Multiple Pathological Changes Research Articles

Retinoid X receptor heterodimers in hepatic function: structural insights and therapeutic potential.

Nuclear receptors (NRs) are key regulators of multiple physiological functions and pathological changes in the liver in response to a variety of extracellular signaling changes. Retinoid X receptor (RXR) is a special member of the NRs, which not only responds to cellular signaling independently, but also regulates multiple signaling pathways by forming heterodimers with various other NR. Therefore, RXR is widely involved in hepatic glucose metabolism, lipid metabolism, cholesterol metabolism and bile acid homeostasis as well as hepatic fibrosis. Specific activation of particular dimers regulating physiological and pathological processes may serve as important pharmacological targets. So here we describe the basic information and structural features of the RXR protein and its heterodimers, focusing on the role of RXR heterodimers in a number of physiological processes and pathological imbalances in the liver, to provide a theoretical basis for RXR as a promising drug target.

Effects of brain estrogen receptor on depression and its mechanism of action

Depression is a refractory disease involving multiple pathologic changes, characterized by long-term disease course, low curative rate, and complex symptoms. However, the pathologic mechanism of this disease is incompletely known. Current research mainly focuses on the monoamine neurotransmitter hypothesis, neuroendocrine-related hypothesis, neuroinflammation hypothesis, and brain structure-function hypothesis. An intimate interplay exists between estrogen with the development and progression of depression. Estrogen receptors are widely distributed in the central nervous system, the expression of which can exert genetic and nongenetic effects to improve depression through regulating the level of neurotransmitters, mediating the function of the hypothalamus-pituitarium-adrenal axis, alleviating neuroinflammation, and protecting neurons. This study elaborated on the regulatory effect and mechanism of brain estrogen receptors on depression, hoping to provide new ideas for the clinical treatment of depression.

Gut microbial metabolites in MASLD: Implications of mitochondrial dysfunction in the pathogenesis and treatment.

With an increasing prevalence, metabolic dysfunction-associated steatotic liver disease (MASLD) has become a major global health problem. MASLD is well-known as a multifactorial disease. Mitochondrial dysfunction and alterations in the gut bacteria are 2 vital events in MASLD. Recent studies have highlighted the cross-talk between microbiota and mitochondria, and mitochondria are recognized as pivotal targets of the gut microbiota to modulate the host's physiological state. Mitochondrial dysfunction plays a vital role in MASLD and is associated with multiple pathological changes, including hepatocyte steatosis, oxidative stress, inflammation, and fibrosis. Metabolites are crucial mediators of the gut microbiota that influence extraintestinal organs. Additionally, regulation of the composition of gut bacteria may serve as a promising therapeutic strategy for MASLD. This study reviewed the potential roles of several common metabolites in MASLD, emphasizing their impact on mitochondrial function. Finally, we discuss the current treatments for MASLD, including probiotics, prebiotics, antibiotics, and fecal microbiota transplantation. These methods concentrate on restoring the gut microbiota to promote host health.

Abnormal Innervation, Demyelination, and Degeneration of Spiral Ganglion Neurons as Well as Disruption of Heminodes are Involved in the Onset of Deafness in Cx26 Null Mice.

GJB2 gene mutations are the most common causes of autosomal recessive non-syndromic hereditary deafness. For individuals suffering from severe to profound GJB2-related deafness, cochlear implants have emerged as the sole remedy for auditory improvement. Some previous studies have highlighted the crucial role of preserving cochlear neural components in achieving favorable outcomes after cochlear implantation. Thus, we generated a conditional knockout mouse model (Cx26-CKO) in which Cx26 was completely deleted in the cochlear supporting cells driven by the Sox2 promoter. The Cx26-CKO mice showed severe hearing loss and massive loss of hair cells and Deiter's cells, which represented the extreme form of human deafness caused by GJB2 gene mutations. In addition, multiple pathological changes in the peripheral auditory nervous system were found, including abnormal innervation, demyelination, and degeneration of spiral ganglion neurons as well as disruption of heminodes in Cx26-CKO mice. These findings provide invaluable insights into the deafness mechanism and the treatment for severe deafness in Cx26-null mice.

Activities of pumpkin seed oil against Biomphalaria alexandrina snails and the infective stages of Schistosoma mansoni with special emphasis on genotoxic and histopathological alterations.

Schistosomiasis is a serious health issue in tropical regions, and natural compounds have gained popularity in medical science. This study investigated the potential effects of pumpkin seed oil (PSO) on Biomphalaria [B.] alexandrina snails (Ehrenberg, 1831), Schistosoma [S.] mansoni (Sambon, 1907) miracidium, and cercariae. The chemical composition of PSO was determined using gas chromatography/mass spectrometry. A bioassay was performed to evaluate the effects of PSO on snails, miracidia, and cercariae. The results showed no significant mortality of B. alexandrina snails after exposure to PSO, but it caused morphological changes in their hemocytes at 1.0 mg/ml for 24 hours. PSO exhibited larvicidal activity against miracidia after 2 hours of exposure at a LC50 of 618.4 ppm. A significant increase in the mortality rate of miracidia was observed in a dose- and time-dependent manner, reaching a 100% death rate after 10 minutes at LC90 and 15 minutes at LC50 concentration. PSO also showed effective cercaricidal activity after 2 hours of exposure at a LC50 of 290.5 ppm. Histological examination revealed multiple pathological changes in the digestive and hermaphrodite glands. The PSO had genotoxic effects on snails, which exhibited a significant increase [p≤0.05] in comet parameters compared to the control. The findings suggest that PSO has potential as a molluscicide, miracidicide, and cercaricide, making it a possible alternative to traditional molluscicides in controlling schistosomiasis.

Characterizing Limbic-Predominant Age-Related TDP-43 Encephalopathy Without Alzheimer's Disease and Lewy Body Dementia in the Oldest Old: A Case Series.

Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is a clinicopathological construct proposed to facilitate studying TDP-43 pathology in older individuals. Our aim was to describe clinical and cognitive characteristics of LATE-NC without Alzheimer's disease neuropathologic change (ADNC) and Lewy body (LB) and to compare this with ADNC and primary age related tauopathy (PART). In 364 autopsies of the oldest old of The 90+ Study, we identified those with LATE-NC without ADNC and LB. Control groups were participants with ADNC and PART. Of 31% of participants who had LATE-NC, only 5 (1.4%) had LATE-NC without ADNC and LB, all of whom had tau. These participants had a gradual and progressive cognitive decline. Four (80%) had dementia at death, a rate that was higher than ADNC (50%) and PART (21.7%). Mean duration of cognitive impairment was twice as long in LATE-NC without ADNC and LB (6.2 years) compared to ADNC (2.9 years) and PART (3 years). LATE-NC without ADNC and LB group had a higher prevalence of syncope, depression, and extrapyramidal signs than the ADNC and PART groups. Despite the high prevalence of LATE-NC, LATE-NC without ADNC and LB was rare in this large oldest-old cohort, highlighting the very high prevalence of multiple pathologic changes in the oldest old. Slowly progressive cognitive decline, ubiquitous memory impairment, history of syncope and depression, and extrapyramidal signs were prominent features among our LATE-NC without ADNC and LB group.

Chinese medicine monomers in the treatment of Alzheimer’s disease: Some preclinical findings

AbstractBackgroundMost of the FDA approved drugs for AD are symptom driven and effects are limited. Because AD is a complex disease involving multiple pathological changes, such as senile plaques formed by amyloid‐β (Aβ) deposition, neurofibrillary tangles caused by tau hyperphosphorylation, microglia‐evoked neuroinflammation, synaptic degeneration, and blood‐brain barrier (BBB) disruption. While the current anti‐dementia drugs are mostly single targets, Chinese medicines have great development potential considering their multi‐target anti‐dementia components.MethodSeveral Chinese medicine monomers, including cryptotanshinone (CTS), pterostilbene (PTE), Ginsenoside Compound K (GCK), and glabridin (Gla) were selected to test their safety and efficacy in AD cell models, and to further explore their possible molecular mechanisms and target of action. Aβ42 oligomers (AβO) were used to establish AD cell models. The cytotoxicity of AβO as well as protective effects of Chinese medicine monomers on cell models were evaluated using the MTT assay. The molecular mechanisms and pathways were tested using qRT‐PCR, ELISA, Western blot and immunofluorescence.ResultAβO induced cell injury, apoptosis, and generation of intracellular reactive oxygen species (ROS). In AβO‐induced cell models, CTS significantly reduced tau hyperphosphorylation at Ser202, Ser404, Thr181, and Thr231, and increased the levels of PSD95 and synaptophysin; PTE attenuated cell injury, apoptosis, and ROS generation; GCK diminished inflammatory cytokine production; Gla attenuated cell injury (figure1). Further study found that their mechanisms of action include PI3K/Akt/GSK3β pathway (figure2), BBB permeability and tight junction scaffold protein (figure3), as well as NF‐kB pathway via LRP1 activation (figure4), respectively.ConclusionThese results provides rational basis for the therapeutic application of Chinese medicine monomers in the treatment of AD, and support further evaluation of these multi‐target action potential in AD treatment.

An Integrative Multiomics Framework for Identification of Therapeutic Targets in Pulmonary Fibrosis.

Pulmonary fibrosis (PF) is a heterogeneous disease with a poor prognosis. Therefore, identifying additional therapeutic modalities is required to improve outcome. However, the lack of biomarkers of disease progression hampers the preclinical to clinical translational process. Here, this work assesses and identifies progressive alterations in pulmonary function, transcriptomics, and metabolomics in the mouse lung at 7, 14, 21, and 28 days after a single dose of oropharyngeal bleomycin. By integrating multi-omics data, this work identifies two central gene subnetworks associated with multiple critical pathological changes in transcriptomics and metabolomics as well as pulmonary function. This work presents a multi-omics-based framework to establish a translational link between the bleomycin-induced PF model in mice and human idiopathic pulmonary fibrosis to identify druggable targets and test therapeutic candidates. This work also indicates peripheralcannabinoid receptor 1 (CB1 R) antagonism as a rational therapeutic target for clinical translation in PF. Mouse Lung Fibrosis Atlas can be accessed freely at https://niaaa.nih.gov/mouselungfibrosisatlas.

Manifestation of infantile scurvy in a skeleton from the high medieval village of Trutmanice (South Moravia, Czech Republic).

The study describes the pathological findings recorded on the human remains of a 3 to 4-year-old child found in the burial site of Trutmanice (Czech Republic), dated to the 13th-15th century. The human remains were examined using standard macroscopic osteological and paleopathological methods, supplemented by radiographic examination. Although the preservation of the bones limited the analysis, multiple pathological changes were observed mainly on the skull: cribra orbitalia, small pores and fine deposits of newly formed bone tissue, hypertrophic diploë, grooves indicating rich branching of meningeal arteries on the intracranial surface of the cranial vault. A very fine periostotic deposition of newly formed bone tissue was also observed at the distal end of the diaphysis of the right tibia and both distal ends of the femora. The radiographs of the femora showed white lines of Frankel, scurvy lines, and Wimberger's rings. The observed pathological changes were possibly consistent with scurvy based on differential diagnosis. Reports about cases of juvenile scurvy from rural areas within the context of landlocked countries of Central Europe are rare. While scurvy is now more frequently reported in the paleopathological literature, evidence for scurvy within one of the most natural agricultural areas in the Czech lands remains rare. We recommend using radiographic examination to complement the diagnosis of scurvy in future paleopathological and epidemiological studies of past populations.

Modulatory effect of ginger on skeletal malformations, cell cycle, apoptosis and structural changes in the liver of rat fetuses prenatally exposed to labetalol

BackgroundDrug-induced liver damage with clinical symptoms has been related to labetalol in a number of instances. In addition to having a wide range of anti-inflammatory and antioxidant qualities, ginger also includes biotrace that are crucial in the fight against disease and skeletal deformity. In this study, we hypothesized that prenatal supplementation of ginger (200 mg/kg) attenuates skeletal malformation and hepatotoxicity mediated by labetalol during the organogenesis period. The tested dams were divided into four groups: control, ginger (200 mg/kg), labetalol (300 mg/kg) and combined group (labetalol and ginger at the same doses).ResultsThe labetalol group showed various skeletal abnormalities represented by mandibular hypoplasia, costal separation and retardation in the ossification. Histological and ultrastructural examination of the fetal liver tissue revealed multiple pathological changes. DNA damage, G0/G1 cell cycle arrest and a high percentage of apoptosis were also detected in the fetal hepatocytes from labetalol groups through gel electrophoresis and flow cytometry using PI and annexin V/PI methods, respectively. Administration of ginger after labetalol caused an evident decrease in these skeletal malformations, structural changes, DNA damage, apoptosis and G0/G1 cell cycle arrest.ConclusionsIt can be concluded that ginger has great potential in attenuating the skeletal malformation, structural changes and cyto-genotoxicity of fetal hepatocytes upon prenatal exposure to labetalol.

MicroRNA-195 rescues the impaired MS-dCA1 neural circuit and spatial memory in rats with chronic cerebral hypoperfusion

Chronic cerebral hypoperfusion (CCH) is a common risk factor for vascular dementia and Alzheimer’s disease (AD). The previous studies have shown that CCH-induced multiple AD-like pathological changes in the hippocampus and cortex through downregulating the microRNA-195 (miR-195) expression. However, whether and how miR-195 participates in the dysfunction of the medial septum (MS)-dorsal hippocampal CA1 (dCA1) neural circuit following CCH is still obscure. In the present study, we found that miR-195 was downregulated in the MS region of CCH rats. Moreover, using electrophysiological recording and immunofluorescence staining technique, we found that the knockdown of miR-195 through the injection of lenti- AMO-195 into the MS region led to a pathological change that mimicked the damage to the MS-dCA1 neural circuit in CCH rats, including the decreased input-output (I/O) curve, increased paired-pulse ratio (PPR), decreased numbers of ChAT+ and PV+ neurons in MS, and diminished theta rhythm in the hippocampus. More importantly, exogenously supplemented miR-195 into the MS region rescued the damaged neural circuit in MS-dCA1 of CCH rats by injecting lenti-pre-miR-195. Gain-of-function of miR-195 in the MS region significantly improved the cognitive dysfunction in CCH rats assessed by the Morris water maze test. In conclusion, knockdown of miR-195 in the MS region can impair MS-dCA1 neural circuit function, while upregulation of miR- 195 can rescue the impaired function of MS-dCA1 neural circuit and spatial memory ability in CCH rats. This provides a valuable reference for future anti-dementia therapy involving miR-195.

ADAMTS18 regulates early branching morphogenesis of lacrimal gland and has a significant association with the risk of dry eye in mice

ADAMTS18 is an orphan member of the ADAMTS family of metalloproteinase. ADAMTS18 mutation has been linked to developmental eye disorders, such as retinal dystrophies and ectopia lentis. Here, we report a new function of ADAMTS18 in modulating the lacrimal gland (LG) branching morphogenesis, and an association with dry eye in mice. Adamts18 mRNA was found to be enriched in the epithelium of branching tips of embryonic (E) LG, but its expression was barely detectable after 2 weeks of birth. Histological analyses of E16.5-E17.5 LG showed that ADAMTS18 deficiency resulted in a significant reduction of epithelial branching in embryonic LG. In vitro culture of E15.5 LG explants showed that the numbers of epithelial buds and branches in Adamts18 knockout (Adamts18−/−) LGs were significantly decreased when compared to those of wild type (Adamts18+/+) LGs after 0 h, 24 h, and 48 h of culture. Increased fibronectin deposition was detected in LG mesenchyme of E16.5 Adamts18−/− mice. At 14 months of age, Adamts18−/− mice manifested multiple LG pathological changes, including acinar atrophy and irregular duct ectasis with periductal fibrosis. The tear volume was significantly decreased in Adamts18−/− mice at 4 months of age, which corresponds to early adulthood in humans.

Quanzhenyiqitang Reverses LPS-Induced Inflammation via Inhibiting PYK2/p38MAPK/HDAC2/CK2 Signaling Pathway in Rat Alveolar Macrophage.

Chronic obstructive pulmonary disease (COPD) is a common chronic pulmonary disease with multiple etiologies and pathological changes. PYK2 expression is significantly increased in lipopolysaccharide-induced lung injury, but it mediates chronic lung inflammation. The mechanism of its occurrence remains unclear. Quanzhenyiqitang is often used in clinical treatment of COPD, so this study explored the mechanism of its treatment of lipopolysaccharide-induced lung injury. In this study, transfection, flow cytometry, QRT-PCR, and Western blotting methods were used to study the mechanism of Quanzhenyiqitang lipopolysaccharide-induced lung injury. The results showed that the mechanism of occurrence remains unclear. Our novel observations imply that the PYK2/p38MAPK/HDAC2/CK2 pathway is one of the fundamental underlying mechanisms that mediate the pathogenic progression of COPD, and Quanzhenyiqitang may be the therapeutic drug to prevent chronic inflammation and delay the progression of COPD by inhibiting PYK2 signaling pathways.

Gadd45 in Preeclampsia.

Preeclampsia is a pregnancy-induced complex of multiple pathological changes. Numerous stresses during pregnancy, including hypoxia, immune activation, inflammatory cytokines, and oxidative stress were reported as contributing factors to the preeclamptic pathology. Seeking common sensors of various stressors in preeclampsia is of new interest and can potentially benefit in disease prevention and treatment. Recent studies have highlighted the role of the Gadd45a protein as a stress sensor in preeclampsia. In response to various pathophysiological stressors, notably hypoxia, oxidative stress, inflammatory cytokines, and AT1-AAs, Gadd45a activates Mkk3-p38 and or JNK signaling. This, in turn, results in immunological and inflammatory changes as well as triggering the production of circulating factors such as sFlt-1, which are believed to account for many of the pathophysiological-related symptoms of preeclampsia. Activation of inflammatory/immune responses in preeclampsia may function in a feedback loop to maintain elevated expression of Gadd45a protein.

Dynamic nanoassemblies for imaging and therapy of neurological disorders.

The past decades have witnessed an increased incidence of neurological disorders (NDs) such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, ischemic stroke, and epilepsy, which significantly lower patients' life quality and increase the economic and social burden. Recently, nanomedicines composed of imaging and/or therapeutic agents have been explored to diagnose and/or treat NDs due to their enhanced bioavailability, blood-brain barrier (BBB) permeability, and targeting capacity. Intriguingly, dynamic nanoassemblies self-assembled from functional nanoparticles to simultaneously interfere with multiple pathogenic substances and pathological changes, have been regarded as one of the foremost candidates to improve the diagnostic and therapeutic efficacy of NDs. To help readers better understand this emerging field, in this review, the pathogenic mechanism of different types of NDs is briefly introduced, then the functional nanoparticles used as building blocks in the construction of dynamic nanoassemblies for NDs theranostics are summarized. Furthermore, dynamic nanoassemblies that can actively cross the BBB to target brain lesions, sensitively and efficiently diagnose or treat NDs, and effectively promote neuroregeneration are highlighted. Finally, we conclude with our perspectives on the future development in this field.

Clock at the Core of Cancer Development.

Simple SummaryThe earth’s rotation produces a daily 24 h cycle of day and night. Many biological functions, such as sleep–wake cycle, feeding/fasting cycle, blood hormone levels and body temperature rhythms occur over a 24 h period. These daily fluctuations are controlled by an internal system known as the circadian clock (Latin circa—“around”—and diem—“day”). This clock coordinates the periodic changes in diverse physiological and behavioral activities and helps adapt to the periodic environment for the benefit of survival and reproduction of organisms. Nearly all organisms, from single-cell to mammals, including humans, possess a self-sustained circadian clock. Disturbances in the functioning of this internal circadian clock can alter the balance in biological functions and compromise organism fitness. In humans, clock disruption is associated with diseases such as diabetes, cardiovascular diseases and cancer. Thus, studying the interplay between the circadian clock and physiology is important in the prevention and management of fatal diseases such as cancer.To synchronize various biological processes with the day and night cycle, most organisms have developed circadian clocks. This evolutionarily conserved system is important in the temporal regulation of behavior, physiology and metabolism. Multiple pathological changes associated with circadian disruption support the importance of the clocks in mammals. Emerging links have revealed interplay between circadian clocks and signaling networks in cancer. Understanding the cross-talk between the circadian clock and tumorigenesis is imperative for its prevention, management and development of effective treatment options. In this review, we summarize the role of the circadian clock in regulation of one important metabolic pathway, insulin/IGF1/PI3K/mTOR signaling, and how dysregulation of this metabolic pathway could lead to uncontrolled cancer cell proliferation and growth. Targeting the circadian clock and rhythms either with recently discovered pharmaceutical agents or through environmental cues is a new direction in cancer chronotherapy. Combining the circadian approach with traditional methods, such as radiation, chemotherapy or the recently developed, immunotherapy, may improve tumor response, while simultaneously minimizing the adverse effects commonly associated with cancer therapies.

The possible manifestation of scurvy on skeletal remains dated to 3800–3700 BC

The presented report describes the skeletal remains of a young man with multiple pathological changes, dated to between 3800-3700 BC. The studied skeletal remains were subjected to classical anthropological analysis. The palaeopathological study was based on detailed macroscopic examination supplemented by histological and radiological examinations. In addition to the disorder of flat cranial bones, dental developmental defects, traces after periodontal and sinus maxillaris inflammation, partially fractured left rib and fracture of the first lumbar vertebra were found on this skeleton. Based on the mentioned examinations, this finding was evaluated as one of the possibly oldest cases of scurvy in Europe.

Efficient dynamic modelling of ECG with myocardial infarction using interacting multiple model and particle filter

The automatic identification of cardiac condition through dynamic modelling of electrocardiogram (ECG) signal has immense clinical significance as it eliminates the task of manual annotation of ECG recordings. In this study, an interacting multiple model (IMM)-based scheme has been proposed that helps in dynamically modelling and estimating the ECG signal. This model is having the adaptability of interchanging among several morphological representations. It offers the advantage of not necessitating user-specific parameters. This model does not necessitate a priori information about the ECG signal to initialise the filter parameters and delimitation of fiducial points of ECG signal. The particle filter (PF)-based schemes show superiority owing to their freedom from a single assumption on the signal model and noise model. Besides, it has got the potential of simultaneously tracking multiple pathological and morphological changes occurring in biomedical signals. Thus, the parameters of the model are estimated by adopting the PF, so that the myocardial infarction (MI) affected ECG signals can be efficiently tracked. Investigations on ECG signals from the MIT-BIH database and PTB diagnostic ECG database signify that the IMM-PF scheme can represent several MI morphologies with minimum prior information without distorting the helpful diagnostic information of ECG accurately.

The prevalence and clinical characteristics of thoracic spinal stenosis: a systematic review.

Thoracic spinal stenosis (TSS) is a rare disease secondary to multiple pathological changes that differ in prevalence and clinical characteristics. The epidemiological characteristics of these pathologies are largely unknown due to the limited case samples and regional differences. Therefore, a systematic review was conducted to elucidate the prevalence and clinical characteristics of TSS. Case series and case reports on the ossification of the posterior longitudinal ligaments (OPLL), ossification of the ligamentum flavum (OLF) and thoracic disk herniation (TDH) were screened from PubMed, Embase and Web of Science databases and systematically reviewed. Epidemiological, demographic and segmental distribution data were extracted and analyzed. A total of 129 studies including 1935 subjects were selected, of which 361 (18.7%) were diagnosed with OPLL, 804 (41.5%) with OLF, 143 (7.4%) with OPLL + OLF and 627 (32.4%) with TDH. Most reports were from China, Japan and USA. Thoracic OPLL occurred mostly at the middle-thoracic spine (43.4%), while OLF predominately occurred at the lower-thoracic spine (63.1%). TDH was mainly localized in the middle (46.0%) and lower-thoracic (50.3%) spine. Thirty-two studies involving 524 patients described tandem spinal stenosis, of which 52.1% had accompanying cervical diseases and 35.9% lumbar diseases. There are significant differences in the age, sex and segment distribution characteristics of different pathologies leading to TSS. Tandem spinal stenosis is not uncommon and should be considered when diagnosing TSS. Our findings provide new insights into the prevalence and clinical characteristics of TSS and can help reduce misdiagnosis.

Stem-Cell Derived Exosomes for the Treatment of Osteoarthritis.

Osteoarthritis(OA) is a common degenerative orthopedic disease with multiple pathologic changes in joints affecting large populations worldwide. No treatment can reverse the progress of OA. Since exosomes were first reported in 1983, researches have been conducted to explore the mechanisms and therapeutic potential of exosomes in treating OA. Exosomes derived from Mesenchymal stem cells have attracted increasing attention in tackling the disease. This article summarizes the current advances and challenges in exosomes for OA, which may providea reference for further research.