Drug Screening and Validation Targeting TDP-43 Proteinopathy for Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) stands as a rare, yet severely debilitating disorder marked by the deterioration of motor neurons (MNs) within the brain and spinal cord, which is accompanied by degenerated corticobulbar/corticospinal tracts and denervation in skeletal muscles. Despite ongoing research efforts, ALS remains incurable, attributed to its intricate pathogenic mechanisms. A notable feature in the pathology of ALS is the prevalence of TAR DNA-binding protein 43 (TDP-43) proteinopathy, detected in approximately 97% of ALS cases, underscoring its significance in the disease's progression. As a result, strategies targeting the aberrant TDP-43 protein have garnered attention as a potential avenue for ALS therapy. This review delves into the existing drug screening systems aimed at TDP-43 proteinopathy and the models employed for drug efficacy validation. It also explores the hurdles encountered in the quest to develop potent medications against TDP-43 proteinopathy, offering insights into the intricacies of drug discovery and development for ALS. Through this comprehensive analysis, the review sheds light on the critical aspects of identifying and advancing therapeutic solutions for ALS.

Association of cigarette smoking with cerebrospinal fluid biomarkers of insulin sensitivity and neurodegeneration.

INTRODUCTION: Cigarette smoking increases both the risk for insulin resistance and amyloid-ß (Aß) aggregation, and impaired brain insulin/insulin-like growth factor 1 (IGF1) signaling might increase risk factors for Alzheimer's disease (AD). We aimed to investigate the association among cerebrospinal fluid (CSF) insulin sensitivity/IGF1, glucose/lactate, and Aß42 and further explore whether insulin sensitivity contributed to the risk for AD in active smokers. METHODS: In this cross-sectional study, levels of insulin, IGF1, and lactate/glucose of 75 active smokers and 78 nonsmokers in CSF were measured. Three polymorphisms regulating IGF1 were genotyped. Analysis of variance was used to compare differences of variables between groups. Partial correlation was performed to test the relationship between CSF biomarkers and smoking status. General linear models were applied to test the interaction of the effect of single nucleotide polymorphisms and cigarette smoking on CSF IGF1 levels. RESULTS: In the CSF from active smokers, IGF1 and lactate levels were significantly lower (p = .016 and p = .010, respectively), whereas Aß42 (derived from our earlier research) and insulin levels were significantly higher (p < .001 and p = .022, respectively) as compared to the CSF from nonsmokers. The AG + GG genotype of rs6218 in active smokers had a significant effect on lower CSF IGF1 levels (p = .004) and lower CSF insulin levels in nonsmokers (p = .016). CONCLUSIONS: Cigarette smoking as the "at-risk" factor for AD might be due to lower cerebral insulin sensitivity in CSF, and the subjects with rs6218G allele seem to be more susceptible to the neurodegenerative risks for cigarette smoking.

Usage Patterns of Traditional Chinese Medicine for Patients with Bipolar Disorder: A Population-Based Study in Taiwan.

BACKGROUND: Patients with bipolar disorder (BD) receive traditional Chinese medicine (TCM) for clinical needs unmet with psychotropic medications. However, the clinical characteristics of practices and outcomes of TCM in BD are not fully understood. This cohort study investigated the clinical characteristics, principal diagnoses, TCM interventions, and TCM prescriptions in patients with BD. METHODS: Data for a total of 12,113 patients with BD between 1996 and 2013 were withdrawn from Taiwan's longitudinal health insurance database 2000 (LHID 2000). The chi-square test was used for categorical variables, and the independent t-test was used for continuous variables. A p-value less than 0.05 indicated significance. RESULTS: One thousand three hundred nineteen patients who visited TCM clinics after the diagnosis of BD were in the TCM group, while those who never visited TCM were in the non-TCM group (n = 1053). Compared to the non-TCM group, patients in the TCM group had younger average age, a higher percentage of female individuals, more comorbidities of anxiety and alcohol use disorders, and higher mood stabilizer usage rates. The TCM group exhibited pain-related indications, including joint pain, myalgia, myositis, headache, and sleep disturbances. Corydalis yanhusuo and Shu-Jing-Huo-Xue-Tang were the most useful single herbs and herbal formulae. CONCLUSIONS: Physicians need to be aware of the use of TCM in patients with BD.

Unraveling the impact of Omega-3 polyunsaturated fatty acids on blood-brain barrier (BBB) integrity and glymphatic function.

Alzheimer's disease (AD) and other forms of dementia represent major public health challenges but effective therapeutic options are limited. Pathological brain aging is associated with microvascular changes and impaired clearance systems. The application of omega-3 polyunsaturated fatty acids (n-3 or omega-3 PUFAs) is one of the most promising nutritional interventions in neurodegenerative disorders from epidemiological data, clinical and pre-clinical studies. As essential components of neuronal membranes, n-3 PUFAs have shown neuroprotection and anti-inflammatory effects, as well as modulatory effects through microvascular pathophysiology, amyloid-beta (Aß) clearance and glymphatic pathways. This review meticulously explores these underlying mechanisms that contribute to the beneficial effects of n-3 PUFAs against AD and dementia, synthesizing evidence from both animal and interventional studies.

Roles of Omega-3 Polyunsaturated Fatty Acids in Managing Cognitive Impairment in Chronic Obstructive Pulmonary Disease: A Review.

Chronic obstructive pulmonary disease (COPD) contributes significantly to the death of people worldwide, especially the elderly. An essential feature of COPD is pulmonary inflammation, which results from long-term exposure to noxious substances from cigarette smoking and other environmental pollutants. Pulmonary inflammatory mediators spill over to the blood, leading to systemic inflammation, which is believed to play a significant role in the onset of a host of comorbidities associated with COPD. A substantial comorbidity of concern in COPD patients that is often overlooked in COPD management is cognitive impairment. The exact pathophysiology of cognitive impairment in COPD patients remains a mystery; however, hypoxia, oxidative stress, systemic inflammation, and cerebral manifestations of these conditions are believed to play crucial roles. Furthermore, the use of medications to treat cognitive impairment symptomatology in COPD patients has been reported to be associated with life-threatening adverse effects, hence the need for alternative medications with reduced side effects. In this Review, we aim to discuss the impact of cognitive impairment in COPD management and the potential mechanisms associated with increased risk of cognitive impairment in COPD patients. The promising roles of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) in improving cognitive deficits in COPD patients are also discussed. Interestingly, ω-3 PUFAs can potentially enhance the cognitive impairment symptomatology associated with COPD because they can modulate inflammatory processes, activate the antioxidant defence system, and promote amyloid-beta clearance from the brain. Thus, clinical studies are crucial to assess the efficacy of ω-3 PUFAs in managing cognitive impairment in COPD patients.

Cellular and molecular mechanisms in vascular repair after traumatic brain injury: a narrative review.

Traumatic brain injury (TBI) disrupts normal brain function and is associated with high morbidity and fatality rates. TBI is characterized as mild, moderate or severe depending on its severity. The damage may be transient and limited to the dura matter, with only subtle changes in cerebral parenchyma, or life-threatening with obvious focal contusions, hematomas and edema. Blood vessels are often injured in TBI. Even in mild TBI, dysfunctional cerebral vascular repair may result in prolonged symptoms and poor outcomes. Various distinct types of cells participate in vascular repair after TBI. A better understanding of the cellular response and function in vascular repair can facilitate the development of new therapeutic strategies. In this review, we analyzed the mechanism of cerebrovascular impairment and the repercussions following various forms of TBI. We then discussed the role of distinct cell types in the repair of meningeal and parenchyma vasculature following TBI, including endothelial cells, endothelial progenitor cells, pericytes, glial cells (astrocytes and microglia), neurons, myeloid cells (macrophages and monocytes) and meningeal lymphatic endothelial cells. Finally, possible treatment techniques targeting these unique cell types for vascular repair after TBI are discussed.

Omega-3 Polyunsaturated Fatty Acids in Managing Comorbid Mood Disorders in Chronic Obstructive Pulmonary Disease (COPD): A Review.

Chronic obstructive pulmonary disease (COPD) is the third-leading cause of mortality globally, significantly affecting people over 40 years old. COPD is often comorbid with mood disorders; however, they are frequently neglected or undiagnosed in COPD management, thus resulting in unintended treatment outcomes and higher mortality associated with the disease. Although the exact link between COPD and mood disorders remains to be ascertained, there is a broader opinion that inflammatory reactions in the lungs, blood, and inflammation-induced changes in the brain could orchestrate the onset of mood disorders in COPD. Although the current management of mood disorders such as depression in COPD involves using antidepressants, their use has been limited due to tolerability issues. On the other hand, as omega-3 polyunsaturated fatty acids (n-3 PUFAs) play a vital role in regulating inflammatory responses, they could be promising alternatives in managing mood disorders in COPD. This review discusses comorbid mood disorders in COPD as well as their influence on the progression and management of COPD. The underlying mechanisms of comorbid mood disorders in COPD will also be discussed, along with the potential role of n-3 PUFAs in managing these conditions.

Clinical efficacy and immune effects of acupuncture in patients with comorbid chronic pain and major depression disorder: A double-blinded, randomized controlled crossover study.

BACKGROUND: Depression and pain are highly comorbid and share biological mechanisms. Acupuncture is commonly used to manage both pain and depression, but the choice of acupoints for specific disorders differs. This study aimed to investigate whether specific acupuncture intervention on pain- and depression-acupoints would have specific efficacy and immune effects in patients with comorbid chronic pain and major depressive disorder (MDD). METHODS: We performed a subject- and assessor-blinded, crossover, and randomized controlled clinical trial of depression- and pain-specific acupuncture intervention and measured clinical responses and proinflammatory cytokines in patients with comorbid chronic pain and MDD. Specific acupoints for pain and depression were used in random order with a washout interval. Forty-seven patients were enrolled and randomly assigned to two groups: (1) the depression-pain group (23 patients who were treated with depression-specific acupoints and then the pain-specific acupoints after the washout) and (2) pain-depression group (24 patients with the reverse order). RESULTS: The pain-specific acupoints for pain did not reduce Brief Pain Inventory scores to a significantly greater degree (-0.97 ± 1.69) than the depression-specific acupoints (-0.28 ± 1.88); likewise, the depression-specific acupoints did not significantly ameliorate Hamilton Depression Rating Scale (-4.59 ± 6.02) than the pain-specific acupoints (-6.69 ± 6.61). The pain-specific acupoints improved Beck Depression Inventory-Second Edition (-6.74 ± 9.76) even better than the depression-specific acupoints (-1.92 ± 10.74). The depression-specific acupoints did not significantly decrease the depression-related interleukin (IL)-6 level (-1.24 ± 6.67) than the pain-specific acupoints (-0.60 ± 4.36). The changed levels of IL-1ß, tumor necrosis factor (TNF)-α between the depression-specific acupoints (-37.41 ± 194.49; -12.53 ± 54.68) and the pain-specific acupoints (-15.46 ± 87.56; -7.28 ± 27.86) could not reach significantly different, too. CONCLUSION: This study rejected our hypothesis that the pain-specific acupoints might produce superior analgesic effects than the depression-specific acupoints and vice versa. The cytokine results might imply that pain and depression share common biological mechanisms. (trial registration: https://www. CLINICALTRIALS: gov: NCT03328819).

Anti-Inflammatory Effect of Traditional Chinese Medicine on the Concept of Mind-Body Interface.

In this chapter, we conducted a systemic literature review for the anti-inflammatory effects of Traditional Chinese Medicine (TCM) applying molecular mechanisms focusing on the neuroinflammation and gut-brain axis in three neuropsychiatric disorders: major depressive disorder, Alzheimer's disease, and Parkinson's disease. We demonstrated the anti-inflammation or immunomodulation effects of TCM, including acupuncture, from basic and clinical research, including cellular and molecular approaches. In conclusion, inflammation plays a critical role in the neuropsychopathological process. At the same time, anti-inflammation seems to be the common biological pathway for the effects of TCM and acupuncture in depression, Alzheimer's disease, and Parkinson's disease.

The Clinical Observation of Inflammation Theory for Depression: The Initiative of the Formosa Long COVID Multicenter Study (FOCuS).

There is growing evidence that the coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with increased risks of psychiatric sequelae. Depression, anxiety, cognitive impairments, sleep disturbance, and fatigue during and after the acute phase of COVID-19 are prevalent, long-lasting, and exerting negative consequences on well-being and imposing a huge burden on healthcare systems and society. This current review presented timely updates of clinical research findings, particularly focusing on the pathogenetic mechanisms underlying the neuropsychiatric sequelae, and identified potential key targets for developing effective treatment strategies for long COVID. In addition, we introduced the Formosa Long COVID Multicenter Study (FOCuS), which aims to apply the inflammation theory to the pathogenesis and the psychosocial and nutrition treatments of post-COVID depression and anxiety.

Bilateral theta-burst stimulation on emotional processing in major depressive disorder: A functional neuroimaging study from a randomized, double-blind, sham-controlled trial.

AIM: Bilateral theta-burst stimulation (biTBS; intermittent TBS over the left dorsolateral prefrontal cortex [DLPFC] and continuous TBS over the right DLPFC) has demonstrated efficacy in improving symptoms in patients with major depressive disorder (MDD). However, the underlying brain mechanisms remain unknown. The authors aimed to investigate the antidepressant efficacy of biTBS monotherapy and its effects on the brain responses measured by functional magnetic resonance imaging (fMRI) during emotional processing in MDD. METHODS: The authors conducted a double-blind, randomized, sham-controlled trial of patients with MDD who exhibited no responses to at least one adequate antidepressant treatment for the prevailing episode. Recruited patients were randomly assigned to 10 biTBS monotherapy or sham stimulation sessions. The fMRI scans during performing emotional recognition task were obtained at baseline and after 10 sessions of treatment. Depressive symptoms were assessed using the 21-item Hamilton Rating Scale for Depression at baseline and the weeks 4, 8, 12, 16, 20, and 24 week. RESULTS: The biTBS group (n = 17) exhibited significant decreases in depression scores compared with the sham group (n = 11) at week 8 (70% vs 40%; P = 0.02), and the significant differences persisted during the 24-week follow-up periods. At week 4, when the treatment course was completed, patients in the biTBS group, but not in the sham group, exhibited increased brain activities over the left superior and middle frontal gyrus during negative emotional stimuli. CONCLUSION: The authors' findings provide the first evidence regarding the underlying neural mechanisms of biTBS therapy to improve clinical symptoms in patients with MDD.

The west meets the east - A need for a renaissance in brain, behavior, and immunity research.

Psychoneuroimmunology (PNI)-the burgeoning concept in recent years, can potentially contribute to developing effective treatments for mental health disorders. Despite the advancement in the modern pharmacological approach for mental disorders, especially Western medicine attributed explicitly to interacting with a specific target has given rise to unmet needs, and treatment failure has led to the proliferation and exploration of traditional and alternative therapies. As research into these exciting under-explored traditional treatment approaches continues to evolve at an unprecedented pace, the need to gain vital insights into the potentiality and mechanism of action in neuropsychiatric disorders has resulted in the current Special Issue. This Special Issue is devoted to psychoneuroimmunology, focusing on introducing the recent advances with traditional and alternative medications in East Asia at the interface of immunology, neurosciences, molecular psychiatry and behavioural medicine neurosciences.

Omega-3 fatty acids and blood-based biomarkers in Alzheimer's disease and mild cognitive impairment: A randomized placebo-controlled trial.

BACKGROUND: Increased serum levels of pro-inflammatory biomarkers are consistently associated with cognitive decline. The omega-3 unsaturated fatty acids (n-3 PUFAs) had been linked to slowing cognitive decline due to their potential anti-inflammatory effects. To our knowledge, the different regiments of pure DHA, pure EPA, and their combination on various associated symptoms of dementia, including a mild form of cognitive impairment (MCI) and Alzheimer's disease (AD), have never been studied. METHODS: This multisite, randomized, double-blind, placebo-controlled trial was conducted at two veteran's retirement centers and one medical center in central Taiwan between 2013 and 2015. 163 MCI or AD patients were randomly assigned to placebo (n = 40), docosahexaenoic acid (DHA, 0.7 g/day, n = 41), eicosapentaenoic acid (EPA, 1.6 g/day, n = 40), or EPA (0.8 g/day) + DHA (0.35 g/day) (n = 42) group for 24 months. The results were measured as the cognitive and functional abilities, biochemical, and inflammatory cytokines profiles. Chi-square tests, two-sample t-test, ANOVA, and linear mixedeffects models were conducted with p < 0.05. RESULTS: 131 (80%) participants had completed the trial with all cognitive, functional, and mood status assessments. The statistically significant difference between the placebo and treatment groups was not determined, concerning the changes in cognitive, functional, and mood status scores, the biochemical profiles, and inflammatory cytokines levels. However, EPA was found to reduce the C-C motif ligands 4 (CCL4) level (p < 0.001). Additionally, EPA could reduce the constructional praxis (p < 0.05) and spoken language ability scores (p < 0.01), and DHA also reduced the spoken language ability score (p < 0.05). CONCLUSION: Overall, n-3 PUFAs supplements did not reduce cognitive, functional, and depressive symptom outcomes, but spoken language ability and constructional praxis subitems of ADAS-cog. These findings show that attention to clinical heterogeneity in dementia is crucial when studying nutrients interventions, such as n-3 PUFAs. In addition, with small effect size CCL4 is a better indicator than other inflammatory cytokines for EPA treatment response.

A Comprehensive Summary of the Knowledge on COVID-19 Treatment.

Currently, the world is challenged by the coronavirus disease 2019 (COVID-19) pandemic. Epidemiologists and researchers worldwide are invariably trying to understand and combat this precarious new disease. Scrutinizing available drug options and developing potential new drugs are urgent needs to subdue this pandemic. Several intervention strategies are being considered and handled worldwide with limited success, and many drug candidates are yet in the trial phase. Despite these limitations, the development of COVID-19 treatment strategies has been accelerated to improve the clinical outcome of patients with COVID-19, and some countries have efficiently kept it under control. Recently, the use of natural and traditional medicine has also set the trend in coronavirus treatment. This review aimed to discuss the prevailing COVID-19 treatment strategies available globally by examining their efficacy, potential mechanisms, limitations, and challenges in predicting a future potential treatment candidate and bridging them with the effective traditional Chinese medicine (TCM). The findings might enrich the knowledge on traditional alternative medication and its complementary role with Western medicine in managing the COVID-19 epidemic.

Experimental alcoholism primes structural and functional impairment of the glymphatic pathway.

Alcoholism is a risk factor for the development of cognitive decline and dementia. Here we demonstrated that the glymphatic function in the brain was impaired by alcohol administration. Acute moderate alcohol administration substantially retarded and reduced the entry of subarachnoid cerebrospinal fluid (CSF) via the paravascular space into the cerebral parenchyma, thus impaired CSF-interstitial fluid (ISF) exchange and parenchymal amyloid ß (Aß) peptide clearance. The elevated release of ß-endorphin and reduced cerebrovascular pulsatility after acute alcohol administration may account for the impairment of the glymphatic function. Chronic moderate alcohol consumption led to pronounced activation of astrocytes and a widespread loss of perivascular AQP4 polarization in the brain, which results in an irreversible impairment of the glymphatic function. The results of the study suggest that impaired glymphatic functions and reduced parenchymal Aß clearance found in both acute and chronic alcohol treatment may contribute to the development of cognitive decline and dementia in alcoholism.

S-adenosyl-l-methionine (SAMe), cannabidiol (CBD), and kratom in psychiatric disorders: Clinical and mechanistic considerations.

Given the limitations of prescription antidepressants, many individuals have turned to natural remedies for the management of their mood disorders. We review three selected natural remedies that may be of potential use as treatments for depressive disorders and other psychiatric or neurological conditions. The best studied and best supported of these three remedies is S-adenosyl-l-methionine (SAMe), a methyl donor with a wide range of physiological functions in the human organism. With the increasing legalization of cannabis-related products, cannabidiol (CBD) has gained popularity for various potential indications and has even obtained approval in the United States and Canada for certain neurological conditions. Kratom, while potentially useful for certain individuals with psychiatric disorders, is perhaps the most controversial of the three remedies, in view of its greater potential for abuse and dependence. For each remedy, we will review indications, doses and delivery systems, potential anti-inflammatory and immunomodulatory action, adverse effects, and will provide recommendations for clinicians who may be considering prescribing these remedies in their practice.

Melatonergic agonist regulates circadian clock genes and peripheral inflammatory and neuroplasticity markers in patients with depression and anxiety.

OBJECTIVE: Circadian dysfunction is a core manifestation and a risk factor for psychiatric disorders. Ramelteon (RMT), a melatonin receptor agonist, has been shown to induce sleep phase shifts and has been used to normalize sleep onset time. RMT has been used in sleep disorders, depression and anxiety. In this study, we aimed to investigate the effects of RMT in regulating gene expression profiles of the circadian clock and peripheral markers of inflammation and neuroplasticity. METHODS: Sixteen patients with a diagnosis of primary insomnia comorbid with depression and anxiety and ten healthy controls were recruited in an 8-week open-label trial. The patients with primary insomnia received RMT 8 mg/day. The morning expression profiles of 15 core clock genes from peripheral blood mononuclear cells (PBMCs), urine and plasma levels of melatonin and its metabolite levels, and plasma inflammatory markers and neurotrophin levels were evaluated at baseline, 4th and 8th week of RMT treatment. RESULTS: RMT treatment was associated with significant clinical improvement in depression scores at 8th week (Hamilton depression rating scale scores (Mean ±â€¯SEM) from 21.5 ±â€¯2.44 to 14.31 ±â€¯2.25, p ≤ 0.05). The overall poor sleep quality (Pittsburgh sleep quality index) of the patient group significantly improved (p ≤ 0.05) following RMT treatment. The mRNA level analysis showed a significant association between RMT treatment and alterations of the nine core circadian genes (CLOCK, PER1, PER2, CRY1, CRY2, NR1D1, NR1D2, DEC1 and TIMELESS) in the patient group when compared with the control group (p ≤ 0.05). Compared with the controls, the patient group had a decrease in neurotrophins (brain-derived neurotrophic factor, glial cell line-derived neurotrophic factor and beta-nerve growth factor; p ≤ 0.05) but an increase in pro-inflammatory cytokine levels (interleukin-6, interleukin-1b, tumour necrosis factor-alpha and interferon gamma; p ≤ 0.05); RMT treatment normalized the levels of neurotrophins and cytokine levels. CONCLUSION: RMT treatment is able to restore phase-shifted melatonin markers, normalized the altered expression of the circadian genes, the levels of inflammatory cytokines and neurotrophins in patients with insomnia comorbid anxiety and depression.

Omega-3 polyunsaturated fatty acids promote brain-to-blood clearance of ß-Amyloid in a mouse model with Alzheimer's disease.

Amyloid-ß (Aß) plaques is one of the typical pathological hallmark of Alzheimer disease (AD). Accumulating evidence suggests that the imbalance between Aß production and clearance leads to extracellular Aß accumulation in the brain. It is reported that the blood-brain barrier (BBB) transport plays a predominant role in Aß clearance from brain to blood. In the present study, we investigated dynamic alterations of BBB transport function in the early disease stage of AD using APPswe/PS1dE9 C57BL/6J (APP/PS1) transgenic mice. Our results showed that the expression of lipoprotein receptor-related protein 1 (LRP-1), a main efflux transporter of BBB, started to decrease at the age of 4 months old. Interestingly, supplementing with fish oil which is rich in omega-3 polyunsaturated fatty acids (PUFAs) significantly enhanced the expression level of LRP-1 and promoted Aß clearance from the bran to circulation, as revealed by reduced soluble/insoluble Aß levels and senile plaques in the brain parenchyma and a corresponding increase of Aß levels in plasma. Besides, fish oil supplement significantly inhibited the NF-κB activation, reduced the expression of interleukin-1ß and tumor necrosis factor-α, and suppressed the glial activation in APP/PS1 mice. The results of the study provide evidence that BBB transport function could be impaired at a very early disease stage, which might contribute to Aß pathological accumulation in AD, and omega-3 PUFAs intervention could be an effective strategy for the prevention of the progression of AD through promoting Aß clearance from brain-to-blood.