Approved drugs and natural products at clinical stages for treating Alzheimer's disease.

Alzheimer's disease (AD) remains the foremost cause of dementia and represents a significant unmet healthcare need globally. The complex pathogenesis of AD, characterized by various pathological and physiological events, has historically challenged the development of anti-AD drugs. However, recent breakthroughs in AD drug development, including the approvals of aducanumab, lecanemab, and sodium oligomannate (GV-971), have ended a nearly two-decade hiatus in the introduction of new AD drugs. These developments have addressed long-standing challenges in AD drug development, marking a substantial shift in the therapeutic landscape of AD. Moreover, natural products (NPs) have shown promise in AD drug research, with several currently under clinical investigation. Their distinct properties and mechanisms of action offer new avenues to complement and enhance existing AD treatment approaches. This review article aims to provide an overview of the recent advancements and prospects in AD therapeutics, focusing on both NPs and approved drugs.

Specific Activation of Dopamine Receptor D1 Expressing Neurons in the PrL Alleviates CSDS-Induced Anxiety-Like Behavior Comorbidity with Postoperative Hyperalgesia in Male Mice.

Postoperative pain is a type of pain that occurs in clinical patients after surgery. Among the factors influencing the transition from acute postoperative pain to chronic postoperative pain, chronic stress has received much attention in recent years. Here, we investigated the role of dopamine receptor D1/D2 expressing pyramidal neurons in the prelimbic cortex (PrL) in modulating chronic social defeat stress (CSDS)-induced anxiety-like behavior comorbidity with postoperative hyperalgesia in male mice. Our results showed that preoperative CSDS induced anxiety-like behavior and significantly prolonged postoperative pain caused by plantar incision, but did not affect plantar wound recovery and inflammation. Reduced activation of dopamine receptor D1 or D2 expressing neurons in the PrL is a remarkable feature of male mice after CSDS, and chronic inhibition of dopamine receptor D1 or D2 expressing neurons in the PrL induced anxiety-like behavior and persistent postoperative pain. Further studies found that activation of D1 expressing but not D2 expressing neurons in the PrL ameliorated CSDS-induced anxiety-like behavior and postoperative hyperalgesia. Our results suggest that dopamine receptor D1 expressing neurons in the PrL play a crucial role in CSDS-induced anxiety-like behavior comorbidity with postoperative hyperalgesia in male mice.

Mechanisms Underlying Sex Differences in Temporomandibular Disorders and Their Comorbidity with Migraine.

Sexual dimorphism in temporomandibular disorders (TMDs) and their comorbidity with migraine are important phenomena observed in clinics. TMDs are the most prevalent orofacial pain conditions with jaw joint and masseter muscle dysfunction. Migraine is the predominant headache commonly associated with TMDs. Women much more often suffer from this orofacial pain than men. However, currently, there is no gender-specific therapy for such pain conditions. Understanding the pathophysiological mechanisms behind sex differences in TMDs as well as their comorbidity with migraines is essential for developing novel approaches for gender-specific treatment of TMDs and related orofacial pain comorbidity. In this review, we summarize recent research progress regarding sex differences in TMDs, focusing on the underlying mechanisms including craniofacial anatomy, hormonal regulation, and roles of opioids, transient receptor potential channels, and endocannabinoid systems. We also discuss the mechanisms of comorbid TMDs and migraine. The information covered in this review will provide mechanistic insights into sex differences in TMDs and their comorbidity with migraine, which could aid in developing effective treatment strategies for the overlapping orofacial pain condition.

The miR-641-STIM1 and SATB1 axes play important roles in the regulation of the Th17/Treg balance in ITP.

Immune thrombocytopenia (ITP) is an autoimmune disease caused by T-cell dysfunction. Recently, several studies have shown that a disturbed Th17/Treg balance contributes to the development of ITP. MicroRNAs (miRNAs) are small noncoding RNA moleculesthat posttranscriptionally regulate gene expression. Emerging evidences have demonstrated that miRNAs play an important role in regulating the Th17/Treg balance. In the present study, we found that miR-641 was upregulated in ITP patients. In primary T cells, overexpression of miR-641 could cause downregulation of its target genes STIM1 and SATB1, thus inducing a Th17 (upregulated)/Treg (downregulated) imbalance. Inhibition of miR-641 by a miR-641 sponge in primary T cells of ITP patients or by antagomiR-641 in an ITP murine model could cause upregulation of STIM1 and SATB1, thus restoring Th17/Treg homeostasis. These results suggested that the miR-641-STIM/SATB1 axis plays an important role in regulating the Th17/Treg balance in ITP.

The ketogenic diet mitigates opioid-induced hyperalgesia by restoring short-chain fatty acids-producing bacteria in the gut.

ABSTRACT: Opioids are commonly prescribed to patients with chronic pain. Chronic opioid usage comes with a slew of serious side effects, including opioid-induced hyperalgesia (OIH). The patients with long-term opioid treatment experience paradoxical increases in nociceptive hypersensitivity, namely, OIH. Currently, treatment options for OIH are extremely lacking. In this study, we show that the ketogenic diet recovers the abnormal pain behavior caused by chronic morphine treatment in male mice, and we further show that the therapeutic effect of the ketogenic diet is mediated through gut microbiome. Our 16S rRNA sequencing demonstrates that chronic morphine treatment causes changes in mouse gut microbiota, specifically a decrease in short-chain fatty acids-producing bacteria, and the sequencing data also show that the ketogenic diet rescues those bacteria in the mouse gut. More importantly, we show that supplementation with short-chain fatty acids (butyrate, propionate, and acetate) can delay the onset of OIH, indicating that short-chain fatty acids play a direct role in the development of OIH. Our findings suggest that gut microbiome could be targeted to treat OIH, and the ketogenic diet can be used as a complementary approach for pain relief in patients with chronic opioid treatment. We only used male mice in this study, and thus, our findings cannot be generalized to both sexes.

Examination of the role of the rotating nursing department in the training of nursing staff based on SWOT analysis.

BACKGROUND: The implementation of the rotation system in the Chinese medical industry has achieved significant results. OBJECTIVES: The present study aims to 1) explore the strengths, weaknesses, opportunities and challenges of rotational nursing department implementation and 2) provide references for developing nursing staff's competencies in leadership, performance evaluation, quality of care, communication in relationships and human resources. METHODS: A total of 16 rotational nursing department staff members from a tertiary tuberculosis specialist hospital in Beijing were interviewed, and the interview data were analysed using a strengths, weaknesses, opportunities and threats analysis and class analysis. RESULTS: The advantages of the rotational nursing department included: (1) stimulating the nursing staff's enthusiasm and creativity; (2) strengthening the communication and collaboration between departments; (3) improving the detailed management of nursing quality; and (4) enhancing the nursing staff's comprehensive abilities. The disadvantages included: (1) the design of the rotation programme focusing on practice; (2) a lack of personalisation; and (3) imperfect performance assessment of the rotating staff. Opportunities included: (1) deepening the connotation of nursing job management and (2) developing the construction of nursing discipline and the need for personal career development and value realisation. Threats included the lack of a sound rotation management model to draw on. CONCLUSION: A rotational nursing department is conducive to enhancing the competence of nursing staff in management positions and providing new ideas for hospitals to select and train nursing management talents. By taking full advantage of the benefits of vertical nursing management, designing personalised rotation training programmes, building a diversified learning and training platform and developing a positive performance incentive mechanism is recommended to fully engage the role of rotation in nursing management talent training.

TET1-mediated epigenetic regulation of tumor necrosis factor-α in trigeminal ganglia contributes to chronic temporomandibular joint pain.

Chronic temporomandibular joint (TMJ) pain profoundly affects patients' quality of life. Trigeminal tumor necrosis factor-α (TNFα) plays a pivotal role in mediating TMJ pain in mice, yet the underlying epigenetic mechanisms remain enigmatic. To unravel these epigenetic intricacies, we employed a multifaceted approach. Hydroxymethylated DNA immunoprecipitation (hMeDIP) and chromatin immunoprecipitation (ChIP) followed by qPCR were employed to investigate the demethylation of TNFα gene (Tnfa) and its regulation by ten-eleven translocation methylcytosine dioxygenase 1 (TET1) in a chronic TMJ pain mouse model. The global levels of 5-hydroxymethylcytosine (5hmc) and percentage of 5hmc at the Tnfa promoter region were measured in the trigeminal ganglia (TG) and spinal trigeminal nucleus caudalis (Sp5C) following complete Freund's adjuvant (CFA) or saline treatment. TET1 knockdown and pain behavioral testing were conducted to ascertain the role of TET1-mediated epigenetic regulation of TNFα in the pathogenesis of chronic TMJ pain. Our finding revealed an increase in 5hmc at the Tnfa promoter region in both TG and Sp5C of CFA-treated mice. TET1 was upregulated in the mouse TG, and the ChIP result showed TET1 direct binding to the Tnfa promoter, with higher efficiency in the CFA-treated group. Immunofluorescence revealed the predominant expression of TET1 in trigeminal neurons. TET1 knockdown in the TG significantly reversed CFA-induced TNFα upregulation and alleviated chronic TMJ pain. In conclusion, our study implicates TET1 as a vital epigenetic regulator contributing to chronic inflammatory TMJ pain via trigeminal TNFα signaling. Targeting TET1 holds promise for epigenetic interventions in TMJ pain management.

The Aurora kinase inhibitor AT9283 inhibits Burkitt lymphoma growth by regulating Warburg effect.

Objective: To investigate the effect of the kinase inhibitor AT9283 on Burkitt lymphoma (BL) cells and elucidate the underlying mechanisms. Methods: The effect of AT9283 on the proliferation of BL cell lines was tested using the MTT assay. Apoptosis and cell cycle were measured by flow cytometry. The proteins associated with the cell cycle, apoptosis, and the Warburg effect were detected using Western blotting. Alterations in glycolytic metabolism in terms of glucose intake and lactate concentrations were determined by glucose and lactate assays. Results: The current study utilized the GEPIA, the Human Protein Atlas (HAP) database and immunohistochemistry to conduct analyses, which revealed a high expression of Aurora kinases and Warburg effect-related proteins in malignant B-cell lymphoma tissues. AT9283 significantly inhibited the cell proliferation of BL cells and induced G2/M arrest. Additionally, AT9283 induced apoptosis in BL cells and reversed the Warburg effect by increasing glucose uptake and reducing lactate production. Moreover, the protein expression of hexokinase 2, pyruvate kinase M2, and lactate dehydrogenase A was significantly suppressed by AT9283, possibly through the inhibition of c-Myc and HIF-1α protein expression. Conclusion: The reversal of the Warburg effect in BL cells and the subsequent inhibition of cell proliferation and induction of apoptosis were observed by targeting Aurora A and Aurora B with AT9283. This finding may present new therapeutic options and targets for BL.

Gut-Brain Crosstalk and the Central Mechanisms of Orofacial Pain.

Accumulated evidence has demonstrated that the gut microbiome can contribute to pain modulation through the microbiome-gut-brain axis. Various relevant microbiome metabolites in the gut are involved in the regulation of pain signaling in the central nervous system. In this review, we summarize recent advances in gut-brain interactions by which the microbiome metabolites modulate pain, with a focus on orofacial pain, and we further discuss the role of gut-brain crosstalk in the central mechanisms of orofacial pain whereby the gut microbiome modulates orofacial pain via the vagus nerve-mediated direct pathway and the gut metabolites/molecules-mediated indirect pathway. The direct and indirect pathways both contribute to the central regulation of orofacial pain through different brain structures (such as the nucleus tractus solitarius and the parabrachial nucleus) and signaling transmission across the blood-brain barrier, respectively. Understanding the gut microbiome-regulated pain mechanisms in the brain could help us to develop non-opioid novel therapies for orofacial pain.

A female-specific role for trigeminal dynorphin in orofacial pain comorbidity.

ABSTRACT: Migraine is commonly reported in patients with temporomandibular disorders (TMDs), but little is known about the mechanisms underlying the comorbid condition. Here, we prepared a mouse model to investigate this comorbidity, in which masseter muscle tendon ligation (MMTL) was performed to induce a myogenic TMD, and the pre-existing TMD enabled a subthreshold dose of nitroglycerin (NTG) to produce migraine-like pain in mice. RNA sequencing followed by real-time quantitative polymerase chain reaction confirmation showed that MMTL plus NTG treatment increased prodynorphin ( Pdyn ) mRNA expression in the spinal trigeminal nucleus caudalis (Sp5C) of female mice but not in male mice. Chemogenetic inhibition of Pdyn -expressing neurons or microinjection of antidynorphin antiserum in the Sp5C alleviated MMTL-induced masseter hypersensitivity and diminished the MMTL-enabled migraine-like pain in female mice but not in male mice. Moreover, chemogenetic activation of Pdyn -expressing neurons or microinjection of dynorphin A (1-17) peptide in the Sp5C enabled a subthreshold dose of NTG to induce migraine-like pain in female mice but not in male mice. Taken together, our results suggest that trigeminal dynorphin has a female-specific role in the modulation of comorbid TMDs and migraine.

LINC00461 Knockdown Enhances the Effect of Ixazomib in Multiple Myeloma Cells.

BACKGROUND: LINC00461 has been implicated to be involved in several types of cancer while its roles in multiple myeloma remain unclear. Our study aims to investigate the roles of LINC00461 in multiple myeloma and explore its effects on ixazomib therapy. METHODS: LINC00461 and small nuclear ribonucleoprotein polypeptide (SNRP) B2 knockdown stable cell lines were constructed. Cell viability assays including MTT, cell number counting, and colony formation were performed. RNA-pull down and immunoblotting assays were conducted to determine the intramolecular interactions. qRT-PCR and western blotting were conducted to determine the levels of target genes. Kaplan-Meier analysis was used to evaluate overall survival rates. RESULTS: Knockdown of LINC00461 or SNRPB2 enhanced ixazomib's cytotoxicity, as well as affected its regulatory effects on cell apoptosis and cell cycle distribution. Further results showed that LINC00461 knockdown reduced the expression levels of SNRPB2 by their interactions. Additionally, a positive correlation between LINC00461 and SNRPB2 was found in patients with multiple myeloma. Low expression of SNRPB2 was associated with a high survival rate in patients with multiple myeloma. CONCLUSION: Knockdown of LINC00461 enhanced the therapeutic effects of ixazomib against multiple myeloma in part by the regulation of SNRPB2.

Assessing Orofacial Pain Behaviors in Animal Models: A Review.

Orofacial pain refers to pain occurring in the head and face, which is highly prevalent and represents a challenge to clinicians, but its underlying mechanisms are not fully understood, and more studies using animal models are urgently needed. Currently, there are different assessment methods for analyzing orofacial pain behaviors in animal models. In order to minimize the number of animals used and maximize animal welfare, selecting appropriate assessment methods can avoid repeated testing and improve the reliability and accuracy of research data. Here, we summarize different methods for assessing spontaneous pain, evoked pain, and relevant accompanying dysfunction, and discuss their advantages and disadvantages. While the behaviors of orofacial pain in rodents are not exactly equivalent to the symptoms displayed in patients with orofacial pain, animal models and pain behavioral assessments have advanced our understanding of the pathogenesis of such pain.

Chidamide works synergistically with Dasatinib by inducing cell-cycle arrest and apoptosis in acute myeloid leukemia cells.

This research aimed to explore whether Chidamide works synergistically with Dasatinib in the therapy of Acute myeloid leukemia (AML) and the potential molecular mechanism. The inhibition rate of the Dasatinib and Chidamide combination was significantly better than that of the single-drug application for HL-60 cells. The combination of Dasatinib and Chidamide significantly enhanced the Abnormal histone deacetylase (HDAC) inhibitory activity of Chidamide in Kasumi-1 and HL-60 cells. In the combined group, the proportion of S phase was significantly decreased, and the proportions of G2/M phase were significantly increased. The inhibitory rate of CD34+ CD38- HL-60 cells or Kasumi-1 cells was elevated when the cells were disposed with both Chidamide and Dasatinib. Dasatinib and Chidamide had synergistic antitumor effect. The combination with Dasatinib enhanced the HDAC inhibitory activity of Chidamide, promoted cell apoptosis and cell-cycle arrest of AML cells, and enhanced the inhibition of leukemia stem cell proliferation.

TNFα Enhances Calcium Influx by Interacting with AMPA Receptors in the Spinal Dorsal Horn Neurons.

Tumor necrosis factor alpha (TNFα) is a proinflammatory cytokine and has been implicated in pain regulation. Neuronal activity in the spinal dorsal horn contributes to nociceptive transmission. However, it is not fully understood how TNFα affects the activity of spinal dorsal horn neurons. In the present study, we used calcium imaging to characterize the mechanism by which TNFα regulates calcium influx in the cultured spinal dorsal horn neurons. We observed that TNFα incubation caused an increase in fluorescent intensity of Fura-2, a specific intracellular calcium indicator, in the cultured spinal dorsal horn neurons, and such effect was significantly inhibited by co-incubation with R7050, a selective TNFα receptor antagonist, which suggests that TNFα can enhance calcium influx and increase neuronal activity via activating TNFα receptors in the spinal dorsal horn. Using double immunofluorescence staining, we showed that TNFα receptors were co-expressed with a-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptor subunit GluA1 in the spinal dorsal horn neurons. We further observed that treatment with 1-naphthyl acetyl spermine (NASPM), a specific calcium-permeable AMPA receptor blocker, completely blocked the effect of TNFα incubation on calcium influx in the cultured neurons. Moreover, lipopolysaccharide (LPS)-induced calcium influx was inhibited by co-incubation with R7050. Together, our results suggest that TNFα in the spinal dorsal horn can increase calcium-indicated neuronal activity through the interaction between its receptor and calcium-permeable AMPA receptors.

Epigenetic Regulation of Neuroinflammation in Alzheimer's Disease.

Alzheimer's disease (AD) is a chronic and progressive neurodegenerative disease and clinically manifests with cognitive decline and behavioral disabilities. Over the past years, mounting studies have demonstrated that the inflammatory response plays a key role in the onset and development of AD, and neuroinflammation has been proposed as the third major pathological driving factor of AD, ranking after the two well-known core pathologies, amyloid ß (Aß) deposits and neurofibrillary tangles (NFTs). Epigenetic mechanisms, referring to heritable changes in gene expression independent of DNA sequence alterations, are crucial regulators of neuroinflammation which have emerged as potential therapeutic targets for AD. Upon regulation of transcriptional repression or activation, epigenetic modification profiles are closely involved in inflammatory gene expression and signaling pathways of neuronal differentiation and cognitive function in central nervous system disorders. In this review, we summarize the current knowledge about epigenetic control mechanisms with a focus on DNA and histone modifications involved in the regulation of inflammatory genes and signaling pathways in AD, and the inhibitors under clinical assessment are also discussed.

Potential Therapeutic Effects of Short-chain Fatty Acids on Chronic Pain.

The intestinal homeostasis maintained by the gut microbiome and relevant metabolites is essential for health, and its disturbance leads to various intestinal or extraintestinal diseases. Recent studies suggest that gut microbiome-derived metabolites short-chain fatty acids (SCFAs) are involved in different neurological disorders (such as chronic pain). SCFAs are produced by bacterial fermentation of dietary fibers in the gut and contribute to multiple host processes, including gastrointestinal regulation, cardiovascular modulation, and neuroendocrine-immune homeostasis. Although SCFAs have been implicated in the modulation of chronic pain, the detailed mechanisms that underlie such roles of SCFAs remain to be further investigated. In this review, we summarize currently available research data regarding SCFAs as a potential therapeutic target for chronic pain treatment and discuss several possible mechanisms by which SCFAs modulate chronic pain.

CHST15 gene germline mutation is associated with the development of familial myeloproliferative neoplasms and higher transformation risk.

Herein, we describe the clinical and hematological features of three genetically related families predisposed to myeloproliferative neoplasms (MPNs). Using whole-exome sequencing, we identified a c.1367delG mutation(p.Arg456fs) in CHST15 (NM_001270764), a gene encoding a type II transmembraneglycoproteinthat acts as a sulfotransferase and participates in the biosynthesis of chondroitin sulfate E, in germline and somatic cells in familial MPN. CHST15defects caused an increased JAK2V617F allele burden and upregulated p-Stat3 activity,leading to an increase in the proliferative and prodifferentiation potential of transgenic HEL cells. We demonstrated that mutant CHST15 is able to coimmmunoprecipitate the JAK2 protein,suggesting the presence of a CHST15-JAK2-Stat3 signaling axis in familial MPN. Gene expression profiling showed that the FREM1, IFI27 and C4B_2 genes are overexpressed in familial MPN, suggesting the activation of an "inflammatory response-extracellular matrix-immune regulation" signaling network in the CHST15 mutation background.We thus concluded that CHST15 is a novel gene that predisposes to familial MPN and increases the probability of disease development or transformation.

Gut microbiota and migraine.

Migraine is a leading cause of disability among the adult population and is a significant burden on the economies of the world. Studies into the underlying causes of migraine have spanned centuries but its underlying mechanisms are still not fully understood. In recent years, accumulating evidence implicates that microbiota-mediated gut-brain crosstalk may contribute to the pathogenesis of migraine. This review provides a brief account of the history of migraine theories and summarizes the recent studies showing how gut microbiota is involved in the pathophysiology of migraine. Future research perspectives for better understanding the role of the gut microbiota in migraine are also discussed.

Mesenchymal Stem Cells Inhibit the Effects of Dexamethasone in Multiple Myeloma Cells.

Mesenchymal stem cells (MSCs) participate in the occurrence and development of multiple myeloma. This study is aimed at exploring whether the presence of MSCs affects dexamethasone's antitumor effects against multiple myeloma. Multiple myeloma cells (OPM-2 and RPMI8226 cells) were cocultured with MSCs with or without dexamethasone. Cell viability was determined by using cell number count, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and colony formation assay, respectively. Cell cycle distribution and cell apoptosis were evaluated by using flow cytometry. The mRNA and protein expressions of target genes were checked by using qRT-PCR and western blotting, respectively. It was found that cell viability of multiple myeloma cells increased in the presence of MSCs. Besides, the presence of MSCs suppressed cell apoptosis induced by dexamethasone via the regulation of BCL-2 (B cell lymphoma 2). The presence of MSCs also affected the effects of dexamethasone on cell cycle distribution. Similarly, LINC00461 overexpression suppressed the inhibition of cell proliferation, suppressed the induction of cell apoptosis, and affected the effects on cell cycle distribution induced by dexamethasone insult. However, LINC00461 knockdown enhanced the inhibitory effects on cell proliferation and the induction of cell apoptosis induced by dexamethasone. In summary, MSCs inhibited the effects of dexamethasone on multiple myeloma and its regulatory effects were associated with LINC00461.

Differential Effects of Sevoflurane Exposure on Long-Term Fear Memory in Neonatal and Adult Rats.

It remains unclear whether exposure to sevoflurane produces different effects on long-term cognitive function in developing and mature brains. In the present study, Sprague-Dawley neonatal rats at postnatal day (PND) 7 and adult rats (PND 56) were used in all experiments. We performed fear conditioning testing to examine long-term fear memory following 4-h sevoflurane exposure. We assessed hippocampal synapse ultrastructure with a transmission electron microscope. Moreover, we investigated the effect of sevoflurane exposure on the expression of postsynaptic protein 95 (PSD-95) and its binding protein kalirin-7 in the hippocampus. We observed that early exposure to sevoflurane in neonatal rats impairs hippocampus-dependent fear memory, reduces hippocampal synapse density, and dramatically decreases the expressions of PSD-95 and kalirin-7 in the hippocampus of the developing brain. However, sevoflurane exposure in adult rats has no effects on hippocampus-dependent fear memory and hippocampal synapse density, and the expressions of PSD-95 and kalirin-7 in the adult hippocampus are not significantly altered following sevoflurane treatment. Our results indicate that sevoflurane exposure produces differential effects on long-term fear memory in neonatal and adult rats and that PSD-95 signaling may be involved in the molecular mechanism for early sevoflurane exposure-caused long-term fear memory impairment.