HSPA12A controls cerebral lactate homeostasis to maintain hippocampal neurogenesis and mood stabilization.

Mood instability, a subjective emotional state defined as rapid mood oscillations of up and down, is a symptom that occurs in several psychiatric disorders, particularly major depressive disorder and bipolar disorder. Heat shock protein A12A (HSPA12A) shows decreased expression in the brains of schizophrenia patients. However, the causal effects of HSPA12A in any psychiatric disorders are completely unknown. To investigate whether HSPA12A affects mood stability, Hspa12a-knockout mice (Hspa12a-/-) and wild-type (WT) littermates were subjected to tests of open field, forced swimming, elevated plus maze, and sucrose preference. Cerebral lactate levels were measured in cerebrospinal fluid (CSF). Adult hippocampal neurogenesis (AHN) was assessed by BrdU labeling. We found that acute mood stress increased hippocampal HSPA12A expression and CSF lactate levels in mice. However, Hspa12a-/- mice exhibited behaviors of mood instability (anhedonia, lower locomotor activity, antidepression, and anxiety), which were accompanied by impaired AHN, decreased CSF lactate levels, and downregulated hippocampal glycolytic enzyme expression. By contrast, HSPA12A overexpression increased lactate production and glycolytic enzyme expression of primary hippocampal neurons. Intriguingly, lactate administration alleviated the mood instability and AHN impairment in Hspa12a-/- mice. Further analyses revealed that HSPA12A was necessary for sustaining cerebral lactate homeostasis, which could be mediated by inhibiting GSK3ß in hippocampal neurons, to maintain AHN and mood stabilization. Taken together, HSPA12A is defined as a novel regulator of mood stability and exerts therapeutic potential for mood disorder. Our findings establish a framework for determining mood disorder and AHN relevance of cerebral lactate homeostasis. HSPA12A is a novel mood stabilizer through inhibiting GSK3ß in hippocampal neurons, thereby sustaining glycolysis-generated lactate to maintain cerebral lactate homeostasis, which ultimately leading to maintenance of hippocampal neurogenesis and mood stabilization.

Heat shock protein A12A encodes a novel prosurvival pathway during ischaemic stroke.

Heat shock protein A12A (HSPA12A) is a newly discovered member of the Hsp70 family. The biological characteristics and functional roles of HSPA12A are poorly understood. This study investigated the effects of HSPA12A on ischaemic stroke in mice. Ischaemic stroke was induced by left middle cerebral artery occlusion for 1 h followed by blood reperfusion. We observed that HSPA12A was highly expressed in brain neurons, and neuronal HSPA12A expression was downregulated by ischaemic stroke and stroke-associated risk factors (aging, obesity and hyperglycaemia). To investigate the functional requirement of HSPA12A in protecting ischaemic brain injury, HSPA12A knockout mice (Hspa12a-/-) were generated. Hspa12a-/- mice exhibited an enlarged infarct volume and aggravated neurological deficits compared to their wild-type (WT) littermates after stroke. These aggravations in Hspa12a-/- mice were accompanied by more apoptosis and severer hippocampal morphological abnormalities in ischaemic hemispheres. Long-term examination revealed impaired motor function recovery and neurogenesis in stroke-affected Hspa12a-/- mice compared to stroke-affected WT controls. Significant reduced activation of GSK-3ß/mTOR/p70S6K signalling was also observed in ischaemic hemispheres of Hspa12a-/- mice compared to WT controls. Administration with lithium (non-selective GSK-3ß inhibitor) activated GSK-3ß/mTOR/p70S6K signalling in stroke-affected Hspa12a-/- mice. Notably, lithium administration attenuated the HSPA12A deficiency-induced aggravation in infarct size, neurological deficits and neuronal death in Hspa12a-/- mice after stroke. Altogether, the findings suggest that HSPA12A expression encodes a critical novel prosurvival pathway during ischaemic stroke. We identified HSPA12A as a novel neuroprotective target for stroke patients.

Innovative development path of ethnomedicines: a case study.

Innovative development extends the vitality of ethnomedicines. Developing ethnomedicines is not only beneficial to the public but also to the related industry and transforms economic growth, driving local social and economic development further. Its economic benefit can be used to optimize and promote the hardware and software of the platform, as well as support the sustainable development of ethnomedicines. Apart from research and discussion on the innovative development of ethnomedicines on the basis of theory and regulations, this series of articles also summarizes cases that are conducive to the overall understanding of the necessity and feasibility of the innovative development. In terms of industrial development, large enterprises and products, such as Yunnan Baiyao, Guizhou Miao ethnomedicines, Cheezheng Tibetan Medicine, products developed from Dengzhanhua (Erigeron breviscapus), the Gold series of Yi ethnomedicines, and products developed from Sanqi (Panax notoginseng), in China are introduced and summarized, focusing on resource superiority, sustainable innovation, standard research and development, and production, as well as intellectual property protection.

Innovative development path of ethnomedicines: the interpretation of the path.

One of the primary purposes of the innovative development of ethnomedicines is to use their excellent safety and significant efficacy to serve a broader population. To achieve this purpose, modern scientific and technological means should be referenced, and relevant national laws and regulations as well as technical guides should be strictly followed to develop standards and to perform systemic research in producing ethnomedicines. Finally, ethnomedicines, which are applied to a limited extent in ethnic areas, can be transformed into safe, effective, and quality-controllable medical products to relieve the pain of more patients. The innovative development path of ethnomedicines includes the following three primary stages: resource study, standardized development research, and industrialization of the achievements and efforts for internationalization. The implementation of this path is always guaranteed by the research and development platform and the talent team. This article is based on the accumulation of long-term practice and is combined with the relevant disciplines, laws and regulations, and technical guidance from the research and development of ethnomedicines. The intention is to perform an in-depth analysis and explanation of the major research thinking, methods, contents, and technical paths involved in all stages of the innovative development path of ethnomedicines to provide useful references for the development of proper ethnomedicine use.

Innovative development path of ethnomedicines: an overview of ethnomedicines in China.

In the long history of disease prevention and treatment, ancestral populations worldwide have gained knowledge and experiences in traditional medicines. For instance, ethnomedicines of Chinese ethnic minorities constitute an important part of traditional medicines. In our study, we firstly clarified the concept of ethnomedicines and the connotations of ethnopharmacology. The particularity of ethnomedicine research were then summed up, and the development profiles of the ethnomedicines of Chinese ethnic minorities were discussed by investigating the current status and existing problems. On this basis, we abstracted the innovative development path of ethnomedicines for the first time, which was found to follows:resource study → standardized development research → industrialization of the achievements and efforts for internationalization. We found that platform establishment and team training are keys to achieving innovative development. Hence, this study provided a basis for ethnomedicine development.

p110Delta Inhibits Monocyte Infiltration by Thioglycollate-Induced Periotoneal Inflammation but Not HCD-Induced Inflammation and Atherosclerosis in APOE KO Mice.

We have previously reported that phosphoinositide 3-kinase p110δ knockout (p110δ KO) diminished the adhesion of leukocytes to capillary venules and suppressed the peritoneal infiltration of leukocytes, both functions that play important roles in atherosclerosis. Therefore, we hypothesized that p110δ deficiency might be protective against atherosclerosis. Apolipoprotein E knockout (ApoE KO) mice were crossed with p110δ KO mice to generate homozygous double knockout mice (ApoE/p110δ DKO). The present study showed that ApoE/p110δ DKO mice fed with a high cholesterol diet (HCD) demonstrated less peritoneal infiltration of leukocytes and monocytes compared with ApoE KO mice after intraperitoneal injection of thioglycollate, an inducer of acute peritoneal inflammation. Unexpectedly, atherosclerosis in the aortic root and in the entire aorta was similar between the ApoE/p110δ DKO and ApoE KO groups. No difference in Mac-3 expression, indicative of macrophage infiltration, was found between the two groups. Further analysis showed that ApoE KO mice chronically fed with HCD had increased levels of total cholesterol, low-density lipoprotein in the blood and counts and percentages of circulating monocytes compared with ApoE KO mice fed with a normal diet. Consistently, the deficiency of p110δ affected neither the counts nor the percentages of monocytes nor the lipid profiles in the blood. The results suggested that p110δ plays an important role in acute but not in chronic inflammation, the latter being included in the early characteristics of atherosclerosis, which might explain the finding that p110δ deficiency fails to inhibit early atherosclerosis.

Inactivation of PI3Kδ induces vascular injury and promotes aneurysm development by upregulating the AP-1/MMP-12 pathway in macrophages.

OBJECTIVE: An aneurysm is an inflammatory vascular condition. Phosphatidylinositol 3-kinases δ is highly expressed in leukocytes, and play a key role in innate immunity. However, the link between phosphatidylinositol 3-kinases δ and aneurysm development has not yet been elucidated. APPROACH AND RESULTS: Carotid ligation unexpectedly induced characteristic aneurysm formation beneath the ligation point in p110δ(D910A/D910A) mice (n=25; P<0.001 versus wild-type). Besides, p110δ inactivation exacerbated CaCl2-induced abdominal aortic aneurysms development. A reverse transcription polymerase chain reaction microarray revealed significant extracellular matrix components degradation and matrix metalloproteinases (MMPs) upregulation in the abdominal aorta of p110δ(D910A/D910A) mice. Similarly, the expression of both collagen I and IV was significantly decreased (n=10; P<0.05 versus wild-type) in carotid artery. Western blot assay confirmed that MMP-12 was significantly upregulated in arteries of p110δ(D910A/D910A) mice (n=10; P<0.01 versus wild-type). In vitro, p110δ inactivation marked increase peritoneal macrophages recruitment and synergistically enhance tumor necrosis factor-α-induced recruitment. A specific phosphatidylinositol 3-kinases δ inhibitor (IC87114) or genetic p110δ inactivation upregulated MMP-12 expression and c-Jun phosphorylation (n=6; P<0.05 versus wild-type macrophages). IC87114 also increased activator protein-1 DNA-binding activity (n=6; P<0.001 versus control) and enhanced the effect of tumor necrosis factor-α on activator protein-1-binding activity (n=5; P<0.01 versus tumor necrosis factor-α treatment groups). Knockdown of c-Jun suppressed the effect of the IC87114 and tumor necrosis factor-α on MMP-12 mRNA expression (n=5 in each group; P<0.01 versus scrRNA treatment groups). CONCLUSIONS: Our findings demonstrate that p110δ inactivation leads to extracellular matrix degradation in vessels and promotes aneurysm development by inducing macrophages migration and upregulating the activator protein-1/MMP-12 pathway in macrophages.