Pathophysiological Manifestations Research Articles

PolyGA targets the ER stress-adaptive response by impairing GRP75 function at the MAM in C9ORF72-ALS/FTD

ER stress signaling is linked to the pathophysiological and clinical disease manifestations in amyotrophic lateral sclerosis (ALS). Here, we have investigated ER stress-induced adaptive mechanisms in C9ORF72-ALS/FTD, focusing on uncovering early endogenous neuroprotective mechanisms and the crosstalk between pathological and adaptive responses in disease onset and progression. We provide evidence for the early onset of ER stress-mediated adaptive response in C9ORF72 patient-derived motoneurons (MNs), reflected by the elevated increase in GRP75 expression. These transiently increased GRP75 levels enhance ER–mitochondrial association, boosting mitochondrial function and sustaining cellular bioenergetics during the initial stage of disease, thereby counteracting early mitochondrial deficits. In C9orf72 rodent neurons, an abrupt reduction in GRP75 expression coincided with the onset of UPR, mitochondrial dysfunction and the emergence of PolyGA aggregates, which co-localize with GRP75. Similarly, the overexpression of PolyGA in WT cortical neurons or C9ORF72 patient-derived MNs led to the sequestration of GRP75 within PolyGA inclusions, resulting in mitochondrial calcium (Ca2+) uptake impairments. Corroborating these findings, we found that PolyGA aggregate-bearing human post-mortem C9ORF72 hippocampal dentate gyrus neurons not only display reduced expression of GRP75 but also exhibit GRP75 sequestration within inclusions. Sustaining high GRP75 expression in spinal C9orf72 rodent MNs specifically prevented ER stress, normalized mitochondrial function, abrogated PolyGA accumulation in spinal MNs, and ameliorated ALS-associated behavioral phenotype. Taken together, our results are in line with the notion that neurons in C9ORF72-ALS/FTD are particularly susceptible to ER–mitochondrial dysfunction and that GRP75 serves as a critical endogenous neuroprotective factor. This neuroprotective pathway, is eventually targeted by PolyGA, leading to GRP75 sequestration, and its subsequent loss of function at the MAM, compromising mitochondrial function and promoting disease onset.

Interconnection between cardiovascular, renal and metabolic disorders: A narrative review with a focus on Japan.

Insights from epidemiological, clinical and basic research are illuminating the interplay between metabolic disorders, cardiovascular disease (CVD) and kidney dysfunction, termed cardio-renal-metabolic (CRM) disease. Broadly defined, CRM disease involves multidirectional interactions between metabolic diseases such as type 2 diabetes (T2D), various types of CVD and chronic kidney disease (CKD). T2D confers increased risk for heart failure, which-although well known-has only recently come into focus for treatment, and may differ by ethnicity, whereas atherosclerotic heart disease is a well-established complication of T2D. Many people with T2D also have CKD, with a higher risk in Asians than their Western counterparts. Furthermore, CVD increases the risk of CKD and vice versa, with heart failure, notably, present in approximately half of CKD patients. Molecular mechanisms involved in CRM disease include hyperglycaemia, insulin resistance, hyperactivity of the renin-angiotensin-aldosterone system, production of advanced glycation end-products, oxidative stress, lipotoxicity, endoplasmic reticulum stress, calcium-handling abnormalities, mitochondrial malfunction and deficient energy production, and chronic inflammation. Pathophysiological manifestations of these processes include diabetic cardiomyopathy, vascular endothelial dysfunction, cardiac and renal fibrosis, glomerular hyperfiltration, renal hypoperfusion and venous congestion, reduced exercise tolerance leading to metabolic dysfunction, and calcification of atherosclerotic plaque. Importantly, recognition of the interaction between CRM diseases would enable a more holistic approach to CRM care, rather than isolated treatment of individual conditions, which may improve patient outcomes. Finally, aspects of CRM diseases may differ between Western and East Asian countries such as Japan, a super-ageing country, with potential differences in epidemiology, complications and prognosis that represent an important avenue for future research.

Just When We Thought That COVID Was Over: A Systematic Review.

As the globe continues to grapple and scuffle with new emerging strains of COVID every day, a set of recovered patients continue to show persistent enervating symptoms. Many patients never fully recovered after COVID and had neurological and psychiatric symptoms for weeks or months. The emphasis of our study is on these long haulers, particularly on the two critical organ systems of the body, i.e., the central nervous system and the muscular system. Depending upon the severity of the disease, many signs and symptoms continue to linger, ranging from weeks to months.A total of 29 studies are included in our review after thorough screening, application of inclusion and exclusion criteria, and quality appraisals. The total number of patients included is 6012.We found many long-term effects, but the emphasis of our study continued to remain on the two main organ systems that resulted in prolonged COVID with debilitating symptoms and thus affected the quality of life of these patients. Various factors and underlying pathophysiologic manifestations result in the predominance of these signs and symptoms.Furthermore, the patient's underlying medical conditions and other environmental factors may add to it. More focus is required on the quality of life post-COVID, and this requires a team of specialists. There are still many unanswered questions like which ethnicity is affected more, why females are more prone to the long symptoms, and the effects of various treatments on the long-term signs and symptoms.

Separation and Analytical Techniques Used in Snake Venomics: A Review Article

The deleterious consequences of snake envenomation are due to the extreme protein complexity of snake venoms. Therefore, the identification of their components is crucial for understanding the clinical manifestations of envenomation pathophysiology and for the development of effective antivenoms. In addition, snake venoms are considered as libraries of bioactive molecules that can be used to develop innovative drugs. Numerous separation and analytical techniques are combined to study snake venom composition including chromatographic techniques such as size exclusion and RP-HPLC and electrophoretic techniques. Herein, we present in detail these existing techniques and their applications in snake venom research. In the first part, we discuss the different possible technical combinations that could be used to isolate and purify SV proteins using what is known as bioassay-guided fractionation. In the second part, we describe four different proteomic strategies that could be applied for venomics studies to evaluate whole venom composition, including the mostly used technique: RP-HPLC. Eventually, we show that to date, there is no standard technique used for the separation of all snake venoms. Thus, different combinations might be developed, taking into consideration the main objective of the study, the available resources, and the properties of the target molecules to be isolated.

Stem Cell-Derived Exosomes: A New Method for Reversing Skin Aging.

Senescence is an inevitable natural life process that involves structural and functional degeneration of tissues and organs. Recently, the process of skin aging has attracted much attention. Determining a means to delay or even reverse skin aging has become a research hotspot in medical cosmetology and anti-aging. Dysfunction in the epidermis and fibroblasts and changes in the composition and content of the extracellular matrix are common pathophysiological manifestations of skin aging. Reactive oxygen species and matrix metalloproteinases play essential roles in this process. Stem cells are pluripotent cells that possess self-replication abilities and can differentiate into multiple functional cells under certain conditions. These cells also possess a strong ability to facilitate tissue repair and regeneration. Stem cell transplantation has the potential for application in anti-aging therapy. Increasing studies have demonstrated that stem cells perform functions through paracrine processes, particularly those involving exosomes. Exosomes are nano-vesicular substances secreted by stem cells that participate in cell-to-cell communication by transporting their contents into target cells. In this chapter, the biological characteristics of exosomes were reviewed, including their effects on extracellular matrix formation, epidermal cell function, fibroblast function and antioxidation. Exosomes derived from stem cells may provide a new means to reverse skin aging.

Highly perturbed genes and hub genes associated with type 2 diabetes in different tissues of adult humans: a bioinformatics analytic workflow

Type 2 diabetes (T2D) has a complex etiology which is not yet fully elucidated. The identification of gene perturbations and hub genes of T2D may deepen our understanding of its genetic basis. We aimed to identify highly perturbed genes and hub genes associated with T2D via an extensive bioinformatics analytic workflow consisting of five steps: systematic review of Gene Expression Omnibus and associated literature; identification and classification of differentially expressed genes (DEGs); identification of highly perturbed genes via meta-analysis; identification of hub genes via network analysis; and downstream analysis of highly perturbed genes and hub genes. Three meta-analytic strategies, random effects model, vote-counting approach, and p value combining approach, were applied. Hub genes were defined as those nodes having above-average betweenness, closeness, and degree in the network. Downstream analyses included gene ontologies, Kyoto Encyclopedia of Genes and Genomes pathways, metabolomics, COVID-19-related gene sets, and Genotype-Tissue Expression profiles. Analysis of 27 eligible microarrays identified 6284 DEGs (4592 downregulated and 1692 upregulated) in four tissue types. Tissue-specific gene expression was significantly greater than tissue non-specific (shared) gene expression. Analyses revealed 79 highly perturbed genes and 28 hub genes. Downstream analyses identified enrichments of shared genes with certain other diabetes phenotypes; insulin synthesis and action-related pathways and metabolomics; mechanistic associations with apoptosis and immunity-related pathways; COVID-19-related gene sets; and cell types demonstrating over- and under-expression of marker genes of T2D. Our approach provided valuable insights on T2D pathogenesis and pathophysiological manifestations. Broader utility of this pipeline beyond T2D is envisaged.

Analysis and Characterization of Lactobacillus paragasseri and Lacticaseibacillus paracasei: Two Probiotic Bacteria that Can Degrade Intestinal Oxalate in Hyperoxaluric Rats.

In the present study, we characterized the probiotic properties of two commercially available bacterial strains, Lactobacillus paragasseri UBLG-36 and Lacticaseibacillus paracasei UBLPC-87, and evaluated their ability to degrade oxalate in vitro and in a hyperoxaluria-induced nephrolithiasis rat model. UBLG-36 harboring two oxalate catabolizing genes, oxalyl coenzyme A decarboxylase (oxc) and formyl coenzyme A transferase (frc), was previously shown to degrade oxalate in vitro effectively. Here, we show that UBLPC-87, lacking both oxc and frc, could still degrade oxalate in vitro. Both these strains harbored several potential putative probiotic genes that may have conferred them the ability to survive in low pH and 0.3% bile, resist antibiotic stress, show antagonistic activity against pathogenic bacteria, and adhere to epithelial cell surfaces. We further evaluated if UBLG-36 and UBLPC-87 could degrade oxalate in vivo and prevent hyperoxaluria-induced nephrolithiasis in rats. We observed that rats treated with 4.5% sodium oxalate (NaOx) developed hyperoxaluria and renal stones. However, when pre-treated with UBLG-36 or UBLPC-87 before administering 4.5% NaOx, the rats were protected against several pathophysiological manifestations of hyperoxaluria. Compared to the hyperoxaluric rats, the probiotic pre-treated rats showed reduced urinary excretion of oxalate and urea (p < 0.05), decreased serum blood urea nitrogen and creatinine (p < 0.05), alleviated stone formation and renal histological damage, and an overall decrease in renal tissue oxalate and calcium content (p < 0.05). Taken together, both UBLG-36 and UBLPC-87 are effective oxalate catabolizing probiotics capable of preventing hyperoxaluria and alleviating renal damage associated with nephrolithiasis.

Clinical research on the use of bordered foam dressings in the treatment of complex wounds: A systematic review of reported outcomes and applied measurement instruments

ObjectiveThe aim of this review article was to identify reported outcomes and measurement instruments used in clinical research on bordered foam dressings in the treatment of complex wounds. MethodsMEDLINE (PubMed interface), Cumulative Index to Nursing and Allied Health Literature (CINAHL), EMBASE, and The Cochrane Library were systematically searched using a combination of key terms including; wounds, bordered foam dressing, and treatment. Studies were included if they (1) targeted an adult population, (2) addressed the treatment of complex wounds with a bordered foam dressing as the primary wound dressing, (3) were retrieved from original research, and (4) were published between 2000 and 2022. There were no restrictions on language or study design. Studies that focused primarily on the prevention of complex wounds were excluded. Data extraction included outcome domains, outcomes, instruments, time points, and outcome measures. The OMERACT Filter 2.0 was used as a conceptual framework for the extraction of outcomes. ResultsA total of 24 outcome domains and 82 outcomes were identified. The outcomes were categorised into five core areas: (1) impact on life, (2) dressing performance, (3) pathophysiological manifestations, (4) resource use, and (5) adverse events. Thirtynine outcomes (47.0%) were measured at more than one time point. The most frequently reported time point was ‘at the end of treatment’ (62.7%). Outcomes were measured using self-report instruments, clinical observations, and bio-physiological instruments. ConclusionThis systematic review identified reported outcomes and measurement instruments in research on bordered foam dressings in the treatment of complex wounds. The variety and lack of consistency in terms of instruments, time points and outcome measurements made it difficult to compare data directly across different reported studies. A solution to the variety in outcome reporting across studies in complex wound care, and moreover for the treatment with bordered foam dressings, is the development of a Core Outcome Set (COS). The outcomes in this review article will inform the next steps of developing a COS, where patients, clinicians and researchers will be involved to decide on the final outcomes included in a COS for the treatment of complex wounds with bordered foam dressings.

Association between type 2 diabetes status and prevalence of liver steatosis and fibrosis among adults aged ≥ 40 years

BackgroundType 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease frequently coexist and share pathophysiological manifestations. This study aimed to explore the association between T2DM status and prevalence of liver steatosis and fibrosis, identified using the controlled attenuation parameter and liver stiffness measurement attained via liver ultrasound transient elastography.MethodsThis was a cross-sectional analysis of data collected in the National Health and Nutrition Examination Survey for 2017–2018. Multivariable logistic regression model was used to evaluate the association between T2DM and prevalence of liver steatosis and fibrosis. Subgroup analyses, stratified by sex age, race, and body mass index (BMI), were further performed.ResultsOf the 2,780 participants aged ≥ 40 years enrolled, 749 had T2DM, and 2,031 did not. After adjustment for potential confounders, T2DM was associated with a higher prevalence of liver steatosis (OR = 1.7, 95% CI, 1.3–2.1). This T2DM-related prevalence was higher among women (OR = 1.8, 95% CI, 1.3–2.5) and in the non-Hispanic Black (OR = 1.8, 95% CI, 1.1–3.0), other race (OR = 1.9, 95% CI, 1.2–3.0), and BMI < 25 kg/m2 (OR = 2.0, 95% CI, 1.1–3.8) groups. T2DM was also associated with a significantly higher prevalence of fibrosis (OR = 2.0, 95% CI, 1.5–2.7), with this association being more prominent for the other race (OR = 2.9, 95% CI, 1.5–5.5) and BMI < 25 kg/m2 (OR = 3.3, 95% CI: 1.3–8.8) groups.ConclusionsOur findings indicated a positive association between T2DM status and prevalence of hepatic steatosis and fibrosis. This association was more prominent for individuals with a BMI < 25 kg/m2 and was influenced by race-specific effects.

A pathological role of the Hsp40 protein Ydj1/DnaJA1 in models of Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of dementia with millions of people affected worldwide. Pathophysiological manifestations of AD include the extracellular accumulation of amyloid beta (Abeta) pep-tides, products of the proteolytic cleavage of the amy-loid precursor protein APP. Increasing evidence sug-gests that Abeta peptides also accumulate intracellular-ly, triggering neurotoxic events such as mitochondrial dysfunction. However, the molecular factors driving formation and toxicity of intracellular Abeta are poorly understood. In our recent study [EMBO Mol Med 2022 - e13952], we used different eukaryotic model systems to identify such factors. Based on a genetic screen in yeast and subsequent molecular analyses, we found that both the yeast chaperone Ydj1 and its human ortholog DnaJA1 physically interact with Abeta, facili-tate the aggregation of Abeta peptides into small oli-gomers and promote their translocation to mitochon-dria. Deletion or downregulation of this chaperone pro-tected from Abeta-mediated toxicity in yeast and Dro-sophila AD models, respectively. Most importantly, the identified chaperone is found to be dysregulated in post-mortem human samples of AD patients. Here, we aim to outline our key findings, highlighting pathological functions of a heat shock protein (Hsp) family member, which are generally considered protective rather than toxic during neurodegeneration. Our results thus chal-lenge the concept of developing generalized chaperone activation-based therapies and call for carefully consid-ering also maladaptive functions of specific heat shock proteins.

Calcium‐Dependent Dual Oxidase 2 is a Novel Source of Reactive Oxygen Species Implicated in Glomerular Mesangial Cell Fibrotic Response to Angiotensin II and Glucose

The vasoactive peptide angiotensin II (Ang II) and hyperglycemia contribute to the initiation and the progression of glomerular fibrosis via activation of glomerular mesangial cells (MCs) and subsequent extracellular matrix expansion. We have previously shown that oxidative stress is critical for MC fibrotic response to Ang II or high concentrations of glucose (HG). Here, we demonstrate that Dual oxidase 2 (Duox2), a member of the Nox/Duox family of NADPH oxidases, is present in MCs and that its protein expression, along with its associated maturation factor, DuoxA2, are upregulated by Ang II and HG.Small interfering RNA (siRNA)‐mediated downregulation of Duox2 significantly reduces Ang II‐induced increase in reactive oxygen (ROS) generation and prevents the stimulatory effect of Ang II on MC fibrotic injury (as assessed by measuring a‐smooth muscle actin and fibronectin expression).To demonstrate that Duox2 activation is Ca2+‐dependent, we show that the extracellular Ca2+ chelator BAPTA prevented Ang II‐induced ROS generation and the stimulation of MC fibrotic injury by Ang II. Moreover, treatment of MCs with ionomycin resulted in increased ROS production and enhanced MC fibrotic injury. These effects were abrogated by siRNA targeting Duox2. Fura‐2 fluorescence was utilized as well to show calcium mobilization in response to Ang II and this effect was abrogated with siDuox2 transfection. These data indicate that Ang II‐stimulated Duox2 activation and ROS generation subsequently lead to MC fibrotic injury.In summary, we have identified a novel role for Duox2 and its cognate maturation factor, DuoxA2, as a major source of ROS in response to Ang II and HG and established the significance of Duox2 in Ang II‐mediated MC activation and fibrotic injury. Therapeutic targeting of this pathway may prevent or reverse pathophysiologic manifestations of renal fibrotic diseases.

Recent Advances on Drug Development and Emerging Therapeutic Agents Through Targeting Cellular Homeostasis for Ageing and Cardiovascular Disease.

Ageing is a progressive physiological process mediated by changes in biological pathways, resulting in a decline in tissue and cellular function. It is a driving factor in numerous age-related diseases including cardiovascular diseases (CVDs). Cardiomyopathies, hypertension, ischaemic heart disease, and heart failure are some of the age-related CVDs that are the leading causes of death worldwide. Although individual CVDs have distinct clinical and pathophysiological manifestations, a disturbance in cellular homeostasis underlies the majority of diseases which is further compounded with aging. Three key evolutionary conserved signalling pathways, namely, autophagy, mitophagy and the unfolded protein response (UPR) are involved in eliminating damaged and dysfunctional organelle, misfolded proteins, lipids and nucleic acids, together these molecular processes protect and preserve cellular homeostasis. However, amongst the numerous molecular changes during ageing, a decline in the signalling of these key molecular processes occurs. This decline also increases the susceptibility of damage following a stressful insult, promoting the development and pathogenesis of CVDs. In this review, we discuss the role of autophagy, mitophagy and UPR signalling with respect to ageing and cardiac disease. We also highlight potential therapeutic strategies aimed at restoring/rebalancing autophagy and UPR signalling to maintain cellular homeostasis, thus mitigating the pathological effects of ageing and CVDs. Finally, we highlight some limitations that are likely hindering scientific drug research in this field.

Definitive Closure of the Patent Ductus Arteriosus in Preterm Infants and Subsequent Short-Term Respiratory Outcomes.

A persistent patent ductus arteriosus (PDA) can have significant clinical consequences in preterm infants, depending on the degree of left-to-right shunting, its impact on cardiac performance, and associated perinatal risk factors that can mitigate or exacerbate the shunt. Although the best management strategy remains contentious, PDAs that have contraindications to, or have failed medical management have historically undergone surgical ligation. Recently smaller occluder devices and delivery systems have allowed for minimally invasive closure in the catheterization laboratory even in extremely premature infants. The present review summarizes the pathophysiologic manifestations, treatment options and management of hemodynamically significant PDA in preterm infants. Additionally, we review the available literature surrounding the respiratory support and outcomes of preterm infants following definitive PDA closure.

Anomalous right coronary artery from distal left circumflex coronary artery: a rare case report

Coronary artery anomalies (CAAs) being a group of congenital disorders, present with highly variable manifestations and have diverse pathophysiological manifestations. In middle aged to elderly patients, a coronary anomaly is often an incidental finding. We presented a case of 65-year-old female with history of diabetes for past 9 years who presented to our emergency department with history of exertional chest pain for past 4 weeks. Anomalous origin of right coronary artery (RCA) from distal left circumflex artery (LCX) was observed on coronary angiography. Patient was managed with optimised medical therapy (OMT).

Diversity and Metabolic Potential of the Gut Microbiome in Adolescents with Functional Bowel Disorder.

The article presents the results of a pilot study of the diversity and metabolic potential of the gut microbiome in adolescents with various forms of functional bowel disorder. The participants were the patients of the Clinic of Research Center for Family Health and Human Reproduction Problems. Biological material was studied using metagenomic sequencing of V3-V4 variable regions of the 16S rRNA gene. We showed that the composition of the minor component of the intestinal microbiome in adolescents with functional bowel disorder differs from that in the healthy subjects (control). Different types of transit disturbances in functional bowel disorder also differ from each other. According to the metabolic potential, adolescents can be divided into two groups irrespective of the pathophysiological manifestations: for one group, a more intensive metabolism in amino acid and lipid biosynthesis pathways was predicted than for the other.

The molecular regulation of autophagy in antimicrobial immunity.

Autophagy is a catabolic process that can degrade worn-out organelles and invading pathogens. The activation of autophagy regulates innate and adaptive immunity, playing a key role in the response to microbial invasion. Microbial infection may cause different consequences such as the elimination of invaders through autophagy or xenophagy, host cell death, and symbiotic relationships. Pathogens adapt to the autophagy mechanism and further relieve intracellular stress, which is conducive to host cell survival and microbial growth. The regulation of autophagy forms a complex network through which host immunity is modulated, resulting in a variety of pathophysiological manifestations. Modification of the autophagic pathway is an essential target for the development of antimicrobial drugs.

Pathophysiological, Cellular, and Molecular Events of the Vascular System in Anaphylaxis.

Anaphylaxis is a systemic hypersensitivity reaction that can be life threatening. Mechanistically, it results from the immune activation and release of a variety of mediators that give rise to the signs and symptoms of this pathological event. For years, most of the research in anaphylaxis has focused on the contribution of the immune component. However, approaches that shed light on the participation of other cellular and molecular agents are necessary. Among them, the vascular niche receives the various signals (e.g., histamine) that elicit the range of anaphylactic events. Cardiovascular manifestations such as increased vascular permeability, vasodilation, hypotension, vasoconstriction, and cardiac alterations are crucial in the pathophysiology of anaphylaxis and are highly involved to the development of the most severe cases. Specifically, the endothelium, vascular smooth muscle cells, and their molecular signaling outcomes play an essential role downstream of the immune reaction. Therefore, in this review, we synthesized the vascular changes observed during anaphylaxis as well as its cellular and molecular components. As the risk of anaphylaxis exists both in clinical procedures and in routine life, increasing our knowledge of the vascular physiology and their molecular mechanism will enable us to improve the clinical management and how to treat or prevent anaphylaxis.Key MessageAnaphylaxis, the most severe allergic reaction, involves a variety of immune and non-immune molecular signals that give rise to its pathophysiological manifestations. Importantly, the vascular system is engaged in processes relevant to anaphylactic events such as increased vascular permeability, vasodilation, hypotension, vasoconstriction, and decreased cardiac output. The novelty of this review focuses on the fact that new studies will greatly improve the understanding of anaphylaxis when viewed from a vascular molecular angle and specifically from the endothelium. This knowledge will improve therapeutic options to treat or prevent anaphylaxis.

Guhong injection promotes post-stroke functional recovery via attenuating cortical inflammation and apoptosis in subacute stage of ischemic stroke

BackgroundAs a leading cause of death and disability, alternative therapies for stroke are still limited by its complicated pathophysiological manifestations. Guhong injection (GHI), consisting of safflower aqueous extract and aceglutamide, has been widely applied for the clinical treatment of cerebrovascular diseases, especially ischemic stroke and post-stroke recovery, in China. Recently, a series of studies have reported the positive effect of GHI against cerebral ischemia/reperfusion injury via targeting various molecular mechanisms. However, questions remain on whether treatment with GHI contributes to better functional recovery after stroke and if so, the potential mechanisms and active substances. PurposeThe aim of this work was to explore the potential therapeutic possibilities of GHI for the neurological and behavioral recovery after stroke and to investigate the underlying molecular mechanisms as well as active substances. MethodsThe neural and motor deficits as well as cortical lesions after GHI treatment were investigated in a mouse model of transient ischemic stroke. Based on the substance identification of GHI, network pharmacology combined with an experimental verification method was used to systematically decipher the biological processes and signaling pathways closely related to GHI intervention in response to post-stroke functional outcomes. Subsequently, ingenuity pathway analysis (IPA) analysis was performed to determine the anti-stroke active substances targeting to the hub targets involved in the significant molecular pathways regulated by GHI treatment. ResultsTherapeutically, administration of GHI observably ameliorated the post-stroke recovery of neural and locomotor function as well as reduced infarct volume and histopathological damage to the cerebral cortex in subacute stroke mice. According to 26 identified or tentatively characterized substances in GHI, the compound-target-pathway network was built. Bioinformatics analysis suggested that inflammatory and apoptotic pathways were tightly associated with the anti-stroke effect of GHI. Based on protein-protein interaction network analysis, the hub targets (such as NF-κB p65, TNF-α, IL-6, IL-1β, Bax, Bcl-2, and Caspase-3) involved in inflammation and apoptosis were selected. On the one hand, immunofluorescence and ELISA results showed that GHI (10 ml/kg) treatment obviously reduced NF-κB p65 nuclear translocation as well as decreased the abnormally elevated concentrations of proinflammatory cytokines (TNF-α, IL-6, and IL-1β) in damaged cortex tissues. On the other hand, GHI (10 ml/kg) treatment significantly downregulated the number of TUNEL-positive apoptotic cells in ischemic cortex and effectively restored the abnormal expression of Bax, Bcl-2, and Caspase-3. Based on the results of IPA, hydroxysafflor yellow A, baicalin, scutellarin, gallic acid, syringin, chlorogenic acid, kaempferol, kaempferol-3-O-β-rutinoside, and rutin acted synergistically on core targets, which could be considered as the active substances of GHI. ConclusionOverall, the current findings showed that the beneficial action of GHI on improving post-stroke functional recovery of subacute stroke mice partly via the modulation of cortical inflammation and apoptosis. These findings not only provide a reliable reference for the clinical application of GHI, but also shed light on a promising alternative therapeutic strategy for ischemic stroke patients.

Constipation in older people: a clinical review for advanced nurse practitioners

Advanced nurse practitioners (ANP) are autonomous practitioners who are required to manage clinical care in partnership with patients, families and carers. This requires analysis and synthesis using evidence to undertake complex decision-making. This clinical review will examine the issue of constipation, with particular emphasis on the older patient group. The aetiology and epidemiology of constipation will be examined, the pathophysiological manifestation considered and the diagnosis and management within this population analysed. In doing so the evidence base will be critiqued to ensure autonomous, safe management of this condition.

Leptin: A Potential Link Between Obstructive Sleep Apnea and Obesity.

Chronic intermittent hypoxia (CIH), a pathophysiological manifestation of obstructive sleep apnea (OSA), is strongly correlated with obesity, as patients with the disease experience weight gain while exhibiting elevated plasma levels of leptin. This study was done to determine whether a relationship may exist between CIH and obesity, and body energy balance and leptin signaling during CIH. Sprague-Dawley rats were exposed to 96 days of CIH or normoxic control conditions, and were assessed for measures of body weight, food and water intake, and food conversion efficiency. At the completion of the study leptin sensitivity, locomotor activity, fat pad mass and plasma leptin levels were determined within each group. Additionally, the hypothalamic arcuate nucleus (ARC) was isolated and assessed for changes in the expression of proteins associated with leptin receptor signaling. CIH animals were found to have reduced locomotor activity and food conversion efficiency. Additionally, the CIH group had increased food and water intake over the study period and had a higher body weight compared to normoxic controls at the end of the study. Basal plasma concentrations of leptin were significantly elevated in CIH exposed animals. To test whether a resistance to leptin may have occurred in the CIH animals due to the elevated plasma levels of leptin, an acute exogenous (ip) leptin (0.04 mg/kg carrier-free recombinant rat leptin) injection was administered to the normoxic and CIH exposed animals. Leptin injections into the normoxic controls reduced their food intake, whereas CIH animals did not alter their food intake compared to vehicle injected CIH animals. Within ARC, CIH animals had reduced protein expression of the short form of the obese (leptin) receptor (isoform OBR100) and showed a trend toward an elevated protein expression of the long form of obese (leptin) receptor (OBRb). In addition, pro-opiomelanocortin (POMC) protein expression was reduced, but increased expression of the phosphorylated extracellular-signal-regulated kinase 1/2 (pERK1/2) and of the suppressor of cytokine signaling 3 (SOCS3) proteins was observed in the CIH group, with little change in phosphorylated signal transducer and activator of transcription 3 (pSTAT3). Taken together, these data suggest that long-term exposure to CIH, as seen in obstructive sleep apnea, may contribute to a state of leptin resistance promoting an increase in body weight.