Damage To Vital Organs Research Articles

Interspecies transcriptome profiles of human T cell activation and liver inflammation in a xenogeneic graft-versus-host disease model

BackgroundXenogeneic transplantation induces acute graft-versus-host disease (aGvHD) and subsequent vital organ damage. Herein, we aimed to examine hepatic damage associated with aGvHD using histopathology and gene expression profiles. MethodsA xenografic GvHD model was established by engrafting human peripheral blood mononuclear cells (PBMCs) into immunodeficient NOD-scid IL2Rγnull (NSG) mice after busulfan conditioning. NSG mice were assigned to groups treated with saline (S group) or a combination of busulfan and PBMCs (BP group). Histological lesions and RNA sequencing analysis of gene profiles in the BP group (GvHD model) were compared with those in the P group. ResultsPredominant T cell subsets (95 %) in the blood of the BP group were identified as cytotoxic CD8+ T cells (56 %) and helper CD4+ T cells (31 %). Symptoms of aGvHD, including hepatocyte necrosis, bile duct hyperplasia, and human T cell infiltration, were observed. Gene expression analysis revealed upregulation of Th1 and Th2 cell differentiation (STAT4, IL4R, and NFACT1), T cell receptor signaling pathway (CD226 and GBP1), IL-1 pathway (CCL3, NAIP, and IRAK4), cell cycle (CDCA5, CDCA8, MCM5, KNL1, BUB1B, FBXO5, and CENPE) in human cells. In mouse cells, Il1a, Ifngr, Tnfrsf, and Il6ra genes (cytokines or their receptors) and Icam, Vcam, and Endra genes (adhesion molecules) were upregulated, whereas genes related to chromosome condensation (H2ac and H2bc) and fatty acid/steroid metabolism (Fasn, Rdh, and Scd) were downregulated. Interspecies gene network analysis revealed that activated human T cells are associated with liver damage through inflammatory and metabolic pathways, accompanied by increased mouse cell adhesion molecules and cytokines. ConclusionOur findings offer valuable insights into the pathophysiology and biomarkers of aGvHD and may contribute to the development of novel therapeutics.

Juvenile Systemic Scleroderma: A comprehensive Review and Clinical Case Report from a Tertiary Care Hospital in India

Juvenile systemic sclerosis (JSSc) is a highly uncommon, chronic connective tissue disorder that affects multiple systems, marked by progressive deposition of collagen under the dermis, and various deep organs. Delay in diagnosis can cause irreversible vital organ damage, leading to severe morbidities and seriously affecting quality of life. We report a clinical case of a 9-year-old boy with extensive and diffuse skin manifestations with vascular, pulmonary, and gastrointestinal involvement. The sero-immunological test revealed positive ANA results and high titers of anti-topoisomerase (Scl-70) antibodies, indicative of severe manifestation of the disease. He was managed with systemic immunosuppression and other pharmacological and rehabilitative measures to prevent ongoing organ damage and alleviate the patient’s symptoms.

Autoantibodies in systemic sclerosis overlap syndrome and their correlation with organ damage and survival

Background Systemic sclerosis (SSc) often overlaps with other autoimmune diseases. More complex autoantibody profiles may be observed in SSc overlap syndrome (SSc OS). To determine the clinical significance of autoantibodies in SSc OS and classify the patients more accurately for better disease assessments, we analysed the correlation between serological profiles, organ involvements and outcomes. Methods A retrospective cohort study was conducted in Peking University People’s Hospital. Chi-square tests and analysis of variance were used to analyse univariate comparisons of clinical symptoms, organ involvement and laboratory indicators. Survival was evaluated using Cox proportional hazards model. Results Among 141 cases, anti-Ro-52 was the most common antibody, followed by anti-centromere antibody and anti-Scl-70 antibody. We analysed the correlation between autoantibodies and vital organ damage in SSc OS patients, and compared the differences across four SSc OS subgroups (SSc SLE, SSc RA, SSc PM/DM and SSc SS) to demonstrate the correlation between autoantibodies and clinical characteristics and organ damage. Cox regression analysis showed that scleroderma renal crisis (SRC) (p = .004) and pulmonary arterial hypertension (PH) (p = .010) were independent risk factors for survival. Conclusions Autoantibodies are associated with clinical features, organ involvement and prognosis in SSc OS patients. Anti-Scl-70 antibody is associated with interstitial lung disease (ILD) and SRC, while ACA is a protective factor of ILD. SRC and PH are risk factors associated with death.

Protective Effects of the Aqueous Extract of Malva sylvestris Plant against the Lethality and Histopathological Damage in Experimental Envenoming of Hemiscorpius lepturus Venom in Balb/c Mice.

Hemiscorpius lepturus envenomation is a serious health problem in the southern provinces of Iran. The antiserum produced in Iran to counteract this scorpion venom is not entirely effective due to the risk of anaphylactic shock and other adverse effects. Therefore, more efficient alternatives to treat patients deserve attention, and plants are extensively good candidates to be studied. This study aimed to assess the potential of the aqueous fraction of Malva sylvestris in inhibiting the toxic effects of H. lepturus venom. Injection of sub-lethal dose of H. lepturus venom leads to severe tissue damage in vital organs including the kidney, liver, heart and intestine, after 24 hours. By injecting 80 mg of the aqueous extract of M. sylvestris into the peritoneum helped treat the damaged tissues caused by H. lepturus venom in mice. Thus, Malva sylvestris could serve as an alternative treatment for scorpion sting envenomation and may be used as a drug to neutralize relevant toxic effects in patients stung by H. lepturus.

Behavioral, biochemical and histopathological alterations induced in Swiss mice by Buthus boumalenii scorpion venom

The yellow scorpion, Buthus boumalenii, has long been recognized as a potentially dangerous species endemic to Morocco. However, there is currently no data on the in vivo toxicity or effects of Buthus boumalenii venom, as it has not been studied to the best of our knowledge. In order to achieve the objective of this study, the LD50 of B. boumalenii venom will be initially calculated, followed by determining its impact on vital organs using histological, biochemical, and behavioral analyses. The investigation also explores potential neurobehavioral impairments in Swiss mice at intervals of 3 hours, 6 hours, and 12 hours post-envenomation. The LD50 for Buthus boumalenii scorpion venom in mice was determined to be 353 µg/kg based on body weight. The findings of the study highlight the potential lethality of B. boumalenii. Observations related to the poisoning provide indications of potential tissue damage in specific vital organs. To sum up, the venom from this scorpion has the potential to result in considerable medical complications, including fatalities, particularly in individuals at risk. Consequently, healthcare practitioners should be knowledgeable about the diverse scorpion species in their regions and adhere to contemporary medical protocols when addressing scorpion envenomation.

Outcomes of Patients with Heavily Pretreated Relapsed/Refractory Multiple Myeloma Receiving Salvage Cytotoxic Therapy with Supportive Stem Cell Boost.

Multiple myeloma (MM) is an incurable hematologic malignancy characterized by the neoplastic proliferation of plasma cells, which produce monoclonal immunoglobulin that can cause vital organ damage, subsequently leading to significant morbidity and mortality. Autologous hematopoietic stem cell transplant (ASCT) is the standard-of-care management of eligible patients with newly diagnosed MM. Experts recommend collecting enough stem cells upfront to support a possible tandem transplant, salvage ASCT, or a stem cell "boost" to allow for the administration of multiagent cytotoxic chemotherapy in patients with relapsed/refractory disease. There is currently a paucity of data on the response rates and outcomes of patients with relapsed MM who undergo cytotoxic chemotherapy followed by a stem cell boost; this study examines the outcomes of patients treated with this approach. We conducted a retrospective chart review from two oncologic treatment centers in the United States of adult patients who underwent a first ASCT between 1999 and 2021 and subsequently received cytotoxic chemotherapy followed by stem cell boost further on in their disease course. Survival analysis was carried out using the Kaplan-Meier method, and the log-rank test was used to compare survival curves. We found that the majority (56.6%) of these patients responded to therapy and that 60.6% of these patients were able to receive at least one subsequent line of therapy post-boost. Furthermore, patients who responded to therapy had significantly longer median overall survival compared to those who did not respond (323 days vs 93 days, p=0.0045), and age did not affect response to therapy. This data allow clinicians to appropriately implement and inform patients of the therapeutic uses and clinical outcomes of stem cell boost in patients with multiply relapsed/refractory MM.

Regional delivery of mesothelin-targeted chimeric antigen receptor T-cell effectively and safely targets colorectal cancer liver metastases in mice.

Liver metastasis is the major cause of colorectal cancer related death. Mesothelin (MSLN)-targeted chimeric antigen receptor (CAR) T-cell therapy has been illustrated effective and safe through regional delivery of breast cancer, ovarian cancer and malignant mesothelioma tumors. Herein, we investigated the safety, efficacy, and immune microenvironment of regional delivery of MSLN (CAR) T-cell in the treatment of colorectal carcinoma liver metastases (CRLM). Second-generation MSLN CAR T-cells were administered by portal vein (PV) or caudal vein (CV, systemic administration) delivery in an orthotopic MSLN+ CRLM nonobese diabetic (NOD)/severe combined immunodeficient (SCID)/γc-/- (NSG) mouse model. A total of 20 mice were randomly divided into control group, non-transduced T cell (NT)-CV group, NT-PV group, MSLN CAR T-cell CV (MSLN-CV) group, and MSLN CAR T-cell PV (MSLN-PV) group, with each group containing four mice to examine the safety and efficacy. The bioluminescence intensity (BLI) of tumor burden, tumor tissue macroscopic and microscopic observation were used to evaluate treatment efficacy. The safety was examined by body weight, survival time, and vital organ damage of mice. CAR T-cell infiltration and cytokine concentration were analyzed by flow cytometry, and immunostaining. The change of immune microenvironment between regional delivery and systemic delivery was investigated on an immune reconstructed CRLM patient-derived xenograft (PDX) model. Additionally, T cell subsets and immunosuppressive markers were examined. PV administration of 1×107/100 μL MSLN CAR T-cells in 20 NSG mice was well tolerated, and no overt toxicity was observed. The tumor burden in the PV group was obviously alleviated. The BLI was (0.73±0.52)×109 in PV group and (1.97±0.11)×109 in CV group (P<0.05), CD8+ granzyme B (GB)+ T cell percentage (MSLN-CV 4.42%±0.47% vs. MSLN-PV 13.5%±4.67%, P<0.01) and cytokine concentration were obviously increased in the MSLN-PV group. In the immune reconstituted CRLM PDX model, intratumor (IT) delivery of MSLN CAR T-cells exhibited much more infiltration of CD4+ and CD8+ T cells accompanied with elevated expression levels of PD-1, LAG-3, and TIM-3. Regional delivery of MSLN-targeted CAR T-cell therapy has encouraging results in the orthotopic CRLM NSG mouse model and PDX model, and converts the tumor microenvironment from cold to hot. This study may provide a new therapeutic approach for CRLM. Further clinical study is needed.

A case series of Fabry diseases with CKD in Japan

BackgroundIt is well known that kidney injury is vital organ damage in Fabry disease (FD). Renin–angiotensin system (RAS) inhibitors are known to reduce proteinuria in patients with chronic kidney disease (CKD) by dilating the glomerular export arteries and reducing intraglomerular pressure. This improvement in intraglomerular pressure, although lowering the glomerular filtration rate, is thought to prevent renal damage and be renoprotective in the long term. RAS inhibitors may be effective in FD patients with proteinuria to prevent the progression of kidney disease, however, the degree to which they are used in clinical practice is unknown.MethodsThe J-CKD-DB-Ex is a comprehensive multicenter database that automatically extracts medical data on CKD patients. J-CKD-DB-Ex contains data on 187,398 patients in five medical centers. FD patients were identified by ICD-10. Clinical data and prescriptions of FD patients between January 1 of 2014, and December 31 of 2020 were used for the analysis.ResultsWe identified 39 patients with FD from the J-CKD-DB-Ex including those with suspected FD. We confirmed 22 patients as FD. Half of the patients received RAS inhibitors. RAS inhibitors tended to be used in CKD patients with more severe renal impairment.ConclusionsThis case series revealed the actual clinical practice of FD patients with CKD. In particular, we found cases in which patients had proteinuria, but were not treated with RAS inhibitors. The database was shown to be useful in assessing the clinical patterns of patients with rare diseases.

Evaluation of copper nanoparticles on growth, organs histology and DNA damage in Japanese quails (Coturnix coturnix japonica)

The effects of Copper oxide nanoparticles (CuO-NPs) have been investigated on human cells and various experimental animals. However, there is a lack of research on the effects of CuO-NPs specifically in Japanese quails. Therefore, the current study aimed to examine the impact of a low and a high doses of CuO-NPs on the growth performance, DNA damage, and histological structures of the liver, kidney, and heart in Japanese quails. In this experiment 120 one-d-old Japanese quails, divided into three experimental groups (n = 40) as follows: Group 1 served as the control group and fed only basic feed, while Group 2 was fed with 6 mg/kg and group 3 received 18 mg/kg body weight CuO-NPs through oral gavage at weekly intervals until 35 days of age. Our findings revealed that, birds fed with 6 mg/kg body weight had significantly (p < 0.05) higher feed intake and weight gain compared to the group receiving the higher dose (18 mg/kg body weight) during weeks 4 and 5 of the study. Both treatment groups indicated DNA damage and histopathological changes, but these effects were more severe in the higher dose group. These results suggested that the lower dose (6 mg/kg) may serve as a growth promoter, whereas the higher dose (18 mg/kg) is detrimental, leading to not only poor growth but also causing DNA damage and histopathological abnormalities in vital organs of the body.

Ocular fundus changes and association with systemic conditions in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease that affects multiple organs and systems. Ocular involvement is estimated to manifest in one-third of individuals with SLE, of which lupus retinopathy and choroidopathy represent the severe subtype accompanied by vision impairment. Advancements in multimodal ophthalmic imaging have allowed ophthalmologists to reveal subclinical microvascular and structural changes in fundus of patients with SLE without ocular manifestations. Both ocular manifestations and subclinical fundus damage have been shown to correlate with SLE disease activity and, in some patients, even precede other systemic injuries as the first presentation of SLE. Moreover, ocular fundus might serve as a window into the state of systemic vasculitis in patients with SLE. Given the similarities of the anatomy, physiological and pathological processes shared among ocular fundus, and other vital organ damage in SLE, such as kidney and brain, it is assumed that ocular fundus involvement has implications in the diagnosis and evaluation of other systemic impairments. Therefore, evaluating the fundus characteristics of patients with SLE not only contributes to the early diagnosis and intervention of potential vision damage, but also holds considerate significance for the evaluation of SLE vasculitis state and prediction of other systemic injuries.

The Optimal Criteria for Patients with Systemic Lupus Erythematosus Should Meet Before Pregnancy: A Large-scale China Multicenter Study

Systemic lupus erythematosus (SLE) is often related to a lower rate of live birth and a higher incidence of adverse pregnancy outcomes (APOs), and pregnancy can lead to an increased risk of SLE flares. Comprehensive preconception assessment is crucial, but global consensus regarding the criteria the patients should meet before pregnancy has not been formed yet. This study, conducted retrospectively based on data from Chinese SLE Treatment and Research group (CSTAR) registry, a multicenter Chinese SLE cohort, aimed to investigate the optimal criteria. Analysis included 347 singleton pregnancies from 333 patients with SLE in total. The criteria that patients with SLE should meet before pregnancy were identified by univariate logistic regression analysis, which were: 1) disease stable for at least 6 months; 2) absent of vital organ damage; 3) on nonfluorinated corticosteroids no more than the dose equivalent to prednisone 7.5mg per day; 4) on hydroxychloroquine. The proportion of live birth was significantly higher in the group meeting the criteria (86.1% vs 73.7%, p=0.004). Furthermore, the gestational week at delivery (38.4 vs 37.6, p&lt;0.001) and the birthweight (2956.7g vs 2810.2g, p=0.004) were significantly larger. Then, APOs occurred less frequently in the group meeting the criteria (29.4% vs 52.1%, p&lt;0.001). For each type of APOs, the incidences of therapeutic abortion (5.0% vs 12.0%, p=0.019), preterm delivery (14.2% vs 33.3%, p&lt;0.001), and preeclampsia (1.1% vs 5.4%, p=0.023) were remarkably lower. When it comes to disease flares, patients in group meeting the criteria experienced flares during pregnancy less frequently (14.7% vs 28.1%, p=0.005), as well as for severe flares (5.8% vs 15.6%, p=0.006). Results were similar when taking both gestation period and one year postpartum into consideration. The results of this study stress the importance of comprehensive preconception assessment and warrant the implementation of such criteria among patients with SLE in clinical practice.

Human in vitro disease modeling of ATTR cardiac amyloidosis

Abstract Background Amyloidosis is a systemic protein-folding disorder characterized by extracellular misfolded fibrillar protein aggregates that are insoluble and resistant to proteolysis, leading to progressive and vital organ damage [1]. Transthyretin amyloidosis (ATTR) is one of the primary amyloidosis types that affect the heart. Based on the TTR gene sequence, ATTR is further classified into wild-type ATTR (ATTRwt) and hereditary ATTR (ATTRv). Advanced stage TTR amyloid infiltration of the myocardium results in progressive thickening and stiffening of the ventricle wall, and symptoms of restrictive cardiomyopathy and congestive heart failure. Due to the lack of specificity of cardiac amyloidosis symptoms, misdiagnosis and delays in diagnosis are common, resulting in worsening symptoms, organ damage, and increased mortality [2]. Despite the development of several disease-modifying agents [3], current experimental cell and animal models do not adequately represent the human situation, thereby limiting disease understanding and therapeutic discovery. Purpose This project aims to develop an in vitro ATTR disease model, which is critical to define early disease stages and disease progression, map human disease-specific pathways, and screen for novel drugs or validating cutting-edge therapeutic strategies. Methods Recombinant WT-TTR and V122I mutated TTR (V122I) were prepared using E.coli protein production system. TTR purification and acid-mediated TTR-fibril were characterized by SDS-PAGE, Thioflavin T fluorescence measurement, and transmission electron microscope (EM). iPSC-derived cardiomyocytes (iPS-CMs) were differentiated using GiWi protocol as described [4,5]. iPS-CMs or HUVECs were seeded on TTR or TTR-fibril, and we measured beating rate, cell viability (AlamarBlue and LiveDead), and cell/fibril morphology using immunofluorescence. Results Purified recombinant WT and V122I TTR was successfully generated (Figure 1A). Fluorescence increase (Thioflavin T) and EM revealed the presence of TTR-fibril (Figure 1B). iPS-CMs seeded on TTR-fibril resulted in a dose- and time-dependent increase in cell death. Confocal microscopy revealed the attachment of TTR-fibril on iPS-CMs, leading to sarcomere disarray, loss of cell-to-cell coupling, resulting in irregular beating (Figure 2A). Additionally, we found drastically affected viability of HUVECs upon TTR-fibril exposure (Figure 2B). Conclusion Here, we demonstrate an established method to generate purified TTR and TTR-fibril. TTR-fibril attached to the surface of iPS-CMs decreased cell viability and functionality. Similar reduction in HUVEC viability were observed as well. These findings reflect the cytotoxicity of TTR-fibril in a human in vitro model.TTR and TTR-fibril characterizationCell viability up TTR-fibril exposure

Role of endothelial cells and angiotensin converting enzyme-II in COVID-19 and brain damages post-infection.

Severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) causes coronavirus disease 2019 (COVID-19), which became a pandemic in late 2019 and early 2020. Apart from many other symptoms of this infection, such as loss of smell and taste, rashes, body aches, fatigue, and psychological and cardiac symptoms, it also causes vasodilation in response to inflammation via nitric oxide release. SARS CoV-2 affects microcirculation, resulting in the swelling and damage of endothelial cells, micro thrombosis, constriction of capillaries, and damage to pericytes that are vital for the integrity of capillaries, angiogenesis, and the healing process. Cytokine storming has been associated with COVID-19 illness. Capillary damage and congestion may cause limited diffusion exchange of oxygen in the lungs and hence hypoxemia and tissue hypoxia occur. This perspective study will explore the involvement of capillary damage and inflammation by their interference with blood and tissue oxygenation as well as brain function in the persistent symptoms and severity of COVID-19. The overall effects of capillary damage due to COVID-19, microvascular damage, and hypoxia in vital organs are also discussed in this perspective. Once initiated, this vicious cycle causes inflammation due to hypoxia, resulting in limited capillary function, which in turn causes inflammation and tissue damage. Low oxygen levels and high cytokines in brain tissue may lead to brain damage. The after-effects may be in the form of psychological symptoms such as mood changes, anxiety, depression, and many others that need to be investigated.

Bioaccumulation and Evaluation of Magnesium Oxide Nanoparticles Toxicity and Combination Effects of Vitamin E and C with it on Exposed Male Rats

In the recent years, MgO nanoparticles (MgO NPs) have been one of the metal oxide nanoparticles that used in various medicinal fields. Despite MgO NPs' widespread use, a little is known regarding their cytotoxic effects on health. The purpose of this study was to determine the toxic dose of MgO NPs that prepared by the sol-gel method and the roles of vitamins E and C in the toxicity that is produced by MgO NPs. The MgO NPs were characterized and several amounts (62.5, 125, 250, and 500 mg/kg BW) were orally administrated for 28 days to male Wister rats. Toxic dosimetry was evaluated using metal content analysis, hematological, biochemical, histopathological, and serum ROS estimation. Then toxic doses of MgO NPs were administered orally with vitamins E and C, or a combination of them for six weeks, twice a week. The result showed 500 mg/kg bw/day MgO NPs is considered as a toxic and leads to a significant Mg bioaccumulation in the liver (P &lt; 0.001) and significantly increased serum ROS (P&lt;0.001) and histopathological damage in the liver and kidney with an immunologic response. Administration of vitamin E with MgO NPs significantly increased serum ROS and adversely affected blood parameters and histological damage to the liver and kidney. The combination of vitamins E and C with MgO NPs significantly reduced the immunologic response to MgO NPs, but serum ROS levels increased significantly with histopathological damage in vital organs. Vitamin C significantly reduced MgO NPs-induced damage in kidney and liver tissues. In the conclusion, MgO NPs are toxic at high doses. Administration of vitamin E alone or combined vitamin E and C with toxic doses of MgO NPs increases their toxicity. However, vitamin C was shown to be histopathologically protective. Therefore, a serious caution should be considered when vitamins are administered with nanoparticles.

Role of SARS-CoV-2-induced cytokine storm in multi-organ failure: Molecular pathways and potential therapeutic options.

Coronavirus disease 2019 (COVID-19) outbreak has become a global public health emergency and has led to devastating results. Mounting evidence proposes that the disease causes severe pulmonary involvement and influences different organs, leading to a critical situation named multi-organ failure. It is yet to be fully clarified how the disease becomes so deadly in some patients. However, it is proven that a condition called "cytokine storm" is involved in the deterioration of COVID-19. Although beneficial, sustained production of cytokines and overabundance of inflammatory mediators causing cytokine storm can lead to collateral vital organ damages. Furthermore, cytokine storm can cause post-COVID-19 syndrome (PCS), an important cause of morbidity after the acute phase of COVID-19. Herein, we aim to explain the possible pathophysiology mechanisms involved in COVID-19-related cytokine storm and its association with multi-organ failure and PCS. We also discuss the latest advances in finding the potential therapeutic targets to control cytokine storm wishing to answer unmet clinical demands for treatment of COVID-19.

Mitochondria-endoplasmic reticulum contacts in sepsis-induced myocardial dysfunction.

Mitochondrial and endoplasmic reticulum (ER) are important intracellular organelles. The sites that mitochondrial and ER are closely related in structure and function are called Mitochondria-ER contacts (MERCs). MERCs are involved in a variety of biological processes, including calcium signaling, lipid synthesis and transport, autophagy, mitochondrial dynamics, ER stress, and inflammation. Sepsis-induced myocardial dysfunction (SIMD) is a vital organ damage caused by sepsis, which is closely associated with mitochondrial and ER dysfunction. Growing evidence strongly supports the role of MERCs in the pathogenesis of SIMD. In this review, we summarize the biological functions of MERCs and the roles of MERCs proteins in SIMD.

IgM-Related Immunoglobulin Light Chain (AL) Amyloidosis

Waldenström macroglobulinemia (WM) is a rare lymphoplasmacytic disorder characterized by an IgM paraprotein. The clinical presentation of WM varies and can include common manifestations such as anemia and hyperviscosity, in addition to less common features such as cryoglobulinemia, IgM-related neuropathy, and immunoglobulin light chain (AL) amyloidosis. Amyloidosis is a protein-folding disorder in which vital organ damage occurs due to the accumulation of misfolded protein aggregates. The most common type of amyloidosis in patients with an IgM paraprotein is AL amyloidosis, although other types of amyloidosis may occur. IgM-related amyloidosis has distinct clinical features when compared with other subtypes of AL amyloidosis. This review highlights the diagnostic criteria of IgM-related AL amyloidosis, as well as the clinical characteristics and treatment options for this disorder.

A cross-sectional study to correlate antioxidant enzymes, oxidative stress and inflammation with prevalence of hypertension

AimsHypertension a multifactorial consequence of environmental factors, life style and genetics is the well-recognized risk factor contributing to coronary heart diseases. The antioxidant imbalance, excessive reactive oxygen species (ROS) leads to oxidative stress which is pivotal in progression of hypertension. The present study aims to understand the complex interaction between oxidative stress, inflammation and antioxidant system which is crucial to maintain cellular homeostasis which further can exaggerate hypertension pathophysiology. Materials and methodsThe metabolic profile of hypertensive and normotensive subjects from Malwa region, Punjab was compared by estimating lipid profile, cardiac, hepatic and renal markers. The oxidative stress markers (protein carbonyls and lipid peroxidation), inflammatory markers (Nitric oxide, Myeloperoxidase and advanced oxygen protein products), and antioxidant enzymes (Superoxide Dismutase, Catalase, and Total Antioxidant Capacity) were analyzed. Key findingsIt is observed that the metabolic markers are altered in hypertensive subjects which further these subjects showed increased oxidative, inflammatory profile and compromised antioxidant status when compared with normotensive subjects. Co-relation analysis validated the involvement of inflammation and oxidative stress in impaired endothelial function and vital organ damage. Significance of studyThese markers may act as early indicators of hypertension which usually do not show any physical symptoms, thus can be diagnosed and treated at the earliest. The current study suggests that disturbed homeostasis, a consequence of altered interaction between antioxidant system and inflammatory events raises the oxidative stress levels which eventually leads to hypertension and associated complications. These indicators can serve as early indicators of future chronic complications of hypertension.

Chlorin e6-loaded goat milk-derived extracellular vesicles for Cerenkov luminescence-induced photodynamic therapy.

Photodynamic therapy (PDT) is a promising cancer treatment strategy with rapid progress in preclinical and clinical settings. However, the limitations in penetration of external light and precise delivery of photosensitizers hamper its clinical translation. As such, the internal light source such as Cerenkov luminescence (CL) from decaying radioisotopes offers new opportunities. Herein, we show that goat milk-derived extracellular vesicles (GEV) can act as a carrier to deliver photosensitizer Chlorin e6 (Ce6) and tumor-avid 18F-FDG can activate CL-induced PDT for precision cancer theranostics. GEV was isolated via differential ultracentrifugation of commercial goat milk and photosensitizer Ce6 was loaded by co-incubation to obtain Ce6@GEV. Tumor uptake of Ce6@GEV was examined using confocal microscopy and flow cytometry. To demonstrate the ability of 18F-FDG to activate photodynamic effects against cancer cells, apoptosis rates were measured using flow cytometry, and the production of 1O2 was measured by reactive oxygen species (ROS) monitoring kit. Moreover, we used the IVIS device to detect Cherenkov radiation and Cerenkov radiation energy transfer (CRET). For animal experiments, a small-animal IVIS imaging system was used to visualize the accumulation of the GEV drug delivery system in tumors. PET/CT and CL images of the tumor site were performed at 0.5, 1, and 2 h. For in vivo antitumor therapy, changes of tumor volume, survival time, and body weight in six groups of tumor-bearing mice were monitored. Furthermore, the blood sample and organs of interest (heart, liver, spleen, lungs, kidneys, and tumor) were collected for hematological analysis, immunohistochemistry, and H&E staining. Confocal microscopy of 4T1 cells incubated with Ce6@GEV for 4 h revealed strong red fluorescence signals in the cytoplasm, which demonstrated that Ce6 loaded in GEV could be efficiently delivered into tumor cells. When Ce6@GEV and 18F-FDG co-existed incubated with 4T1 cells, the cell viability plummeted from more than 88.02 ± 1.30% to 23.79 ± 1.59%, indicating excellent CL-induced PDT effects. In vivo fluorescence images showed a peak tumor/liver ratio of 1.36 ± 0.09 at 24 h after Ce6@GEV injection. For in vivo antitumor therapy, Ce6@GEV + 18F-FDG group had the best tumor inhibition rate (58.02%) compared with the other groups, with the longest survival rate (35 days, 40%). During the whole treatment process, neither blood biochemical analysis nor histological observation revealed vital organ damage, suggesting the biosafety of this treatment strategy. The simultaneous accumulation of 18F-FDG and Ce6 in tumor tissues is expected to overcome the deficiency of traditional PDT. This strategy has the potential to extend PDT to a variety of tumors, including metastases, using targeted radiotracers to provide internal excitation of light-responsive therapeutics. We expect that our method will play a critical role in precision treatment of deep solid tumors.

Pathologic light chain amyloidosis oligomer detection in urinary extracellular vesicles as a diagnostic tool for response and progression of disease.

Light Chain (AL) Amyloidosis is a plasma cell dyscrasia producing amyloidogenic light chains (LC) that misfold and form amyloid deposits that cause damage in vital organs, primarily the heart and kidneys. Urinary extracellular vesicles (uEVs) are nanoparticles produced by renal epithelial cells throughout the nephron. We previously showed that uEVs from active renal AL amyloidosis patients contain LC oligomers that are large (>250kDa), resistant to heat and chemical denaturation, but of low abundance. Renal dysfunction in AL amyloidosis results in high urine protein, compounding technical challenges to use uEVs as analytical tools. In this study, we assess the use of uEVs as analytical diagnostic tools for response and disease progression in AL amyloidosis. Our results suggest that uEV protein concentration, urine volume, and particle concentrations are not directly correlated. Multiple strategies for overcoming non-specific antibody binding in uEV samples were validated in our study. We demonstrated that the sensitivity for pre-clinical testing is improved with a urine sample requirement algorithm that we developed. The findings of our study will provide a pathway toward development of critically needed tools for patient management. Sensitive detection of LC oligomers from a non-invasive urine sample rather than an invasive renal biopsy will reduce patient burden and healthcare costs. The ability to detect LC oligomers in patients with renal progression, despite positive hematologic response; will allow clinicians to confidently treat, but not overtreat, patients at risk of ongoing significant renal injury.