Clemastine-induced enhancement of hippocampal myelination alleviates memory impairment in mice with chronic pain.

Patients with chronic pain often experience memory impairment, but the underlying mechanisms remain elusive. The myelin sheath is crucial for rapid and accurate action potential conduction, playing a pivotal role in the development of cognitive abilities in the central nervous system. The study reveals that myelin degradation occurs in the hippocampus of chronic constriction injury (CCI) mice, which display both chronic pain and memory impairment. Using fiber photometry, we observed diminished task-related neuronal activity in the hippocampus of CCI mice. Interestingly, the repeated administration with clemastine, which promotes myelination, counteracts the CCI-induced myelin loss and reduced neuronal activity. Notably, clemastine specifically ameliorates the impaired memory without affecting chronic pain in CCI mice. Overall, our findings highlight the significant role of myelin abnormalities in CCI-induced memory impairment, suggesting a potential therapeutic approach for treating memory impairments associated with neuropathic pain.

Dual regulation of the actin cytoskeleton by CARMIL-GAP.

Capping protein Arp2/3 myosin I linker (CARMIL) proteins are multi-domain scaffold proteins that regulate actin dynamics by regulating the activity of capping protein (CP). Here, we characterize CARMIL-GAP (GAP for GTPase-activating protein), a Dictyostelium CARMIL isoform that contains a ∼130 residue insert that, by homology, confers GTPase-activating properties for Rho-related GTPases. Consistent with this idea, this GAP domain binds Dictyostelium Rac1a and accelerates its rate of GTP hydrolysis. CARMIL-GAP concentrates with F-actin in phagocytic cups and at the leading edge of chemotaxing cells, and CARMIL-GAP-null cells exhibit pronounced defects in phagocytosis and chemotactic streaming. Importantly, these defects are fully rescued by expressing GFP-tagged CARMIL-GAP in CARMIL-GAP-null cells. Finally, rescue with versions of CARMIL-GAP that lack either GAP activity or the ability to regulate CP show that, although both activities contribute significantly to CARMIL-GAP function, the GAP activity plays the bigger role. Together, our results add to the growing evidence that CARMIL proteins influence actin dynamics by regulating signaling molecules as well as CP, and that the continuous cycling of the nucleotide state of Rho GTPases is often required to drive Rho-dependent biological processes.

Contribution of activating lateral hypothalamus-lateral habenula circuit to nerve trauma-induced neuropathic pain in mice.

Neuropathic pain, a severe clinical symptom, significantly affects the quality of life in the patients. The molecular mechanisms underlying neuropathic pain have been the focus of research in recent decades; however, the neuronal circuit-mediated mechanisms associated with this disorder remain poorly understood. Here, we report that a projection from the lateral hypothalamus (LH) glutamatergic neurons to the lateral habenula (LHb), an excitatory LH-LHb neuronal circuit, participates in nerve injury-induced nociceptive hypersensitivity. LH glutamatergic neurons are activated and display enhanced responses to normally non-noxious stimuli following chronic constriction injury. Chemogenetic inhibition of LH glutamatergic neurons or excitatory LH-LHb circuit blocked CCI-induced nociceptive hypersensitivity. Activation of the LH-LHb circuit led to augmented responses to mechanical and thermal stimuli in mice without nerve injury. These findings suggest that LH neurons and their triggered LH-LHb circuit participate in central mechanisms underlying neuropathic pain and may be targets for the treatment of this disorder.

Advances in photobiomodulation for cognitive improvement by near-infrared derived multiple strategies.

Cognitive function is an important ability of the brain, but cognitive dysfunction can easily develop once the brain is injured in various neuropathological conditions or diseases. Photobiomodulation therapy is a type of noninvasive physical therapy that is gradually emerging in the field of neuroscience. Transcranial photobiomodulation has been commonly used to regulate neural activity in the superficial cortex. To stimulate deeper brain activity, advanced photobiomodulation techniques in conjunction with photosensitive nanoparticles have been developed. This review addresses the mechanisms of photobiomodulation on neurons and neural networks and discusses the advantages, disadvantages and potential applications of photobiomodulation alone or in combination with photosensitive nanoparticles. Photobiomodulation and its associated strategies may provide new breakthrough treatments for cognitive improvement.

Melanin-like polydopamine nanoparticles mediating anti-inflammatory and rescuing synaptic loss for inflammatory depression therapy.

Inflammatory depression is closely related to neuroinflammation. However, current anti-inflammatory drugs have low permeability to cross blood-brain barrier with difficulties reaching the central nervous system to provide therapeutic effectiveness. To overcome this limitation, the nano-based drug delivery technology was used to synthesize melanin-like polydopamine nanoparticles (PDA NPs) (~ 250 nm) which can cross the blood-brain barrier. Importantly, PDA NPs with abundant phenolic hydroxyl groups function as excellent free radical scavengers to attenuate cell damage caused by reactive oxygen species or acute inflammation. In vitro experiments revealed that PDA NPs exhibited excellent antioxidative properties. Next, we aimed to investigate the therapeutic effect of PDA NPs on inflammatory depression through intraperitoneal injection to the lipopolysaccharide-induced inflammatory depression model in mice. PDA NPs significantly reversed the depression-like behavior. PDA NPs was also found to reduce the peripheral and central inflammation induced by LPS, showing that alleviated splenomegaly, reduced serum inflammatory cytokines, inhibited microglial activation and restored synaptic loss. Various experiments also showed that PDA NPs had good biocompatibility both in vivo and in vitro. Our work suggested that PDA NPs may be biocompatible nano-drugs in treating inflammatory depression but their clinical application requires further study.

Hoxa5 inhibits adipocyte proliferation through transcriptional regulation of Ccne1 and blocking JAK2/STAT3 signaling pathway in mice.

The highly regulated proliferation of adipocytes plays a momentous role in fat development and obesity. Hoxa5 is an important member of the Hox family, its encoded protein is an important transcription factor related to development, and its differential expression in different adipose tissues seems to indicate that Hoxa5 may be involved in the regulation of adipocyte proliferation. To evaluate the regulatory mechanism of Hoxa5 on adipocyte proliferation, we constructed a variety of Hoxa5 expression vectors in vivo and in vitro to explore its mechanism on adipocyte proliferation and its potential impact on obesity. We observed that the overexpression of Hoxa5 strongly reduces cell counts and Hoxa5 can inhibit cell proliferation and block cell cycle progression by regulating the expression of genes such as Cyclin E, Cyclin D1, and p53. Most importantly, we demonstrated that Hoxa5 exerts its effect by regulating the signaling pathway of Janus kinase 2 (JAK2) signal transduction and transcription 3 (STAT3) activator, as well as binding to the promoter region of Ccne1 and inhibiting the transcription of Ccne1. This study provides an in-depth understanding of the potential molecular mechanism of Hoxa5 inhibiting adipocyte proliferation. Our results suggest the importance of Hoxa5 in the treatment of obesity.

A G-protein-coupled chemoattractant receptor recognizes lipopolysaccharide for bacterial phagocytosis.

Phagocytes locate microorganisms via chemotaxis and then consume them using phagocytosis. Dictyostelium amoebas are stereotypical phagocytes that prey on diverse bacteria using both processes. However, as typical phagocytic receptors, such as complement receptors or Fcγ receptors, have not been found in Dictyostelium, it remains mysterious how these cells recognize bacteria. Here, we show that a single G-protein-coupled receptor (GPCR), folic acid receptor 1 (fAR1), simultaneously recognizes the chemoattractant folate and the phagocytic cue lipopolysaccharide (LPS), a major component of bacterial surfaces. Cells lacking fAR1 or its cognate G-proteins are defective in chemotaxis toward folate and phagocytosis of Klebsiella aerogenes. Computational simulations combined with experiments show that responses associated with chemotaxis can also promote engulfment of particles coated with chemoattractants. Finally, the extracellular Venus-Flytrap (VFT) domain of fAR1 acts as the binding site for both folate and LPS. Thus, fAR1 represents a new member of the pattern recognition receptors (PRRs) and mediates signaling from both bacterial surfaces and diffusible chemoattractants to reorganize actin for chemotaxis and phagocytosis.

Overexpression of long non-coding RNA ANRIL promotes post-ischaemic angiogenesis and improves cardiac functions by targeting Akt.

Angiogenesis is critical for re-establishing the blood supply to the surviving myocardium after myocardial infarction (MI). Long non-coding RNA ANRIL (lncRNA-ANRIL) has been reported to regulate endothelial functions in cardiovascular diseases. This study was to determine the role of lncRNA-ANRIL in Akt regulation and cardiac functions after MI. Human umbilical vein endothelial cells (HUVECs) were exposed to oxygen-glucose deprivation (OGD) to mimic in vivo ischaemia. The MI model in mice was induced by ligating left anterior descending coronary artery. OGD remarkably decreased lncRNA-ANRIL expression level, reduced the phosphorylated levels of Akt and eNOS proteins, and inhibited NO release and cell viability, which were duplicated by shRNA-mediated gene knockdown of lncRNA-ANRIL. Conversely, all these effects induced by OGD were abolished by adenovirus-mediated overexpression of lncRNA-ANRIL in HUVECs. Further, OGD impaired cell migrations and tube formations in HUVECs, which were reversed by lncRNA-ANRIL overexpression or Akt up-regulation. RNA immunoprecipitation analysis indicated that the affinity of lncRNA-ANRIL to Akt protein was increased in OGD-treated cells. In animal studies, adenovirus-mediated lncRNA-ANRIL overexpression increased the phosphorylated levels of Akt and eNOS, promoted post-ischaemic angiogenesis and improved heart functions in mice with MI surgery. LncRNA-ANRIL regulates Akt phosphorylation to improve endothelial functions, which promotes angiogenesis and improves cardiac functions in mice following MI. In this perspective, targeting lncRNA-ANRIL/Akt may be considered to develop a drug to treat angiogenesis-related diseases.

NFAT5 promotes arteriogenesis via MCP-1-dependent monocyte recruitment.

Studies have demonstrated that nuclear factor of activated T cells 5 (NFAT5) is not only a tonicity-responsive transcription factor but also activated by other stimuli, so we aim to investigate whether NFAT5 participates in collateral arteries formation in rats. We performed femoral artery ligature (FAL) in rats for hindlimb ischaemia model and found that NFAT5 was up-regulated in rat adductors with FAL compared with sham group. Knockdown of NFAT5 with locally injection of adenovirus-mediated NFAT5-shRNA in rats significantly inhibited hindlimb blood perfusion recovery and arteriogenesis. Moreover, NFAT5 knockdown decreased macrophages infiltration and monocyte chemotactic protein-1 (MCP-1) expression in rats adductors. In vitro, with interleukin-1ß (IL-1ß) stimulation and loss-of-function studies, we demonstrated that NFAT5 knockdown inhibits MCP-1 expression in endothelial cells and chemotaxis of THP-1 cells regulated by ERK1/2 pathway. More importantly, exogenous MCP-1 delivery could recover hindlimb blood perfusion, promote arteriogenesis and macrophages infiltration in rats after FAL, which were depressed by NFAT5 knockdown. Besides, NFAT5 knockdown also inhibited angiogenesis in gastrocnemius muscles in rats. Our results indicate that NFAT5 is a critical regulator of arteriogenesis and angiogenesis via MCP-1-dependent monocyte recruitment, suggesting that NFAT5 may represent an alternative therapeutic target for ischaemic diseases.

Mark4 Inhibited the Browning of White Adipose Tissue by Promoting Adipocytes Autophagy in Mice.

Autophagy can remove excess or dysfunctional proteins and organelles to maintain cellular homeostasis. Browning of white adipose tissue increases the energy expenditure. Microtubules affinity regulated kinase 4 (Mark4) can regulate a variety of physiological processes. According to previous studies, we speculated that Mark4-autophagy-browning of white adipose tissue had certain linkages. Here, we established two autophagy models through serum starvation and rapamycin treatment and detected that the overexpression of Mark4 increased the expression of autophagy-related factors Beclin1, ATG7, and significantly decreased the autophagy substrate P62. Further tests showed that the overexpression of Mark4 promoted the conversion of autophagy marker protein LC3A to LC3B-II by activating the AMP-activated protein kinase (AMPK) pathway and inhibition of the AKT/mTOR signaling. Moreover, Mark4 decreased the expression of thermogenesis genes via promoting autophagy. These results indicated that Mark4 inhibited the browning of white adipose tissue via promoting autophagy.

ColXV Aggravates Adipocyte Apoptosis by Facilitating Abnormal Extracellular Matrix Remodeling in Mice.

The extracellular matrix (ECM) is a highly dynamic structural network and plays an essential role in cell behavior and regulation during metabolic homeostasis and obesity progression. Abnormal ECM remodeling impairs adipocyte plasticity required for diverse cellular functions. Collagen XV (ColXV) is a proteoglycan localized to the outermost layer of basement membranes (BMs) and forms a bridge between the BMs and the fibrillar collagen matrix. Nevertheless, how ColXV affects ECM composition and the reason for subsequent adipocyte apoptosis is still unclear. This report found, through RNA-seq data, that ColXV is linked to cell growth and ECM remodeling. Findings show that, in response to excessive expression of extracellular ColXV, the AMPK/mTORC1 pathway is strongly activated and triggers a cascade of mitochondrial apoptosis. This is the first study to make use of ECM three-dimensional reconstruction, based on decellularization in the adipose tissues and the study reveals that ColXV is an activation factor that alters ECM remodeling in adipose tissues. It was also demonstrated that the fibroblast growth factor 2 (FGF2)/fibroblast growth factor receptor 1 (FGFR1) axis involved in ECM remodeling is suppressed by ColXV due to reduction of FGF2 translocation to FGFR1. Furthermore, ColXV induced remodeling of ECM preceding apoptosis and continued to induce apoptosis in adipocytes. Collectively, our findings establish ColXV as a basement membrane collagen with homology to ColXVIII, indicating that it is one of the positive regulators for inducing ECM remodeling and further promoting adipocyte apoptosis.

Canonical TGF-ß Signaling Negatively Regulates Neuronal Morphogenesis through TGIF/Smad Complex-Mediated CRMP2 Suppression.

Functional neuronal connectivity requires proper neuronal morphogenesis and its dysregulation causes neurodevelopmental diseases. Transforming growth factor-ß (TGF-ß) family cytokines play pivotal roles in development, but little is known about their contribution to morphological development of neurons. Here we show that the Smad-dependent canonical signaling of TGF-ß family cytokines negatively regulates neuronal morphogenesis during brain development. Mechanistically, activated Smads form a complex with transcriptional repressor TG-interacting factor (TGIF), and downregulate the expression of a neuronal polarity regulator, collapsin response mediator protein 2. We also demonstrate that TGF-ß family signaling inhibits neurite elongation of human induced pluripotent stem cell-derived neurons. Furthermore, the expression of TGF-ß receptor 1, Smad4, or TGIF, which have mutations found in patients with neurodevelopmental disorders, disrupted neuronal morphogenesis in both mouse (male and female) and human (female) neurons. Together, these findings suggest that the regulation of neuronal morphogenesis by an evolutionarily conserved function of TGF-ß signaling is involved in the pathogenesis of neurodevelopmental diseases.SIGNIFICANCE STATEMENT Canonical transforming growth factor-ß (TGF-ß) signaling plays a crucial role in multiple organ development, including brain, and mutations in components of the signaling pathway associated with several human developmental disorders. In this study, we found that Smads/TG-interacting factor-dependent canonical TGF-ß signaling regulates neuronal morphogenesis through the suppression of collapsin response mediator protein-2 (CRMP2) expression during brain development, and that function of this signaling is evolutionarily conserved in the mammalian brain. Mutations in canonical TGF-ß signaling factors identified in patients with neurodevelopmental disorders disrupt the morphological development of neurons. Thus, our results suggest that proper control of TGF-ß/Smads/CRMP2 signaling pathways is critical for the precise execution of neuronal morphogenesis, whose impairment eventually results in neurodevelopmental disorders.

A minimally invasive approach to induce myocardial infarction in mice without thoracotomy.

Acute myocardial infarction (MI) is a leading cause of morbidity and mortality in the world. Traditional method to induce MI by left coronary artery (LCA) ligation is typically performed by an invasive approach that requires ventilation and thoracotomy, causing serious injuries in animals undergoing this surgery. We attempted to develop a minimally invasive method (MIM) to induce MI in mice. Under the guide of ultrasound, LCA ligation was performed in mice without ventilation and chest-opening. Compared to sham mice, MIM induced MI in mice as determined by triphenyltetrazolium chloride staining and Masson staining. Mice with MIM surgery revealed the reductions of LVEF, LVFS, E/A and ascending aorta (AAO) blood flow, and the elevations of S-T segment and serum cTn-I levels at 24 post-operative hours. The effects of MI induced by MIM were comparable to the effects of MI produced by traditional method in mice. Importantly, MIM increased the survival rates and caused less inflammation after the surgery of LCA ligation, compared to the surgery of traditional method. Further, MIM induced angiogenesis and apoptosis in ischaemic hearts from mice at postoperative 28 days as similarly as traditional method did. Finally, the MIM model was able to develop into the myocardial ischaemia/reperfusion model by using a balloon catheter with minor modifications. The MI model is able to be efficiently induced by a minimally invasive approach in mice without ventilation and chest-opening. This new model is potentially to be used in studying ischaemia-related heart diseases.

MiR-15b-5p Regulates Collateral Artery Formation by Targeting AKT3 (Protein Kinase B-3).

OBJECTIVE: To identify circulating microRNAs that are differentially expressed in severe coronary heart disease with well or poorly developed collateral arteries and to investigate their mechanisms of action in vivo and in vitro. APPROACH AND RESULTS: In our study, we identified a circulating microRNA, miR-15b-5p, with low expression that, nevertheless, characterized patients with sufficient coronary collateral artery function. Moreover, in murine hindlimb ischemia model, in situ hybridization identified that miR-15b-5p was specifically expressed in vascular endothelial cells of adductors in sham group and was remarkably downregulated after femoral artery ligation. Overexpressed miR-15b-5p significantly inhibited arteriogenesis and angiogenesis in mice. In vitro, both under basal and vascular endothelial growth factor stimulation, loss-of-function or gain-of-function studies suggested that miR-15b-5p significantly promoted or depressed the migration and proliferation of endothelial cells. We identified AKT3 (protein kinase B-3) as a direct target of miR-15b-5p. Interestingly, AKT3 deficiency by injection with Chol-AKT3-siRNA obviously suppressed arteriogenesis and the recovery of blood perfusion after femoral ligation in mice. CONCLUSIONS: These results indicate that circulating miR-15b-5p is a suitable biomarker for discriminating between patients with well-developed or poorly developed collaterals. Moreover, miR-15b-5p is a key regulator of arteriogenesis and angiogenesis, which may represent a potential therapeutic target for ischemic disease.

HAS4: A Heuristic Adaptive Sink Sensor Set Selection for Underwater AUV-Aid Data Gathering Algorithm.

In this paper, we target solving the data gathering problem in underwater wireless sensor networks. In many underwater applications, it is not quick to retrieve sensed data, which gives us the opportunity to leverage mobile autonomous underwater vehicles (AUV) as data mules to periodically collect it. For each round of data gathering, the AUV visits part of the sensors, and the communication between AUV and sensor nodes is a novel high-speed magnetic-induction communication system. The rest of the sensors acoustically transmit their sensed data to the AUV-visit sensors. This paper deploys the HAS 4 (Heuristic Adaptive Sink Sensor Set Selection) algorithm to select the AUV-visited sensors for the purpose of energy saving, AUV cost reduction and network lifetime prolonging. By comparing HAS 4 with two benchmark selection methods, experiment results demonstrate that our algorithm can achieve a better performance.

Crystal structures of two active proliferating cell nuclear antigens (PCNAs) encoded by Thermococcus kodakaraensis.

Proliferating cell nuclear antigen (PCNA) is a ring-shaped protein that encircles duplex DNA and plays an essential role in many DNA metabolic processes in archaea and eukarya. The eukaryotic and euryarchaea genomes contain a single gene encoding for PCNA. Interestingly, the genome of the euryarchaeon Thermococcus kodakaraensis contains two PCNA-encoding genes (TK0535 and TK0582), making it unique among the euryarchaea kingdom. It is shown here that the two T. kodakaraensis PCNA proteins support processive DNA synthesis by the polymerase. Both proteins form trimeric structures with characteristics similar to those of other archaeal and eukaryal PCNA proteins. One of the notable differences between the TK0535 and TK0582 rings is that the interfaces are different, resulting in different stabilities for the two trimers. The possible implications of these observations for PCNA functions are discussed.

Effect of nursing intervention on rehabilitation of patients with chronic sinusitis and nasal polyps after nasal endoscopy.

BACKGROUND: Chronic sinusitis is a kind of chronic suppurative inflammation of the sinus mucosa. Nasal endoscopy is a good method to treat nasal polyps. However postoperative rehabilitation and care should not be neglected. AIM: To investigate the Effect of nursing intervention on the rehabilitation of patients with chronic sinusitis and nasal polyps (CSNPS) after nasal endoscopy. METHODS: A total of 129 patients with CSNPS hospitalized from February 2017 to February 2019 were studied. Using the digital parity method, we investigated nursing cooperation strategies for endoscopic surgery. The comparison group (64 cases): Surgical nursing was carried out with traditional nursing measures; experimental group (65 cases): Surgical nursing was carried out by traditional nursing countermeasures + comprehensive nursing measures. We compared postoperative recovery rates, nursing satisfaction rates, and nasal cavity ratings between the two groups. RESULTS: Experimental group patients with CSNPS had a significantly higher recovery rate (98.46%) compared to the control group (79.69%). This difference was statistically significant (χ 2 = 11.748, P < 0.05). Additionally, the satisfaction rate with treatment was also significantly higher in the experimental group (98.46%) compared to the control group (79.69%), with a statistically significant difference (χ 2 = 11.748, P < 0.05). Before nursing, there was no significant difference in sinus nasal cavity scores between the experimental group (20.29 ± 7.25 points) and the control group (20.30 ± 7.27 points) (t = 0.008, P > 0.05). However, after nursing, the sinus nasal cavity score in the experimental group (8.85 ± 3.22 points) was significantly lower than that in the control group (14.99 ± 5.02 points) (t = 8.282, P < 0.05). CONCLUSION: Comprehensive nursing intervention in patients with CSNPS can significantly improve the total recovery rate after endoscopic surgery.

Polygonati Rhizoma: A review on the extraction, purification, structural characterization, biosynthesis of the main secondary metabolites and anti-aging effects.

ETHNOPHARMACOLOGICAL RELEVANCE: Polygonati Rhizome (PR) is a plant that is extensively widespread in the temperate zones of the Northern Hemisphere. It is a member of the Polygonatum family of Asparagaceae. PR exhibits diverse pharmacological effects and finds applications in ethnopharmacology, serving as a potent tonic for more than two millennia. PR's compounds endow it with various pharmacological properties, including anti-aging, antioxidant, anti-fatigue, anti-inflammatory, and sleep-enhancing effects, as well as therapeutic potential for osteoporosis and age-related diseases. AIM OF THE STUDY: This review seeks to offer a thorough overview of the processing, purification, extraction, structural characterization, and biosynthesis pathways of PR. Furthermore, it delves into the anti-aging mechanism of PR, using organ protection as an entry point. MATERIALS AND METHODS: Information on PR was obtained from scientific databases (Google Scholar, Web of Science, ScienceDirect, SciFinder, PubMed, CNKI) and books, doctoral theses, and master's dissertations. RESULTS: In this investigation, 49 polysaccharides were extracted from PR, and the impact of various processing, extraction, and purification techniques on the structure and activity of these polysaccharides was evaluated. Additionally, 163 saponins and 46 flavonoids were identified, and three key biosynthesis pathways of secondary metabolites were outlined. Notably, PR and Polygonat Rhizomai polysaccharides (PRP) exhibit remarkable protective effects against age-induced injuries to the brain, liver, kidney, intestine, heart, and vessels, thereby promoting longevity and ameliorating the aging process. CONCLUSIONS: PR, a culinary and therapeutic herb, is rich in active components and pharmacological activities. Based on this review, PR plays a meaningful role in lifespan extension and anti-aging, which can be attributed to PRP. Future research should delve deeper into the structural aspects of PRP that underlie its anti-aging effects and explore potential synergistic interactions with other compounds. Moreover, exploring the potential applications of PR in functional foods and pharmaceutical formulations is recommended to advance the development of industries and resources focused on healthy aging.