming to delineate their precise mechanistic contributions to neuropsychiatric symptoms with greater specificity. This review aims to analyze the current advances regarding PDE4 inhibition—specifically the selective targeting of its isoforms and elucidate the therapeutic implications of enhanced cAMP signaling and the consequent anti-inflammatory responses in ameliorating the symptomatology associated with AD and ADRD.

Cognitive impairment is a defining feature of neurodegenerative diseases such as Alzheimer's disease (AD) and vascular dementia (VaD). However, the pathogenesis of cognitive impairment remains unclear, mainly because it involves complex pathological processes in which multiple cytokines and pathways contribute to its progression. Among key molecular regulators, cyclic nucleotide phosphodiesterase 1 (PDE1), a Calcium/calmodulin (Ca²⁺/CaM) activated enzyme that regulates intracellular levels of cAMP and cGMP by degrading them to inactive forms. PDE1 may play a critical role in influencing cognitive function through modulating these second messengers. PDE1 integrates calcium fluctuations with cyclic nucleotide metabolism, affecting a series of events including synaptic plasticity, neuronal survival, vascular tone, and neuroinflammatory responses. This review summarizes the distribution of PDE1 and its isoforms, and their regulatory mechanisms and functional roles, particularly those of PDE1A, PDE1B, and PDE1C, in the central nervous system (CNS) disorders. We also discussed the involvement of PDE1 in modulating cAMP/PKA and cGMP/PKG signaling pathways, and its impact on oxidative stress, neuroinflammation, and apoptotic cascades associated with cognitive dysfunction. In addition, this review integrates current evidence on PDE1 isoforms in both neuronal and vascular regulation of cognition, emphasizing their dual neurovascular roles in cognitive impairment. We further summarized recent progress on PDE1 target validation and the reported efficacy of PDE1A inhibitors in alleviating memory deficits associated with neurodegenerative disorders, such as AD and VaD.

Background:Chronic alcohol use disorder (AUD) is recognized as one of the most critical risk factors for the progression of Alzheimer's disease (AD). Epigenetic and neuroimmune alterations are closely associated with the development of memory impairment related to AUD and AD. Methods:Adult APP/PS1 transgenic mice received intermittently intraperitoneal injections of ethanol (EtOH, 2.5 g/kg, i.p.) or vehicle with two "drug" treatment days, and one and two "drug-free" days every 7 days for 10 weeks. The novel object recognition (NOR) and Y-maze tests were performed to determine whether chronic ethanol treatment exacerbated memory impairment in these mice. The brain tissues were collected for pathological changes through MeRIP/RNA-sequence analyses and molecular biological assays. Results:The results suggested that chronic intermittent ethanol (CIE) treatment for 10 weeks exacerbated sporadic and spatial memory deficits in NOR and Y-maze tests in the APP/PS1 mice. The pathological assays revealed that CIE procedure increased Aβ plaque burden in the brain of the AD mice, which were consistent with memory behavioral deficits. The subsequent MeRIP/RNA sequence analyses showed that two genes, e.g. Rbm15b and Hnrnpa2b1, were related to N6-methyladenosine (m6A) methylation that plays an important role in the development of memory loss. These results were further supported by molecular biological and mRNA-microRNA-lncRNA ceRNA network analyses that demonstrated that the increased Rbm15b and decreased Hnrnpa2b1 were involved in synaptic dysfunction and neuroinflammation in CIE-induced memory impairment in these AD mice. Conclusions:The conclusion is drawn that m6A mediated epigenetic dysfunction and immune cells infiltration participate in chronic alcohol use disorder related memory loss in AD mice.

Cognitive disorders and psychiatric pathologies, particularly Alzheimer's disease (AD) and Major depressive disorder (MDD), represent a considerable health burden, impacting millions of people in the United States and worldwide. Notably, comorbidities of MDD and anxiety are prevalent in the early stages of mild cognitive impairment (MCI), which is the preceding phase of Alzheimer's disease and related dementia (ADRD). The symptoms of MDD and anxiety affect up to 80% of individuals in the advanced stages of the neurodegenerative conditions. Despite overlapping clinical manifestations, the pathogenesis of AD/ADRD and MDD remains inadequately elucidated. Until now, dozens of drugs for treating AD/ADRD have failed in clinical trials because they have not proven beneficial in reversing or preventing the progression of these neuropsychiatric indications. This underscores the need to identify new drug targets that could reverse neuropsychiatric symptoms and delay the progress of AD/ADRD. In this context, phosphodiesterase 4 (PDE4) arises as a primary enzyme in the modulation of cognition and mood disorders, particularly through its enzymatic action on cyclic adenosine monophosphate (cAMP) and its downstream anti-inflammatory pathways. Despite the considerable cognitive and antidepressant potential of PDE4 inhibitors, their translation into clinical practice is hampered by profound side effects. Recent studies have focused on the effects of PDE4 and its subtype-selective isoform inhibitors, aiming to delineate their precise mechanistic contributions to neuropsychiatric symptoms with greater specificity. This review aims to analyze the current advances regarding PDE4 inhibition-specifically the selective targeting of its isoforms and elucidate the therapeutic implications of enhanced cAMP signaling and the consequent anti-inflammatory responses in ameliorating the symptomatology associated with AD and ADRD.

Dysfunction of cyclic nucleotide phosphodiesterase 7 (PDE7) has been associated with excess intracellular cAMP concentrations, fueling pathogenic processes that are implicated in neurodegenerative disorders. This study aimed to develop a suitable positron emission tomography (PET) probe that allows noninvasive mapping of PDE7 in the mammalian brain. Based on a spiro cyclohexane-1,4'-quinazolinone scaffold with known inhibitory properties toward PDE7, we designed and synthesized a carbon-11 labeling tolerant methoxy analog. The resulting PET probe, code named [11C]-P7-2104 (27), was synthesized in high molar activities (170-220 GBq/μmol) with decay-corrected radiochemical yields of 34 ± 7%. In vitro cell uptake of [11C]27 was 6-7-fold higher in PDE7 overexpressing cells compared to the controls, whereas an in vitro specificity of up to 90% was measured. Ex vivo metabolite studies revealed a high fraction of intact parent in the rat brain (98% at 5 min and 75% at 30 min postinjection). Considerable brain penetration was further corroborated by ex vivo biodistribution and PET imaging studies, the latter showing heterogenic brain uptake. While marginal blockade was observed by PET studies in rodents, a moderate, but dose-dependent, blockade was observed in the non-human primate brain following pretreatment with nonradioactive 27. Accordingly, [11C]27 will serve as a valuable lead compound for the development of a new arsenal of PDE7-targeted probes.

It has been reported that long non-coding RNA (lncRNA) is closely related to tumor development and chemotherapy resistance. Cancer susceptibility candidate 15 (CASC15) is a cancer-related lncRNA located on chromosome 6p22.3 which is abnormally expressed in different malignant tumors. CASC15 is involved in a variety of biological processes, such as cell growth, migration and invasion. Various studies have shown that CASC15 is expected to become a novel biomarker and therapeutic target for cancer. In this review, we summarize the regulatory function and mechanism of CASC15 in malignant tumors, as well as its potential value in the diagnosis and treatment of tumors.

Long COVID is a poorly understood condition characterized by persistent symptoms following the acute phase of COVID-19, including fatigue, cognitive impairment, and joint pain. Acupuncture, a key component of traditional Chinese medicine treatment, has shown potential in alleviating long COVID symptoms. However, the molecular mechanisms underlying its therapeutic effects remain largely unknown. In this study, we employed bioinformatics approaches to explore the potential molecular mechanisms of acupuncture's therapeutic effects on long COVID symptoms. We screened protein targets of active ingredients produced by the body after acupuncture and identified potential therapeutic targets of long COVID. Protein-protein interaction networks were constructed, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to identify key targets and pathways. Our findings provide valuable insights into the potential molecular mechanisms of acupuncture's therapeutic effects on long COVID symptoms and may contribute to the development of targeted therapies for managing this challenging condition.

Cyclic adenosine monophosphates (cAMP) and cyclic guanosine monophosphate (cGMP) are two essential second messengers, which are hydrolyzed by phosphodiesterase's (PDEs), such as PDE-2. Pharmacological inhibition of PDE-2 (PDE2A) in the central nervous system improves cAMP and cGMP signaling, which controls downstream proteins related to neuropsychiatric, neurodegenerative, and neurodevelopmental disorders. Considering that there are no specific treatments for these disorders, PDE-2 inhibitors' development has gained more attention in the recent decade. There is high demand for developing new-generation drugs targeting PDE2 for treating diseases in the central nervous and peripheral systems. This review summarizes the relationship between PDE-2 with neuropsychiatric, neurodegenerative, and neurodevelopmental disorders as well as its possible treatment, mainly involving inhibitors of PDE2.

BackgroundAcid-sensing ion channels are activated during myocardial ischemia and are implicated in the mechanism of myocardial ischemia-reperfusion injury (MIRI). Acid-sensing ion channel 3 (ASIC3), the most pH-sensitive member of the ASIC family, is highly expressed in myocardial tissues. However, the role of ASIC3 in MIRI and its precise effects on the myocardial metabolome remain unclear. These unknowns might be related to the cardioprotective effects observed with APETx2 post-conditioning.MethodRat hearts subjected to Langendorff perfusion were randomly assigned to the normal (Nor) group, ischemia/reperfusion (I/R) group, ASIC3 blockade (AP) group. Rat hearts in group AP were treated with the ASIC3-specific inhibitor APETx2 (630 nM). Molecular and morphological changes were observed to elucidate the role of ASIC3 in MIRI. Bioinformatics analyses identified differential metabolites and pathways associated with APETx2 post-conditioning.ResultsAPETx2 post-conditioning stabilized hemodynamics in the isolated rat heart model of MIRI. It also reduced myocardial infarct size, mitigated mitochondrial damage at the ultrastructural level, and improved markers of myocardial injury and oxidative stress. Further more, we observed that phosphatidylcholine, phosphatidylethanolamine, citric acid, cyanidin 5-O-beta-D-glucoside, and L-aspartic acid decreased after MIRI. The levels of these metabolites were partially restored by APETx2 post-conditioning. These metabolites are primarily involved in autophagy and endogenous cannabinoid signaling pathways.ConclusionASIC3 is potentially a key player in MIRI. APETx2 post-conditioning may improve MIRI through specific metabolic changes. This study provides valuable data for future research on the metabolic mechanisms underlying the effects of APETx2 post-conditioning in MIRI.

OBJECTIVES:To investigate self-reported sleep duration, sleep timing, sleep status and influencing factors in the Chinese population.METHODS:This web-based cross-sectional survey was conducted in 2022, covering 31 provinces (91%) in China. 11,000 questionnaires were collected, of which 8970 were valid for analysis. Self-reported sleep habits, problems and quality were investigated. Good or fair sleep ratings, enough duration, regular, with no sleep disturbances and <30 min sleep latency was defined as a composite variable: 'Good sleep'. Factors influencing sleep patterns and 'Good sleep' were analyzed by multivariate logistic regression.RESULTS:Most participants sleep less than 7 h per night (55.13%), usually go to bed at 10-12 pm (47.99%), wake up at 6-8 am (49.86%), and take less than 30 min to fall asleep (66.30%) with regular sleep schedule (76.01%). Only 12.36% have 'Good sleep'. In the past 3 months, 46.80% of the participants reported symptoms of insomnia, and 21.54% had snoring problems. Among the adults, the young, males, college students, freelancers, and those who resided in urban areas and pandemic-free areas slept later, and the northerners woke up earlier. The adults with low-moderate and moderate income and the minors at elementary and middle school slept earlier and woke up earlier. Mid-aged adults who often napped at noon were more likely to have 'Good sleep' than any other age group, and urban dwellers with the same habit were more likely to have 'Good sleep' than people dwelled in other regions. While people who slept late, woke up too early or too late, slept too little or too much, resided at GMT 7-8 area or pandemic area, had high income, or took up some occupations (entrepreneurs/individuals, professionals, manual and non-manual workers, housewives) were less likely to get a 'Good sleep'.CONCLUSIONS:The national survey provided a sleep profile of the Chinese population. Both socio-economic status and personal sleep hygiene habits had an impact on 'Good sleep'.

This paper proposes a sound field separation technique based on the time-domain equivalent method for real-time separating the pressure field belonging to every source from the unsteady rotating loading multi-source sound field. In the proposed method, the transfer relationship between the mixed time-dependent pressure and the equivalent unsteady rotating forces is first established. Then, all the equivalent unsteady rotating forces are solved via time-domain inversion procedure. Finally, the corresponding equivalent unsteady rotating forces distributed on one interested source are used to calculate the pressure field generated by that source alone. Numerical simulations with four unsteady point forces rotating at different speeds around two different axes examine the validity of the proposed method. Keywords: Multiple unsteady loading sources rotating at different speeds around different axes, Sound field separation, Time-domain equivalent method

Disorders affecting memory and cognition including Alzheimer’s disease (AD) affect millions of Americans. Although dozens of compounds have been reported for the treatment of mild cognitive deficits (MCI) in Alzheimer’s disease (AD), these drugs have not proven beneficial in ameliorating cognitive impairment in clinic. Phosphodiesterase 4B (PDE4B) plays a crucial role in the mediation of memory due to its primary role in hydrolyzing cyclic adenosine monophosphate (cAMP). However, the development of PDE4B inhibitors is challengeable due to the high conservation of the catalytic site of PDE4, across subtypes, to which classical inhibitors bind. The present study suggested that the newly synthesized allosteric inhibitor of PDE4, T2409, exhibits at least 150‐fold PDE4B selectivity. It exhibited low potency in a mouse surrogate model of emesis and nausea, suggesting its low side effects. Chronic treatment of T2409 for 14 days reversed cognitive and memory deficits in the novel object recognition and Morris water maze tests as evidenced by increased discrimination index and reduced the mean latency to platform via decreasing beta amyloid plaques both in the cortex and hippocampus in 8‐month‐old APP/PS1 mouse model of AD. Further study showed that these effects were related to decreased inflammatory factors, such as IL‐6, IL‐1β and TNF‐α, in the brain, and increased cAMP signaling dependent markers of neuroprotection associated with memory, such as p‐CREB and BDNF. These results accelerate the development of highly selective PDE4B inhibitors as novel treatments for illnesses that affect memory and cognitive function, such as AD.

The spinal phosphodiesterase‐4 (PDE4) plays an important role in chronic pain. Inhibition of PDE4, an enzyme catalyzing the hydrolysis of cyclic adenosine monophosphate AMP (cAMP), produces potent antinociceptive activity. However, the antinociceptive mechanism remains largely unknown. Connexin43 (Cx43), a gap junction protein, has been shown to be involved in controlling pain transduction at the spinal level; restoration of Cx43 expression in spinal astrocytes to the normal levels reduces nerve injury‐induced pain. Here, we evaluate the novel mechanisms involving spinal cAMP‐Cx43 signaling by which PDE4 inhibitors produce antinociceptive activity.

A classical hallmark of Alzheimer’s disease (AD) is the accumulation of amyloid‐β (Aβ), which correlates significantly with progressive cognitive and learning and memory impairment. BPN14770, an allosteric inhibitor of PDE4D, has been proposed to improve memory deficits induced by Aβ oligomers (AβOs) and provide overall AD pathology improvement. However, the causal relationship between PDE4D‐related cAMP signaling and the prevalence of AβOs‐induced cognitive deficits has not been investigated. The present study examined whether the memory and cognitive enhancing effects of BPN14770 in humanized PDE4D‐APP/PS1 (hPDE4D/Tg‐AD) mice, which are engineered to express a primate‐specific N‐terminal region of PDE4D and crossed with transgenic APP/PS1 mice, were directly involved in reduced cAMP signaling dependent amyloid pathway. The results suggested that the PDE4D inhibitor BPN14770 significantly improved cognitive index in novel object recognition task, and memory acquisition and retrieval in Morris water maze test in h hPDE4D/Tg‐AD mice. Pretreatment with protein kinase A (PKA) inhibitor H89 completely blocked this BPN14770‐induced memory and cognitive enhancement, suggesting the key role of PDE4D dependent cAMP signaling in cognitive processes. Furthermore, the hPDE4D/Tg‐AD mice showed increases in Aβ plaque and soluble/insoluble Aβ concentration both in the cortex and hippocampus. While treatment of BPN14770 for two weeks (via gavage) prevented these pathological changes, which can be blocked by H89. The subsequent studies suggested that BPN14770 affected the synthesis and degradation of Aβ as evidenced by decreases in amyloidgenic and non‐amyloidgenic pathways such as BACE‐1, sAPPβ, ADAM10 and sAPPα protein expression, and increases in Aβ degrading enzymes including IDE and NEP levels, and downstream neuroprotective proteins such as pCREB/CREB and BDNF expression in hAPP/PS1‐PDE4D mice. Further chromatin co‐immunoprecipitation assays showed cAMP‐dependent CREB directly increased ADAM10 and IDE expression, and inhibited BACE‐1 expression through NF‐κB, resulting in reduction of Aβ production and increase in Aβ degradation. These findings reveal a causal relationship between PDE4D signaling and the progress of AD and demonstrate the clinical potential of BPN14770 in the treatment of AD.

Our previous study suggested that inhibition of Phosphodiesterase 2 ameliorates memory loss upon exposure to oxidative stress. While whether memory enhancing effects of PDE2 inhibition on Alzheimer's disease mouse model are involved in antioxidant defense and neuronal remodeling, are largely unexplored. The present study addressed whether and how PDE2 inhibitor Bay 60–7550 rescued Aβ oligomers (Aβo)-induced neuronal damage and memory impairment. The results suggested that exposure of primary cortical neurons to Aβo induced neuronal cells damage and increased PDE2 expression, which were paralleled to an increase in the oxidative parameter malondialdehyde (MDA) level and cellular apoptosis. However, this Aβo-induced oxidative damage was blocked by pre-treatment with protein kinase A or G (PKA or PKG) inhibitor, suggesting the involvement of cAMP/cGMP signaling. Moreover, microinjection of Aβo into the prefrontal cortex of mice increased the MDA level; while Bay 60–7550 reversed this effect and increased antioxidant and anti-apoptotic factors, i.e. increased trolox-equivalent-antioxidant capacity and Bcl-2/Bax ratio. Bay 60–7550 also rescued Aβo-induced synaptic atrophy and memory deficits, as evidenced by the increased synaptic proteins' levels and spine density in the prefrontal cortex, and improved cognitive behaviors by decreased working memory errors in the eight-arm maze and increased discrimination index in the novel object recognition test. These findings suggest that inhibition of PDE2 contributes to antioxidant defense and neuronal remodeling by regulation of cAMP/cGMP signaling, which provide a theoretical basis for the future use of PDE2 inhibitors as the anti-AD drugs.