Acta Physiologica最新文献_第3页

Chronic intermittent hypoxia triggers cardiac fibrosis: Role of epididymal white adipose tissue senescent remodeling? 慢性间歇性缺氧引发心脏纤维化：附睾白色脂肪组织衰老重塑的作用？

IF 5.6 2区医学 Q1 PHYSIOLOGY

Acta Physiologica

Pub Date : 2024-09-12 DOI: 10.1111/apha.14231

Suzain Naushad, Jonathan Gaucher, Zaineb Mezdari, Maximin Détrait, Elise Belaidi, Yanyan Zhang, Guillaume Vial, Sophie Bouyon, Gabor Czibik, Maria Pini, Sahar Aldekwer, Hao Liang, Véronique Pelloux, Judith Aron-Wisnewsky, Renaud Tamisier, Jean-Louis Pépin, Geneviève Derumeaux, Daigo Sawaki, Claire Arnaud

Aim

Obstructive sleep apnea (OSA) is a growing health problem affecting nearly 1 billion people worldwide. The landmark feature of OSA is chronic intermittent hypoxia (CIH), accounting for multiple organ damage, including heart disease. CIH profoundly alters both visceral white adipose tissue (WAT) and heart structure and function, but little is known regarding inter-organ interaction in the context of CIH. We recently showed that visceral WAT senescence drives myocardial alterations in aged mice without CIH. Here, we aimed at investigating whether CIH induces a premature visceral WAT senescent phenotype, triggering subsequent cardiac remodeling.

Methods

In a first experiment, 10-week-old C57bl6J male mice (n = 10/group) were exposed to 14 days of CIH (8 h daily, 5%–21% cyclic inspired oxygen fraction, 60 s per cycle). In a second series, mice were submitted to either epididymal WAT surgical lipectomy or sham surgery before CIH exposure. Finally, we used p53 deficient mice or Wild-type (WT) littermates, also exposed to the same CIH protocol. Epididymal WAT was assessed for fibrosis, DNA damages, oxidative stress, markers of senescence (p16, p21, and p53), and inflammation by RT-qPCR and histology, and myocardium was assessed for fibrosis and cardiomyocyte hypertrophy.

Results

CIH-induced epididymal WAT remodeling characterized by increased fibrosis, oxidative stress, DNA damage response, inflammation, and increased expression of senescent markers. CIH-induced epididymal WAT remodeling was associated with subtle and early myocardial interstitial fibrosis. Both epididymal WAT surgical lipectomy and p53 deletion prevented CIH-induced myocardial fibrosis.

Conclusion

Short-term exposure to CIH induces epididymal WAT senescent remodeling and cardiac interstitial fibrosis, the latter being prevented by lipectomy. This finding strongly suggests visceral WAT senescence as a new target to mitigate OSA-related cardiac disorders.

目的阻塞性睡眠呼吸暂停（OSA）是一个日益严重的健康问题，影响着全球近 10 亿人。OSA 的主要特征是慢性间歇性缺氧 (CIH)，导致包括心脏病在内的多种器官损伤。慢性间歇性缺氧会严重改变内脏白色脂肪组织（WAT）和心脏的结构与功能，但人们对慢性间歇性缺氧背景下器官间的相互作用知之甚少。我们最近的研究表明，内脏白脂肪组织的衰老驱动了无 CIH 的老年小鼠心肌的改变。方法在第一个实验中，10 周大的 C57bl6J 雄性小鼠（n = 10/组）暴露于 14 天的 CIH（每天 8 小时，5%-21% 的循环吸氧分数，每个循环 60 秒）。在第二个系列中，小鼠在暴露于 CIH 前接受附睾 WAT 手术切除术或假手术。最后，我们使用了 p53 缺陷小鼠或野生型（WT）同窝小鼠，它们也暴露于相同的 CIH 方案。结果CIH诱导的附睾WAT重塑以纤维化、氧化应激、DNA损伤反应、炎症和衰老标记物（p16、p21和p53）表达增加为特征。CIH诱导的附睾WAT重塑与微妙的早期心肌间质纤维化有关。结论短期暴露于CIH诱导附睾WAT衰老重塑和心肌间质纤维化，切除附睾WAT可防止后者的发生。这一发现有力地表明，内脏WAT衰老是缓解OSA相关心脏疾病的一个新靶点。

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引用次数: 0

A gender perspective on diet, microbiome, and sex hormone interplay in cardiovascular disease 从性别角度看饮食、微生物组和性激素在心血管疾病中的相互作用

IF 5.6 2区医学 Q1 PHYSIOLOGY

Acta Physiologica

Pub Date : 2024-09-12 DOI: 10.1111/apha.14228

Nina Jovanovic, Veronika Zach, Claudia Crocini, Lina Samira Bahr, Sofia Kirke Forslund-Startceva, Kristina Franz

A unique interplay between body and environment embeds and reflects host–microbiome interactions that contribute to sex-differential disease susceptibility, symptomatology, and treatment outcomes. These differences derive from individual biological factors, such as sex hormone action, sex-divergent immune processes, X-linked gene dosage effects, and epigenetics, as well as from their interaction across the lifespan. The gut microbiome is increasingly recognized as a moderator of several body systems that are thus impacted by its function and composition. In humans, biological sex components further interact with gender-specific exposures such as dietary preferences, stressors, and life experiences to form a complex whole, requiring innovative methodologies to disentangle. Here, we summarize current knowledge of the interactions among sex hormones, gut microbiota, immune system, and vascular health and their relevance for sex-differential epidemiology of cardiovascular diseases. We outline clinical implications, identify knowledge gaps, and place emphasis on required future studies to address these gaps. In addition, we provide an overview of the caveats associated with conducting cardiovascular research that require consideration of sex/gender differences. While previous work has inspected several of these components separately, here we call attention to further translational utility of a combined perspective from cardiovascular translational research, gender medicine, and microbiome systems biology.

身体与环境之间独特的相互作用体现并反映了宿主与微生物组之间的相互作用，这种相互作用导致了不同性别对疾病的易感性、症状和治疗效果。这些差异来自个体生物因素，如性激素作用、性别差异免疫过程、X 连锁基因剂量效应和表观遗传学，以及它们在整个生命周期中的相互作用。人们越来越认识到，肠道微生物组是多个身体系统的调节器，因此其功能和组成会对这些系统产生影响。在人类中，生物性别成分进一步与饮食偏好、压力因素和生活经历等性别特异性暴露相互作用，形成一个复杂的整体，需要创新的方法来加以区分。在此，我们总结了目前关于性激素、肠道微生物群、免疫系统和血管健康之间相互作用的知识，以及它们与心血管疾病性别差异流行病学的相关性。我们概述了其临床意义，确定了知识差距，并强调了为弥补这些差距而需要进行的未来研究。此外，我们还概述了在开展心血管研究时需要考虑性别差异的注意事项。虽然以前的工作已对其中的几个部分进行了单独研究，但在此我们呼吁人们关注从心血管转化研究、性别医学和微生物组系统生物学的角度进行综合研究的进一步转化效用。

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引用次数: 0

Delaying post-exercise carbohydrate intake impairs next-day exercise capacity but not muscle glycogen or molecular responses 运动后延迟摄入碳水化合物会影响第二天的运动能力，但不会影响肌糖原或分子反应

IF 5.6 2区医学 Q1 PHYSIOLOGY

Acta Physiologica

Pub Date : 2024-09-12 DOI: 10.1111/apha.14215

Javier Díaz-Lara, Elizabeth Reisman, Javier Botella, Bianka Probert, Louise M. Burke, David J. Bishop, Matthew J. Lee

Aim

To investigate how delayed post-exercise carbohydrate intake affects muscle glycogen, metabolic- and mitochondrial-related molecular responses, and subsequent high-intensity interval exercise (HIIE) capacity.

Methods

In a double-blind cross-over design, nine recreationally active men performed HIIE (10 × 2-min cycling, ~94% W˙_peak) in the fed state, on two occasions. During 0–3 h post-HIIE, participants drank either carbohydrates (“Immediate Carbohydrate” [IC], providing 2.4 g/kg) or water (“Delayed Carbohydrate” [DC]); total carbohydrate intake over 24 h post-HIIE was matched (~7 g/kg/d). Skeletal muscle (sampled pre-HIIE, post-HIIE, +3 h, +8 h, +24 h) was analyzed for whole-muscle glycogen and mRNA content, plus signaling proteins in cytoplasmic- and nuclear-enriched fractions. After 24 h, participants repeated the HIIE protocol until failure, to test subsequent HIIE capacity; blood lactate, heart rate, and ratings of perceived effort (RPE) were measured throughout.

Results

Muscle glycogen concentrations, and relative changes, were similar between conditions throughout (p > 0.05). Muscle glycogen was reduced from baseline (mean ± SD mmol/kg dm; IC: 409 ± 166; DC: 352 ± 76) at post-HIIE (IC: 253 ± 96; DC: 214 ± 82), +3 h (IC: 276 ± 62; DC: 269 ± 116) and + 8 h (IC: 321 ± 56; DC: 269 ± 116), returning to near-baseline by +24 h. Several genes (PGC-1ɑ, p53) and proteins (p-ACC^Ser79, p-P38 MAPK^{Thr180/Tyr182}) elicited typical exercise-induced changes irrespective of condition. Delaying carbohydrate intake reduced next-day HIIE capacity (5 ± 3 intervals) and increased RPE (~2 ratings), despite similar physiological responses between conditions.

Conclusion

Molecular responses to HIIE (performed in the fed state) were not enhanced by delayed post-exercise carbohydrate intake. Our findings support immediate post-exercise refueling if the goal is to maximize next-day HIIE capacity and recovery time is ≤24 h.

目的研究运动后延迟摄入碳水化合物如何影响肌糖原、代谢和线粒体相关分子反应以及随后的高强度间歇运动（HIIE）能力。方法在双盲交叉设计中，9 名休闲运动男性在进食状态下进行了两次 HIIE（10 × 2 分钟自行车运动，约 94% W˙峰值）。在 HIIE 后的 0-3 小时内，参与者饮用碳水化合物（"即时碳水化合物"[IC]，提供 2.4 克/千克）或水（"延迟碳水化合物"[DC]）；HIIE 后 24 小时内的碳水化合物总摄入量相匹配（约 7 克/千克/天）。对骨骼肌（HIIE 前、HIIE 后、+3 小时、+8 小时、+24 小时采样）的全肌糖原和 mRNA 含量，以及细胞质和细胞核富集部分的信号蛋白进行分析。24 小时后，参与者重复 HIIE 方案直至失败，以测试随后的 HIIE 能力；在整个过程中测量血乳酸、心率和感知努力值（RPE）。肌糖原在HIIE后（IC：253±96；DC：214±82）、+3 h（IC：276±62；DC：269±116）和+8 h（IC：321±56；DC：269±116）从基线降低（平均值±标度mmol/kg dm；IC：409±166；DC：352±76），到+24 h恢复到接近基线。一些基因（PGC-1ɑ、p53）和蛋白质（p-ACCSer79、p-P38 MAPKThr180/Tyr182）在任何条件下都会引起典型的运动诱导变化。尽管不同条件下的生理反应相似，但延迟摄入碳水化合物会降低第二天的 HIIE 能力（5 ± 3 个间隔）并增加 RPE（~2 个评级）。如果目标是最大限度地提高第二天的 HIIE 能力，且恢复时间不超过 24 小时，我们的研究结果支持运动后立即补充能量。

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引用次数: 0

Maternal physical activity in healthy pregnancy: Effect on fetal oxygen supply 健康孕妇的体力活动：对胎儿供氧的影响

IF 5.6 2区医学 Q1 PHYSIOLOGY

Acta Physiologica

Pub Date : 2024-09-12 DOI: 10.1111/apha.14229

Mireille N. M. van Poppel, Annika Kruse, Anthony M. Carter

Aim

We review evidence for effects of physical activity before and during gestation on the course of pregnancy and ask if there are circumstances where physical activity can stress the fetus due to competition for oxygen and energy substrates.

Results

We first summarize physiological responses to exercise in nonpregnant people and known physiological adaptations to pregnancy. Comparing the two, we conclude that physical activity prior to and continuing during gestation is beneficial to pregnancy outcome. The effect of starting an exercise regimen during pregnancy is less easy to assess as few studies have been undertaken. Results from animal models suggest that the effects of maternal exercise on the fetus are transient; the fetus can readily compensate for a short-term reduction in oxygen supply.

Conclusion

In general, we conclude that physical activity before and during pregnancy is beneficial, and exercise started during pregnancy is unlikely to affect fetal development. We caution, however, that there are circumstances where this may not apply. They include the intensive exercise regimens of elite athletes and pregnancies at high altitudes where hypoxia occurs even in the resting state.

目的我们回顾了妊娠前和妊娠期体育锻炼对妊娠过程影响的证据，并询问在某些情况下，体育锻炼是否会因争夺氧气和能量基质而对胎儿造成压力。将两者进行比较后，我们得出结论：妊娠前和妊娠期间持续进行体育锻炼对妊娠结果有益。由于相关研究较少，因此在孕期开始运动的效果不太容易评估。动物模型的研究结果表明，母体运动对胎儿的影响是短暂的；胎儿可以很容易地补偿氧气供应的短期减少。不过，我们要提醒的是，在某些情况下这一结论可能并不适用。这些情况包括精英运动员的高强度运动和在高海拔地区怀孕，因为那里即使在静止状态下也会出现缺氧。

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引用次数: 0

Metformin modulates microbiota and improves blood pressure and cardiac remodeling in a rat model of hypertension 二甲双胍调节微生物群，改善高血压大鼠模型的血压和心脏重塑

IF 5.6 2区医学 Q1 PHYSIOLOGY

Acta Physiologica

Pub Date : 2024-09-10 DOI: 10.1111/apha.14226

Moritz I. Wimmer, Hendrik Bartolomaeus, Harithaa Anandakumar, Chia-Yu Chen, Valentin Vecera, Sarah Kedziora, Sakshi Kamboj, Fabian Schumacher, Sidney Pals, Ariana Rauch, Jutta Meisel, Olena Potapenko, Alex Yarritu, Theda U. P. Bartolomaeus, Mariam Samaan, Arne Thiele, Lucas Stürzbecher, Sabrina Y. Geisberger, Burkhard Kleuser, Peter J. Oefner, Nadine Haase, Ulrike Löber, Wolfram Gronwald, Sofia K. Forslund-Startceva, Dominik N. Müller, Nicola Wilck

Aims

Metformin has been attributed to cardiovascular protection even in the absence of diabetes. Recent observations suggest that metformin influences the gut microbiome. We aimed to investigate the influence of metformin on the gut microbiota and hypertensive target organ damage in hypertensive rats.

Methods

Male double transgenic rats overexpressing the human renin and angiotensinogen genes (dTGR), a model of angiotensin II-dependent hypertension, were treated with metformin (300 mg/kg/day) or vehicle from 4 to 7 weeks of age. We assessed gut microbiome composition and function using shotgun metagenomic sequencing and measured blood pressure via radiotelemetry. Cardiac and renal organ damage and inflammation were evaluated by echocardiography, histology, and flow cytometry.

Results

Metformin treatment increased the production of short-chain fatty acids (SCFA) acetate and propionate in feces without altering microbial composition and diversity. It significantly reduced systolic and diastolic blood pressure and improved cardiac function, as measured by end-diastolic volume, E/A, and stroke volume despite increased cardiac hypertrophy. Metformin reduced cardiac inflammation by lowering macrophage infiltration and shifting macrophage subpopulations towards a less inflammatory phenotype. The observed improvements in blood pressure, cardiac function, and inflammation correlated with fecal SCFA levels in dTGR. In vitro, acetate and propionate altered M1-like gene expression in macrophages, reinforcing anti-inflammatory effects. Metformin did not affect hypertensive renal damage or microvascular structure.

Conclusion

Metformin modulated the gut microbiome, increased SCFA production, and ameliorated blood pressure and cardiac remodeling in dTGR. Our findings confirm the protective effects of metformin in the absence of diabetes, highlighting SCFA as a potential mediators.

目的即使没有糖尿病，二甲双胍也能保护心血管。最近的观察表明，二甲双胍会影响肠道微生物群。我们的目的是研究二甲双胍对高血压大鼠肠道微生物群和高血压靶器官损伤的影响。方法过表达人肾素和血管紧张素原基因（dTGR）的雄性双转基因大鼠是血管紧张素 II 依赖性高血压的模型，在其 4 至 7 周龄期间接受二甲双胍（300 毫克/千克/天）或药物治疗。我们使用散弹枪元基因组测序评估了肠道微生物组的组成和功能，并通过放射性遥测测量了血压。结果二甲双胍治疗增加了粪便中短链脂肪酸（SCFA）乙酸盐和丙酸盐的产生，但没有改变微生物的组成和多样性。二甲双胍能明显降低收缩压和舒张压，并改善心功能（以舒张末期容积、E/A 和每搏容积来衡量），尽管心脏肥大程度有所增加。二甲双胍可降低巨噬细胞浸润，并使巨噬细胞亚群向炎症较轻的表型转变，从而减轻心脏炎症。观察到的血压、心脏功能和炎症改善与 dTGR 粪便中的 SCFA 水平相关。在体外，乙酸盐和丙酸盐改变了巨噬细胞中 M1 样基因的表达，加强了抗炎作用。结论二甲双胍可调节肠道微生物组，增加 SCFA 的产生，改善 dTGR 的血压和心脏重塑。我们的研究结果证实了二甲双胍在无糖尿病情况下的保护作用，并强调 SCFA 是一种潜在的介质。

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引用次数: 0

Did you know? Is there a reserve in myocardial work via the Frank-Starling mechanism in healthy humans? 您知道吗？健康人通过弗兰克-斯塔林机制进行的心肌工作有储备吗？

IF 5.6 2区医学 Q1 PHYSIOLOGY

Acta Physiologica

Pub Date : 2024-09-06 DOI: 10.1111/apha.14230

Meihan Guo, David Montero

引用次数: 0

The pattern of CNI nephrotoxicity differs between treatments 不同疗法的氯化萘肾毒性模式各不相同。

IF 5.6 2区医学 Q1 PHYSIOLOGY

Acta Physiologica

Pub Date : 2024-09-05 DOI: 10.1111/apha.14227

Jenny Nyström, Kerstin Ebefors

<p>Immunosuppressants have greatly improved the outcomes of organ transplantation and calcineurin inhibitors (CNI) have been used extensively to prevent graft rejection since their development over 40 years ago.<span><sup>1</sup></span> The most commonly used CNIs are cyclosporine A (CsA) and tacrolimus (Tac), and in the United States, Tac is the most commonly prescribed immunosuppressant (in combination with mycophenolate agents and/or steroids) after kidney transplantation in adults.<span><sup>2</sup></span> CsA was approved by the FDA for immunosuppression following transplantation in 1983, and Tac in 1994. But like many great drugs, there are drawbacks. For CNIs, one of the major adverse effects is nephrotoxicity, which has been investigated extensively and it is known that CsA and Tac in part have a different side effect pattern, but details are still lacking.<span><sup>3</sup></span> In this issue of Acta Physiologica, Demirci et al. have investigated how CsA and Tac affect the renal compartments, and if there are differences in the mechanisms behind the nephrotoxicity caused by CNIs.<span><sup>4</sup></span> A recent review by Attachaipanich et al. in Acta Physiologica regarding cardiotoxicity after CNI treatment indicate that the cardiovascular toxicity profiles between CsA and Tac differ substantially,<span><sup>5</sup></span> implying that this could be true for other organs as well. Understanding the differences in CsA and Tac nephrotoxicity could improve patient treatment, allowing adapted treatment for each patient and hopefully reducing allograft damage caused by CNIs, alongside careful consideration of the non-renal side effects of the two drugs as well.</p><p>Although both CsA and Tac have immunosuppressive properties through the inhibition of the calcineurin/NFAT pathway, the compounds are quite different. CsA is a lipophilic cyclic peptide and Tac is a macrolide antibiotic and they are both derived from fungi. CsA binds to cyclophilins and Tac to FK-binding proteins present in the cytoplasm and both the complexes inhibit calcineurin. Calcineurin is regulated by calcium and calmodulin and activates transcription factors in the NFAT family inducing an immune response with proliferation of T lymphocytes. Calcineurin is not only expressed by lymphocytes but also other cells in the body; hence, the effects of CNIs are not exclusive for lymphocytes. Calcineurin is, for example, involved in regulating the renal potassium and sodium transport in the kidneys, which is reviewed in this number of Acta Physiologica.<span><sup>6</sup></span></p><p>To give further insight into the different effects of CsA and Tac on the kidneys, Demirci et al. has explored the effects of CsA and Tac in a rat model, and after 4 weeks of treatment investigating the early chronic phase of nephrotoxicity. The histopathology of the rats has been investigated in great detail in combination with omics techniques (RNA sequencing, global proteomics and phosphoproteomi

大鼠研究的结果非常重要，人类活检的结果也部分验证了这些结果，但要将这些结果完全应用于人类环境，还需要人类研究的进一步验证。特别是，将患者肾脏活组织切片的肿瘤数据与大鼠的特征进行比较将具有重要价值。为了进一步转化肾脏中的分区研究结果，单细胞转录组学以及蛋白质组学都很有价值。总之，这项研究有助于人们了解最常用的 CNIs 在肾毒性方面的差异，并进一步了解这些差异背后的分子机制。由于氯化萘类药物是实体器官移植中免疫抑制疗法的基石，这些结果凸显了在这一领域进行个性化治疗的必要性，而这篇文章也为这一前进道路提供了大量资料。

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引用次数: 0

Cytokine relay from the peripheral to the central: Secrets behind fever 从外周到中枢的细胞因子中继：发烧背后的秘密

IF 5.6 2区医学 Q1 PHYSIOLOGY

Acta Physiologica

Pub Date : 2024-09-02 DOI: 10.1111/apha.14225

Xianshu Bai

<p>Fever is often triggered by infections or inflammatory conditions, primarily mediated by the immune system. Immune cells like macrophages and dendritic cells detect pathogens through pathogen-associated molecular patterns, such as lipopolysaccharides (LPS).<span><sup>1</sup></span> In response, these immune cells release a significant number of inflammatory factors or cytokines, which travel through the bloodstream to the hypothalamus, the body's thermoregulatory center. Once in the hypothalamus, these cytokines stimulate various cells, including microglia—the innate immune cell in the central nervous system.<span><sup>2</sup></span> This stimulation initiates a complex cascade that raises body temperature. However, the precise mechanisms by which hypothalamic microglia interact with peripheral immune cells to induce fever remain unclear.<span><sup>3</sup></span></p><p>In this issue of <i>Acta Physiologica</i>, Yu et al. elucidate the molecular mechanisms of fever driven by interactions between peripheral macrophages and preoptic anterior hypothalamus (POAH) microglia.<span><sup>4</sup></span> In this study, they administered 20 μg/kg of LPS via the tail vein, which triggered a characteristic biphasic fever at 2 and 6 hours post-injection (hpi). At each time point, the levels of key pro-inflammatory cytokines involved in fever development, including IL-1β, IL-18, interferon (IFN)-β, and TNF-α, were measured. At 2 hpi, there was a slight but not significant increase in the number of macrophages in the blood and in the levels of cytokines in the serum. However, by 6 hpi, there was a significant increase in both peripheral macrophages and CNS microglia, accompanied by a dramatic rise in PGE2 and IL-1β levels in the blood and POAH region. Importantly, this was not due to LPS entering the brain, as neither Evans blue nor FITC-LPS applied peripherally was detected in the brain, indicating that microglia activation was not a direct result of LPS exposure. As these sets of cytokines are mainly expressed by macrophages and microglia, authors hypothesized that the activation of microglia is due to the entry of cytokines derived from macrophages.</p><p>To further investigate, the authors selectively depleted peripheral macrophages by administering clodronate-liposome via tail-vein injection 24 h before LPS treatment. In the absence of macrophages, even after 6 h of LPS injection, neither the microglia number nor the body temperature changed. Depleting macrophages also suppressed the LPS-induced increase in cytokine levels in both serum and the POAH region, suggesting that peripheral macrophages play a key role in fever development. Conversely, when POAH microglia were depleted using the same drug injected directly into the POAH region, cytokine levels in the serum were similarly elevated but remained low in the PO/AH region even after LPS treatment. Although body temperature was significantly reduced in comparison to LPS-treated control mice, it remained

发热通常由感染或炎症引发，主要由免疫系统介导。巨噬细胞和树突状细胞等免疫细胞通过脂多糖（LPS）等病原体相关分子模式检测到病原体。1 作为反应，这些免疫细胞会释放大量炎症因子或细胞因子，通过血液循环到达人体的体温调节中枢--下丘脑。一旦进入下丘脑，这些细胞因子就会刺激各种细胞，包括小胶质细胞--中枢神经系统中的先天性免疫细胞2。3 在本期《生理学报》（Acta Physiologica）上，Yu 等人阐明了外周巨噬细胞与视前下丘脑（POAH）小胶质细胞相互作用导致发热的分子机制。4 在这项研究中，他们通过尾静脉注射 20 μg/kg LPS，在注射后 2 小时和 6 小时（hpi）引发了特征性的双相发热。在每个时间点，测量了参与发热的主要促炎细胞因子的水平，包括IL-1β、IL-18、干扰素（IFN）-β和TNF-α。2 小时后，血液中巨噬细胞的数量和血清中细胞因子的水平略有增加，但不明显。然而，到了 6 小时后，外周巨噬细胞和中枢神经系统小胶质细胞都显著增加，同时血液和 POAH 区域的 PGE2 和 IL-1β 水平也急剧上升。重要的是，这并不是因为 LPS 进入了大脑，因为在大脑中既没有检测到埃文斯蓝，也没有检测到外周应用的 FITC-LPS，这表明小胶质细胞的激活并不是 LPS 暴露的直接结果。由于这几组细胞因子主要由巨噬细胞和小胶质细胞表达，作者假设小胶质细胞的活化是由于来自巨噬细胞的细胞因子的进入。为了进一步研究，作者在 LPS 处理前 24 小时通过尾静脉注射氯屈膦酸脂质体，选择性地消耗外周巨噬细胞。在没有巨噬细胞的情况下，即使注射了 6 小时的 LPS，小胶质细胞的数量和体温都没有发生变化。消耗巨噬细胞还能抑制 LPS 诱导的血清和 POAH 区域细胞因子水平的升高，这表明外周巨噬细胞在发热的发生中起着关键作用。相反，当使用直接注射到 POAH 区域的相同药物耗竭 POAH 小胶质细胞时，血清中的细胞因子水平同样升高，但即使在 LPS 处理后，PO/AH 区域的细胞因子水平仍然很低。虽然与经 LPS 处理的对照组小鼠相比，体温明显降低，但仍略高于健康小鼠，这可能是由于 POAH 中仍有巨噬细胞衍生的细胞因子在起作用。通过大量 RNA 测序，作者发现在 LPS 6 hpi 的 POAH 区域，特别是在小胶质细胞中，与 NOD 样受体信号通路相关的基因，尤其是 Caspase11-NLRP3 炎性体显著增加。这些观察结果表明，发热的第一阶段（注射 LPS 2 hpi）可能是巨噬细胞衍生的细胞因子进入大脑的直接效应，而第二个温度峰值则是由下丘脑小胶质细胞内的细胞因子扩增驱动的。体外共培养实验显示，经 LPS 处理的活化骨髓源性巨噬细胞（BMDM）和与活化骨髓源性巨噬细胞共培养的 BV-2 小胶质细胞都会上调细胞因子。此外，这些小胶质细胞还明显增加了 Caspase11 的表达。当用活化的 BMDM 细胞的条件培养基处理 BV-2 小胶质细胞时，也观察到了这种效应。这表明小胶质细胞 Caspase11 参与了巨噬细胞和小胶质细胞之间的细胞因子中继，从而导致发热。通过选择性沉默小胶质细胞特异性 Caspase11，作者能够在不影响第一个温度峰值的情况下抑制第二个温度峰值，而 POAH 区域的细胞因子表达则恢复到健康水平。相反，在 POAH 小胶质细胞中过表达 Caspase11 会显著增加该区域的细胞因子水平，第二阶段的体温升高也会略微升高。这项研究通过确定小胶质细胞中的 Caspase11 是通过非典型炎性体途径驱动发热的关键角色，极大地推动了我们对发热分子机制的理解。此外，从外周到中枢神经系统的细胞因子中继在机体内的复杂合作关系也非常引人关注，因为这可能为在各种临床环境中控制发热带来新的治疗方法。未来还需要进一步研究，以确定巨噬细胞衍生的细胞因子是否直接作用于 POAH 小胶质细胞或其他细胞群。5 最近的一项研究表明，LPS 会引发外周腺苷的增加，而腺苷会作用于星形胶质细胞，并进一步调节系统诱导的败血症模型中的小胶质细胞反应性。10 因此，除了巨噬细胞衍生的细胞因子对 POAH 小胶质细胞的直接作用外，中枢神经系统中的其他胶质细胞是否参与了发热的驱动，还有待研究。目前还不清楚小胶质细胞衍生的细胞因子是如何直接或通过与其他神经胶质细胞（如少突胶质细胞）相互作用来调节发热的。例如，在小胶质细胞中追踪巨噬细胞衍生的细胞因子（使用 Rosa26-methionyl tRNA 合成酶报告物）将是一个很有希望的起点：写作-原稿；构思。

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引用次数: 0

Evolutionary physiology 进化生理学

IF 5.6 2区医学 Q1 PHYSIOLOGY

Acta Physiologica

Pub Date : 2024-08-29 DOI: 10.1111/apha.14221

Pontus B. Persson, Anja Bondke Persson

<p>Evolution, a “process of heritable change in populations of organisms over multiple generations […] through mechanisms including natural selection, sexual selection and genetic drift,”<span><sup>1</sup></span> is the unifying framework that explains the diversity of life, guiding our understanding of biological processes, species interactions, and the development of new medical and biotechnological innovations. Evolutionary physiology is a multidisciplinary field that explores how organisms adapt their physiological functions to changing environmental conditions. Some authors attribute the development or emergence of evolutionary physiology as a subspecialty to the late 1980s<span><sup>2</sup></span> as a field which integrates perspectives from genetics, ecology, and evolutionary biology to understand the origins, adaptability and maintenance of physiological diversity. Svante Pääbo, so-called “reader of the Neanderthal genome,”<span><sup>3</sup></span> may be seen as a prime example who opened the door to ancient genomics. However, for a study to touch upon evolutionary physiology, it does not necessarily have to focus primarily on elucidating developments from eons past. In this paper, we take a closer look at recent publications, which aim to investigate the physiological adaptations and trade-offs that have arisen through natural selection, shedding light on evolutionary pathways, outcomes and perspectives.</p><p>Recent developments, including climate change, are increasingly recognized as significant drivers of evolutionary processes in various species. These environmental changes create new selective pressures, leading to adaptations that can alter genetic diversity and influence species' survival and reproduction.<span><sup>4</sup></span> The study by Sokolova et al. sheds light on the impact of environmental temperature changes on energy metabolism and thus on the mitochondrial function.</p><p>Mitochondria, usually introduced in Bio 101 classes as cellular power plants, are in themselves almost bizarre examples of evolutionary development. Other entities within the mammalian organism are also of questionable descent, such as retrovirus-like Gag Protein Arc1, which—and we do not know why—bears a domain which resembles retroviral/retrotransposon -like proteins, which multimerize into a capsid that packages viral RNA.<span><sup>5</sup></span> Most likely, once upon a time, mitochondria started out as α-Proteobacteria. Until recently, the most common theory was an endosymbiont hypothesis, that is, an incorporation of bacterial cell compounds into eukaryotic cells. Recently, however, evidence has emerged which prompts the question of whether the mitochondrion really emerged after the eukaryotic cell, or if this organelle even originated simultaneously with the cell that contains it.<span><sup>6</sup></span> Nevertheless, mitochondrial bacterial characteristics, such as cytosine-phosphate-guanosine, the membrane lipid cardiolipin, N-formyla

进化是 "通过自然选择、性选择和遗传漂变等机制，在生物种群中经过多代[......]发生可遗传变化的过程 "1 ，是解释生命多样性的统一框架，指导我们理解生物过程、物种相互作用以及新医疗和生物技术创新的发展。进化生理学是一个多学科领域，探讨生物如何使其生理功能适应不断变化的环境条件。一些作者认为，进化生理学作为一门亚专业的发展或出现是在 20 世纪 80 年代末2 ，该领域综合了遗传学、生态学和进化生物学的观点，以了解生理多样性的起源、适应性和维持。被称为 "尼安德特人基因组的读者 "3 的斯万特-佩博（Svante Pääbo）可被视为开启远古基因组学大门的典范。然而，一项研究若要触及进化生理学，并不一定要把主要精力放在阐明远古时代的发展上。在本文中，我们将对近期发表的旨在研究通过自然选择产生的生理适应性和权衡的文章进行更深入的探讨，从而揭示进化的途径、结果和前景。4 索科洛娃等人的研究揭示了环境温度变化对能量代谢的影响，进而对线粒体功能的影响。线粒体通常在生物 101 课程中被介绍为细胞发电厂，其本身几乎就是进化发展的奇异范例。哺乳动物机体内的其他实体的血统也值得商榷，例如类似逆转录病毒的 Gag 蛋白 Arc1，我们不知道为什么它有一个类似逆转录病毒/逆转录转座子蛋白的结构域，这些蛋白多聚成一个包有病毒 RNA 的噬菌体。直到最近，最常见的理论是内共生假说，即细菌细胞化合物融入真核细胞。不过，最近出现的证据引发了线粒体是否真的在真核细胞之后出现，或者说这种细胞器是否与含有线粒体的细胞同时起源的问题6。然而，线粒体的细菌特性，如胞嘧啶-磷酸鸟苷、膜脂心磷脂、N-醛化肽和环状双链 DNA，可能是线粒体受损后诱发或延续炎症过程的原因：棕色脂肪组织（BAT）表达产热解偶联蛋白1（UCP1），使人类能够在寒冷应激时保持体温。最近发现成年人如何保留BAT，这可能在非颤抖性产热中发挥作用，因此有人假设BAT的可塑性是人类向环极地区扩张的主要因素。最近开发的 UCP-1 缺陷动物模型可以更仔细地观察非颤抖性产热9 和对寒冷挑战的产热适应10 ，并在 UCP-1 被发现和描述 50 年后进一步了解哺乳动物棕色脂肪（非颤抖性）产热11 的进化。12 此外，线粒体似乎在脊椎动物适应缺氧甚至缺氧环境13 的进化过程中发挥了关键作用，主要包括心肺功能14、15 和神经肌肉16 的适应。老普林尼在其《自然史》第 XXXI 卷中提到了一种盐，他将其命名为 "hammoniacum"，人们认为这种盐的得名是因为它靠近位于罗马昔兰尼加省的朱庇特阿蒙神庙（希腊语为Ἄμμων Ammon）17。氨是所谓的 "氮废物 "之一，它与尿素、尿酸和肌酐一起产生于哺乳动物的蛋白质新陈代谢，必须排出体外以避免中毒。

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引用次数: 0

Modulation of olfactory bulb activity by serotoninergic inputs in odor-associative learning 气味联想学习中血清素能输入对嗅球活动的调节

IF 5.6 2区医学 Q1 PHYSIOLOGY

Acta Physiologica

Pub Date : 2024-08-27 DOI: 10.1111/apha.14222

Yue Hao, Zheng Wang, Qian Li

<p>Olfaction is critical for animal survival, enabling them to discern complex environmental cues such as food, mates, and predators. This sensory modality can trigger innate animal behaviors through detecting distinct odorants and activating hardwired neural circuits. In addition, the olfactory system mediates odor-associative learning, allowing animals to link odors with beneficial or harmful contexts and form long-term memories. Several olfactory cortical regions including piriform cortex, anterior olfactory nucleus, and lateral entorhinal cortex have been implicated in the formation of odor-associative learning and memory.<span><sup>1-3</sup></span> Surprisingly, the olfactory bulb (OB)—the first relay station in the olfactory system—also exhibits neuronal plasticity during odor learning, suggesting that the OB is able to encode odor values in addition to basic odor information.<span><sup>4, 5</sup></span> However, it is still not fully understood how the odor values are encoded in the OB neurons and how the neuronal plasticity is shaped during odor learning.</p><p>In the current issue of Acta Physiologica, Jing et al. elucidate the serotonergic inputs from the dorsal raphe nucleus (DRN) to the OB as the neural mechanisms underlying plasticity of odor response in the OB during odor-associative learning.<span><sup>6</sup></span> Odors are initially detected by olfactory receptors on olfactory sensory neurons and transmitted to the OB, where the olfactory information is integrated. This information is then relayed by secondary neurons in the OB, mainly mitral and tufted (M/T) cells, to higher brain regions, including the piriform cortex, olfactory tubercle, and anterior olfactory nucleus. Beyond direct projections from olfactory sensory neurons, the OB is modulated by feedback from the olfactory cortex and centrifugal inputs from systems such as serotonergic, cholinergic, and noradrenergic pathways. These higher central inputs are believed to regulate OB responses to odors and play a role in odor-associative learning and memory, though direct evidence has been limited. The authors focused on serotonergic inputs to the OB that are mainly originated from the DRN (Figure 1A). Previous studies have indicated that the DRN modulates OB neural activity and odor response. The DRN neurons activated by optogenetics and electrical stimulation can release serotonin, regulate synaptic activity in the OB, and modulate outputs of M/T cells.<span><sup>7, 8</sup></span> However, there is limited evidence connecting this neural regulation to olfactory perception and discrimination under physiological conditions such as odor-associative learning process.</p><p>Using GCaMP to detect DRN neuronal activity, the authors found that the serotoninergic neurons in DRN is specifically activated during odor-associative tasks with a reward (both go/go task and go/no-go tasks) but not during passive odor recognition. However, during early learning stage of the go/no go task,

9 值得注意的是，自闭症谱系障碍（ASD）等神经发育障碍会伴随血清素水平的下降。10 研究表明，ASD 患者会误解人类产生的气味，在接触恐惧和平静的气味时会表现出与正常人相反的生理和心理反馈。因此，未来探索 DRN-OB 血清素能通路是否在精神疾病中受损也很重要。这项研究还存在一些局限性，它只关注了与奖励相关的气味，而没有探讨DRN-OB血清素通路在与惩罚相关的气味学习中的作用。此外，DRN血清素能神经元调控OB M/T细胞的确切机制--无论是直接还是间接--仍不清楚。在OB中，血清素能输入也可通过抑制性颗粒细胞靶向M/T细胞，而星形胶质细胞中的组蛋白血清素化可调控参与嗅觉感觉处理的基因表达。总之，Jing 等人的研究揭示了 DRN-OB 血清素回路在气味联觉学习中的重要生理作用，以及血清素能输入如何影响气味辨别过程中的 OB 神经活动。这些发现加深了我们对动物在不同行为状态下感知和储存气味信息的机制的理解，并可能为嗅觉相关疾病提供启示。未来的研究应深入探讨DRN血清素能投射的细胞和分子机制，以及不同神经调节剂在嗅觉神经网络中的协同作用：构思；写作-原稿。王铮写作-审稿和编辑。李倩：构思；写作-原稿；写作-审阅和编辑。本研究得到国家自然科学基金（32122038和32371042）、上海市科委基础研究项目（21JC1404500和23ZR1480000）、上海市教育发展基金会和上海市教委曙光计划（21SG16）、中国科学院基金（JCTD-2021-06）和中国公共卫生联合会博士后基金项目（GZC20241066）的资助。

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引用次数: 0