Cognate antigen-independent differentiation of resident memory T cells in chronic kidney disease.

Resident memory T cells (TRMs), which are memory T cells that are retained locally within tissues, have recently been described as antigen-specific frontline defenders against pathogens in barrier and nonbarrier epithelial tissues. They have also been noted for perpetuating chronic inflammation. The conditions responsible for TRM differentiation are still poorly understood, and their contributions, if any, to sterile models of chronic kidney disease (CKD) remain a mystery. In this study, we subjected male C57BL/6J mice and OT-1 transgenic mice to five consecutive days of 2 mg/kg aristolochic acid (AA) injections intraperitoneally to induce CKD or saline injections as a control. We evaluated their kidney immune profiles at 2 wk, 6 wk, and 6 mo after treatment. We identified a substantial population of TRMs in the kidneys of mice with AA-induced CKD. Flow cytometry of injured kidneys showed T cells bearing TRM surface markers and single-cell (sc) RNA sequencing revealed these cells as expressing well-known TRM transcription factors and receptors responsible for TRM differentiation and maintenance. Although kidney TRMs expressed Cd44, a marker of antigen experience and T cell activation, their derivation was independent of cognate antigen-T cell receptor interactions, as the kidneys of transgenic OT-1 mice still harbored considerable proportions of TRMs after injury. Our results suggest a nonantigen-specific or antigen-independent mechanism capable of generating TRMs in the kidney and highlight the need to better understand TRMs and their involvement in CKD.NEW & NOTEWORTHY Resident memory T cells (TRMs) differentiate and are retained within the kidneys of mice with aristolochic acid (AA)-induced chronic kidney disease (CKD). Here, we characterized this kidney TRM population and demonstrated TRM derivation in the kidneys of OT-1 transgenic mice with AA-induced CKD. A better understanding of TRMs and the processes by which they can differentiate independent of antigen may help our understanding of the interactions between the immune system and kidneys.

Clinical Application of Adaptive Optics Imaging in Diagnosis, Management, and Monitoring of Ophthalmological Diseases: A Narrative Review.

Visualization of the retinal structure is crucial for understanding the pathophysiology of ophthalmic diseases, as well as for monitoring their course and treatment effects. Until recently, evaluation of the retina at the cellular level was only possible using histological methods, because the available retinal imaging technology had insufficient resolution due to aberrations caused by the optics of the eye. Adaptive optics (AO) technology improved the resolution of optical systems to 2 µm by correcting optical wave-front aberrations, thereby revolutionizing methods for studying eye structures in vivo. Within 25 years of its first application in ophthalmology, AO has been integrated into almost all existing retinal imaging devices, such as the fundus camera (FC), scanning laser ophthalmoscopy (SLO), and optical coherence tomography (OCT). Numerous studies have evaluated individual retinal structures, such as photoreceptors, blood vessels, nerve fibers, ganglion cells, lamina cribrosa, and trabeculum. AO technology has been applied in imaging structures in healthy eyes and in various ocular diseases. This article aims to review the roles of AO imaging in the diagnosis, management, and monitoring of age-related macular degeneration (AMD), diabetic retinopathy (DR), glaucoma, hypertensive retinopathy (HR), central serous chorioretinopathy (CSCR), and inherited retinal diseases (IRDs).

The immunology of corneal limbal stem cells: the up-to-date approach to stem cell transplantation.

Limbal epithelial stem cells (LSC, LESC) are multipotent cells used as regenerative treatment of the cornea in patients with limbal epithelial stem cell deficiency (LSCD, LESCD). There are different types of stem cell grafting including cultivated limbal epithelial transplantation (CET) and simple limbal epithelial transplantation (SLET). The outcomes of the techniques have been assessed as similar, with differences in the sample size required during the procedures. The most important culture components for stem cell cultivation include 3T3 murine fibroblasts, human amniotic membrane (HAM), fibrin gel, and culture medium. The culture medium may be enriched with serum or not; however, xenobiotic-free materials are preferred because of the low risk of pathogen transmission. Multiple studies have defined molecules important for maintaining the function of LSC including C/EBP δ, Bmi-1, p63 α, interleukins (IL-6), epithelial structural proteins - keratins, and antibodies against epidermal growth factor receptor (EGFR). The cell phenotype of LSC has been described with factors of transplantation success rate such as a high percentage of p63 positive cells. The article emphasizes the role of recipient tissue preparation, modern cultivation techniques and pathophysiological processes in LSC transplantation effectiveness.

Impact of Arterial Hypertension on the Eye: A Review of the Pathogenesis, Diagnostic Methods, and Treatment of Hypertensive Retinopathy.

The number of patients with arterial hypertension is continually increasing. Hypertension can cause organ complications, called hypertension-mediated organ damage (HMOD). One example is hypertensive retinopathy, in which high blood pressure (BP) damages both the retinal microcirculation and the retinal nerve fiber layer (RNFL). This can result in progressive and painless vision deterioration in some groups of patients. Unlike anywhere else in the human body, the microvasculature of the retina can be observed in vivo, and the progression of changes can be closely monitored. The harmful effect of increased BP on the eye is not only limited to hypertensive retinopathy, but can also lead to an exacerbation of diabetic retinopathy (DR) and to an increase in intraocular pressure (IOP), and it can also trigger the formation of thromboembolic lesions. This review presents an update on the pathogenesis of hypertensive retinopathy and the use of adaptive optics (AO) combined with optical coherence tomography (OCT) to evaluate the retinal microvasculature. The latest progress and directions of research in the field of hypertensive retinopathy are also discussed.

VEGFR3 tyrosine kinase inhibition aggravates cisplatin nephrotoxicity.

Expansion of renal lymphatic networks, or lymphangiogenesis (LA), is well recognized during development and is now being implicated in kidney diseases. Although LA is associated with multiple pathological conditions, very little is known about its role in acute kidney injury. The purpose of this study was to evaluate the role of LA in a model of cisplatin-induced nephrotoxicity. LA is predominately regulated by vascular endothelial growth factor (VEGF)-C and VEGF-D, ligands that exert their function through their cognate receptor VEGF receptor 3 (VEGFR3). We demonstrated that use of MAZ51, a selective VEGFR3 inhibitor, caused significantly worse structural and functional kidney damage in cisplatin nephrotoxicity. Apoptotic cell death and inflammation were also increased in MAZ51-treated animals compared with vehicle-treated animals following cisplatin administration. Notably, MAZ51 caused significant upregulation of intrarenal phospho-NF-κB, phospho-JNK, and IL-6. Cisplatin nephrotoxicity is associated with vascular congestion due to endothelial dysfunction. Using three-dimensional tissue cytometry, a novel approach to explore lymphatics in the kidney, we detected significant vascular autofluorescence attributed to erythrocytes in cisplatin alone-treated animals. Interestingly, no such congestion was detected in MAZ51-treated animals. We found increased renal vascular damage in MAZ51-treated animals, whereby MAZ51 caused a modest decrease in the endothelial markers endomucin and von Willebrand factor, with a modest increase in VEGFR2. Our findings identify a protective role for de novo LA in cisplatin nephrotoxicity and provide a rationale for the development of therapeutic approaches targeting LA. Our study also suggests off-target effects of MAZ51 on the vasculature in the setting of cisplatin nephrotoxicity.NEW & NOTEWORTHY Little is known about injury-associated LA in the kidney and its role in the pathophysiology of acute kidney injury (AKI). Observed exacerbation of cisplatin-induced AKI after LA inhibition was accompanied by increased medullary damage and cell death in the kidney. LA inhibition also upregulated compensatory expression of LA regulatory proteins, including JNK and NF-κB. These data support the premise that LA is induced during AKI and lymphatic expansion is a protective mechanism in cisplatin nephrotoxicity.

Bioenergetic maladaptation and release of HMGB1 in calcineurin inhibitor-mediated nephrotoxicity.

Calcineurin inhibitors (CNIs) are potent immunosuppressive agents, universally used following solid organ transplantation to prevent rejection. Although effective, the long-term use of CNIs is associated with nephrotoxicity. The etiology of this adverse effect is complex, and effective therapeutic interventions remain to be determined. Using a combination of in vitro techniques and a mouse model of CNI-mediated nephrotoxicity, we found that the CNIs, cyclosporine A (CsA), and tacrolimus (TAC) share a similar mechanism of tubular epithelial kidney cell injury, including mitochondrial dysfunction and release of High-Mobility Group Box I (HMGB1). CNIs promote bioenergetic reprogramming due to mitochondrial dysfunction and a shift toward glycolytic metabolism. These events were accompanied by diminished cell-to-cell adhesion, loss of the epithelial cell phenotype, and release of HMGB1. Notably, Erk1/2 inhibitors effectively diminished HMGB1 release, and similar inhibitor was observed on inclusion of pan-caspase inhibitor zVAD-FMK. In vivo, while CNIs activate tissue proremodeling signaling pathways, MAPK/Erk1/2 inhibitor prevented nephrotoxicity, including diminished HMGB1 release from kidney epithelial cells and accumulation in urine. In summary, HMGB1 is an early indicator and marker of progressive nephrotoxicity induced by CNIs. We suggest that proremodeling signaling pathway and loss of mitochondrial redox/bioenergetics homeostasis are crucial therapeutic targets to ameliorate CNI-mediated nephrotoxicity.

Immunological and molecular basics of the primary open angle glaucoma pathomechanism.

Glaucoma is a degenerative process of the optic nerve. Increased intraocular pressure is believed to be the main factor leading to the glaucomatous damage. The in vitro and in vivo animal glaucoma research models provide insight into the molecular changes in the retina in response to the injury factor. The damage is a complex process incorporating molecular and immunological changes. Such changes involve NF kB activity and complement activation. The processes affect the human antigen, JNK, MAPK, p53, MT2 and DBA/2J molecular pathways, activate the autophagy processes and compromise neuroprotective mechanisms. Activation and inhibition of immunological responses contribute to cell injury. The immunological mechanisms of glaucomatous degeneration include glial response, the complement, tumor necrosis factor α (TNF-α) pathways and toll-like receptors athways. Oxidative stress and excitotoxicity are factors contributing to cell death in glaucoma. The authors present an up-to-date review of the mechanisms involved and update on research focusing on a possible innovative glaucoma treatment.

Rapha Myr®, a Blend of Sulforaphane and Myrosinase, Exerts Antitumor and Anoikis-Sensitizing Effects on Human Astrocytoma Cells Modulating Sirtuins and DNA Methylation.

Brain and other nervous system cancers are the 10th leading cause of death worldwide. Genome instability, cell cycle deregulation, epigenetic mechanisms, cytoarchitecture disassembly, redox homeostasis as well as apoptosis are involved in carcinogenesis. A diet rich in fruits and vegetables is inversely related with the risk of developing cancer. Several studies report that cruciferous vegetables exhibited antiproliferative effects due to the multi-pharmacological functions of their secondary metabolites such as isothiocyanate sulforaphane deriving from the enzymatic hydrolysis of glucosinolates. We treated human astrocytoma 1321N1 cells for 24 h with different concentrations (0.5, 1.25 and 2.5% v/v) of sulforaphane plus active myrosinase (Rapha Myr®) aqueous extract (10 mg/mL). Cell viability, DNA fragmentation, PARP-1 and γH2AX expression were examined to evaluate genotoxic effects of the treatment. Cell cycle progression, p53 and p21 expression, apoptosis, cytoskeleton morphology and cell migration were also investigated. In addition, global DNA methylation, DNMT1 mRNA levels and nuclear/mitochondrial sirtuins were studied as epigenetic biomarkers. Rapha Myr® exhibited low antioxidant capability and exerted antiproliferative and genotoxic effects on 1321N1 cells by blocking the cell cycle, disarranging cytoskeleton structure and focal adhesions, decreasing the integrin α5 expression, renewing anoikis and modulating some important epigenetic pathways independently of the cellular p53 status. In addition, Rapha Myr® suppresses the expression of the oncogenic p53 mutant protein. These findings promote Rapha Myr® as a promising chemotherapeutic agent for integrated cancer therapy of human astrocytoma.

Curcumin induces multiple signaling pathways leading to vascular smooth muscle cell senescence.

Curcumin, a phytochemical present in the spice named turmeric, and one of the promising anti-aging factors, is itself able to induce cellular senescence. We have recently shown that cells building the vasculature senesced as a result of curcumin treatment. Curcumin-induced senescence was DNA damage-independent; however, activation of ATM was observed. Moreover, neither increased ROS production, nor even ATM were indispensable for senescence progression. In this paper we tried to elucidate the mechanism of curcumin-induced senescence. We analyzed the time-dependence of the level and activity of numerous proteins involved in senescence progression in vascular smooth muscle cells and how inhibition p38 or p38 together with ATM, two proteins involved in canonical signaling pathways, influenced cell senescence. We showed that curcumin was able to influence many signaling pathways of which probably none was dominant and sufficient to induce senescence by itself. However, we cannot exclude that the switch between initiation and progression of senescence is the result of the impact of curcumin on signaling pathways engaging AMPK, ATM, sirtuin 1 and p300 and on their reciprocal interplay. Cytostatic concentration of curcumin induced cellular stress, which exceeded the adaptive response and, in consequence, led to cellular senescence, which is triggered by time dependent activation of several signaling pathways playing diverse roles in different phases of senescence progression. We also showed that activity of ß-glucuronidase, the enzyme involved in deconjugation of the main metabolites of curcumin, glucuronides, increased in senescent cells. It suggests a possible local elevation of curcumin concentration in the organism.

The Role of Curcumin in the Modulation of Ageing.

It is believed that postponing ageing is more effective and less expensive than the treatment of particular age-related diseases. Compounds which could delay symptoms of ageing, especially natural products present in a daily diet, are intensively studied. One of them is curcumin. It causes the elongation of the lifespan of model organisms, alleviates ageing symptoms and postpones the progression of age-related diseases in which cellular senescence is directly involved. It has been demonstrated that the elimination of senescent cells significantly improves the quality of life of mice. There is a continuous search for compounds, named senolytic drugs, that selectively eliminate senescent cells from organisms. In this paper, we endeavor to review the current knowledge about the anti-ageing role of curcumin and discuss its senolytic potential.

What is and what is not cell senescence.

Cell senescence is a process that occurs due to telomere erosion or can be induced by various stresses. Senescent cells cease to divide but remain alive, metabolically active and able to secrete many molecules. They also show many hallmarks of senescence, such as enlarged size, increased granularity, increased activity of SA-ß-galactosidase, increased level of cyclin-dependent kinase inhibitors, p16 and p21, and DNA damage foci. Originally, cell senescence was attributed to proliferating normal cells, in contrast to cancer cells, which were considered as those endowed with indefinite growth ability. Recently, it has become evident that anticancer treatment induces senescence in cancer cells. Moreover, certain hallmarks of senescence were detected in non-proliferating post-mitotic cells. There are many signalling pathways involved in cell senescence, but the most prevalent is the DNA damage response pathway. In this review we have summarized our long lasting input in the global study of the mechanisms of senescence of normal and cancer cells and discussed the diversity of the concept of cell senescence.

Sirtuins, a promising target in slowing down the ageing process.

Ageing is a plastic process and can be successfully modulated by some biomedical approaches or pharmaceutics. In this manner it is possible to delay or even prevent some age-related pathologies. There are some defined interventions, which give promising results in animal models or even in human studies, resulting in lifespan elongation or healthspan improvement. One of the most promising targets for anti-ageing approaches are proteins belonging to the sirtuin family. Sirtuins were originally discovered as transcription repressors in yeast, however, nowadays they are known to occur in bacteria and eukaryotes (including mammals). In humans the family consists of seven members (SIRT1-7) that possess either mono-ADP ribosyltransferase or deacetylase activity. It is believed that sirtuins play key role during cell response to a variety of stresses, such as oxidative or genotoxic stress and are crucial for cell metabolism. Although some data put in question direct involvement of sirtuins in extending human lifespan, it was documented that proper lifestyle including physical activity and diet can influence healthspan via increasing the level of sirtuins. The search for an activator of sirtuins is one of the most extensive and robust topic of research. Some hopes are put on natural compounds, including curcumin. In this review we summarize the involvement and usefulness of sirtuins in anti-ageing interventions and discuss the potential role of curcumin in sirtuins regulation.

Cyclosporine-mediated allograft fibrosis is associated with micro-RNA-21 through AKT signaling.

Calcineurin inhibitors (CNIs) are potent immunosuppressants with associated long-term nephrotoxicity mediated by tubular epithelial cell injury and arterial vasoconstriction. We hypothesized that CNI-induced renal injury is regulated by specific microRNAs (miRNAs). In this study, we found that 46 miRNAs were significantly altered in human proximal tubular epithelial cells (HPTECs) following exposure to cyclosporine A (CsA), particularly miR-21 (5.47 ± 0.47-fold versus vehicle, P = 0.002). This increase was accompanied by alterations in epithelial-mesenchymal transformation (EMT) markers including vimentin (2.80 ± 0.28-fold; P = 0.03), S100A4 (2.29 ± 0.29-fold; P = 0.04), and α-SMA (5.0 ± 0.31-fold; P = 0.03). Notably, transfection of HPTECs with miR-21 precursor also resulted in significant induction of EMT-associated genes, which were inhibited by a single-stranded nucleic acid inhibitor of miR-21. miR-21 induction resulted in a rapid increase of phosphorylated AKT and downregulation of PTEN. While CsA induces SMAD7 downregulation and TGF-ß1 upregulation in HPTECs, such changes were independent of miR-21. Moreover, there was no effect on ERK phosphorylation. We confirmed these changes using a mouse model of CsA toxicity. Collectively, our results suggest that miR-21 mediates CsA nephrotoxicity via PTEN/AKT signaling pathway. Further exploration into the epigenetic response to CsA exposure may provide new therapeutic targets to ameliorate CsA nephrotoxicity.

Electrophysiological testing as a method of cone-rod and cone dystrophy diagnoses and prediction of disease progression.

PURPOSE: To determine the characteristics of patients with cone (CD) and cone-rod dystrophies (CRD) and to evaluate the changes in flash electroretinograms in both groups. METHODS: The retrospective study involved 48 patients-34 with CRD and 14 with CD. The patients underwent full ophthalmological examination, including Goldmann perimetry and full-field flash electroretinogram (FERG) within the initial examination. These examinations were then repeated seven, or more, years later. The longest follow-up period was 10 years, with the mean at 8.2 years. During both examinations, we assessed the amplitudes of the b wave in the scotopic ERG test 0.01 (which reflects rod response), the maximal scotopic ERG test 3.0 (which reflects cone and rod response) and the photopic 3.0 ERG test (which reflects cone response). The results were then compared against normal values. RESULTS: The progression over time of ERG b wave amplitudes in the scotopic ERG 0.01, maximal scotopic ERG 3.0 and photopic ERG tests was assessed. There were significant differences in rod, maximal and cone responses, between CD and CRD patients. While rod responses were markedly decreased in CRD patients during their initial examination, the decrease in the rod function in both CD and CRD patients was similar in their follow-up examination (p = 0.2398). Moreover, during initial examination, maximal responses were less common amongst CRD patients, over those with CD. Following the observation period, patients suffering from CRD exhibited a significant decrease in both maximal (p = 0.0125) and cone (p = 0.0046) responses. CONCLUSION: The clinical course of CRD and CD may vary; however, the latter appears to have a more favourable course than former. Although, at initial examination, the cone function was more diminished in CD patients, the final examinations reveal a more significant drop for CRD patients. Consequently, a differential diagnosis is essential for treating patients and forecasting their disease progression.

A comparison of replicative senescence and doxorubicin-induced premature senescence of vascular smooth muscle cells isolated from human aorta.

Senescence of vascular smooth muscle cells (VSMCs) contributes to aging as well as age-related diseases of the cardiovascular system. Senescent VSMCs have been shown to be present in atherosclerotic plaques. Both replicative (RS) and stress-induced premature senescence (SIPS) accompany cardiovascular diseases. We aimed to establish the signature of RS and SIPS of VSMCs, induced by a common anticancer drug, doxorubicin, and to discover the so far undisclosed features of senescent cells that are potentially harmful to the organism. Most of the senescence hallmarks were common for both RS and SIPS; however, some differences were observed. 32 % of doxorubicin-treated cells were arrested in the G2/M phase of the cell cycle, while 73 % of replicatively senescing cells were arrested in the G1 phase. Moreover, on the basis of alkaline phosphatase activity measurements, we show that a 7-day treatment with doxorubicin (dox), does not cause precocious cell calcification, which is a characteristic feature of RS. We did not observe calcification even though after 7 days of dox-treatment many other markers characteristic for senescent cells were present. It can suggest that dox-induced SIPS does not accelerate the mineralization of vessels. We consider that detailed characterization of the two types of cellular senescence can be useful in in vitro studies of potential anti-aging factors.

[Impact of cellular senescence on organismal aging and age-related diseases]. / Rola starzenia komórkowego w starzeniu organizmu i chorobach zwiazanych z wiekiem.

Development of the civilization and medicine enables an even longer lifespan of people. To modulate the aging process it is necessary to discover its molecular mechanism and its causes. It has been known for almost 60 years that cells undergo senescence. A lot of markers of senescence have been described to distinguish senescent cells. Every year we can observe an increase in the number of data, supporting the thesis that the reason for aging of the whole organism is cellular senescence. We age because cells building tissues and organs undergo senescence. It is also believed that cellular senescence can increase the frequency of age-related diseases. The role of cellular senescence strictly depends on the age of the individual. In young ones it is essential for: protection against cancer and tissue regeneration. In old ones it causes tissues and organs dysfunctions and leads to age-related diseases. Slowing down aging could prevent age-related diseases and this seems to be more promising than curing them. To enrich our knowledge concerning aging it is important to understand signaling pathways leading to senescence. Recently a new role of cellular senescence has been discovered, namely during embryogenesis. This observation is very surprising and shows a new face of cellular senescence. It is possible that, similarly to the previously described role of apoptosis in embryogenesis, senescence is indispensable for proper organogenesis. Cellular senescence seems to be the universal and fundamental process, the role of which changes during the lifespan.

Retinal Microcirculation Measurements in Response to Endurance Exercises Analysed by Adaptive Optics Retinal Camera.

This study aimed to precisely investigate the effects of intensive physical exercise on retinal microvascular regulation in healthy volunteers through adaptive optics retinal camera (AO) measurement. We included healthy volunteers (11 men and 14 women) aged 20.6 ± 0.9. The heart rate (HR) and systolic and diastolic blood pressures (SBP, DBP) were recorded before and after a submaximal physical exertion of continuously riding a training ergometer. The superior temporal retinal artery measurements were captured using the AO-rtx1TM (Imagine Eyes, Orsay, France) without pupil dilation. We compared measures of vessel diameter (VD), lumen diameter (LD), two walls (Wall 1, 2), wall-to-lumen ratio (WLR), and wall cross-sectional analysis (WCSA) before and immediately after the cessation of exercise. Cardiovascular parameter results: After exercise, SBP, DBP, and HR changed significantly from 130.2 ± 13.2 to 159.7 ± 15.6 mm Hg, 81.2 ± 6.3 to 77.1 ± 8.2 mm Hg, and 80.8 ± 16.1 to 175.0 ± 6.2 bpm, respectively (p < 0.002). Retinal microcirculation analysis showed no significant decrease in LD, Wall 1 after exercise: from 96.0 ± 6.8 to 94.9 ± 6.7 (p = 0.258), from 11.0 ± 1.5 to 10.4 ± 1.5 (p = 0.107), respectively, and significant reduction in VD from 118.5 ± 8.3 to 115.9 ± 8.3 (p = 0.047), Wall 2 from 11.5 ± 1.0 to 10.7 ± 1.3 (p = 0.017), WLR from 0.234 ± 0.02 to 0.222 ± 0.010 (p = 0.046), WCSA from 3802.8 ± 577.6 to 3512.3 ± 535.3 (p = 0.016). The AO is a promising technique for investigating the effects of exercise on microcirculation, allowing for the tracking of changes throughout the observation. Intensive dynamic physical exertion increases blood pressure and heart rate and causes the vasoconstriction of small retinal arterioles due to the autoregulation mechanism.

Is Primary Open-Angle Glaucoma a Vascular Disease? Assessment of the Relationship between Retinal Arteriolar Morphology and Glaucoma Severity Using Adaptive Optics.

BACKGROUND: Retinal vascular abnormalities may be associated with glaucomatous damage. Adaptive optics (AO) is a new technology that enables the analysis of retinal vasculature at the cellular level in vivo. The purpose of this study was to evaluate retinal arteriolar parameters using the rtx1 adaptive optics fundus camera (AO-FC) in patients with primary open-angle glaucoma (POAG) at different stages and to investigate the relationship between these parameters and changes in spectral-domain optical coherence tomography (SD-OCT) and perimetry. METHODS: Parameters of the retinal supratemporal and infratemporal arterioles (wall thickness (WT), lumen diameter (LD), total diameter (TD), wall-to-lumen ratio (WLR), and cross-sectional area of the vascular wall (WCSA)) were analysed with the rtx1 in 111 POAG eyes, which were divided into three groups according to the severity of the disease, and 70 healthy eyes. The associations between RTX1 values and the cup-to-disk ratio, SD-OCT parameters, and visual field parameters were assessed. RESULTS: Compared with the control group, the POAG groups showed significantly smaller TD and LD values (p < 0.05) and significantly higher WLR and WT values (p < 0.05) for the supratemporal and infratemporal arterioles. TD was significantly positively correlated with the retinal nerve fibre layer (RNFL) and ganglion cell complex (GCC) (p < 0.05). LD was significantly positively correlated with the RNFL, GCC, and rim area (p < 0.05). The WLR was significantly negatively correlated with the RNFL, GCC, rim area, and MD (p < 0.05), while it was significantly positively correlated with the cup-to-disc ratio and PSD (p < 0.05). CONCLUSIONS: The results suggest that vascular dysfunction is present in POAG, even at a very early stage of glaucoma, and increases with the severity of the disease.

Malignant Hypertension:A Systemic Cardiovascular Disease: JACC Review Topic of the Week.

Malignant hypertension (MHT) is a hypertensive emergency with excessive blood pressure (BP) elevation and accelerated disease progression. MHT is characterized by acute microvascular damage and autoregulation failure affecting the retina, brain, heart, kidney, and vascular tree. BP must be lowered within hours to mitigate patient risk. Both absolute BP levels and the pace of BP rise determine risk of target-organ damage. Nonadherence to the antihypertensive regimen remains the most common cause for MHT, although antiangiogenic and immunosuppressant therapy can also trigger hypertensive emergencies. Depending on the clinical presentation, parenteral or oral therapy can be used to initiate BP lowering. Evidence-based outcome data are spotty or lacking in MHT. With effective treatment, the prognosis for MHT has improved; however, patients remain at high risk of adverse cardiovascular and kidney outcomes. In this review, we summarize current viewpoints on the epidemiology, pathogenesis, and management of MHT; highlight research gaps; and propose strategies to improve outcomes.

DNA damage-independent apoptosis induced by curcumin in normal resting human T cells and leukaemic Jurkat cells.

Curcumin, a phytochemical derived from the rhizome of Curcuma longa, is a very potent inducer of cancer cell death. It is believed that cancer cells are more sensitive to curcumin treatment than normal cells. Curcumin has been shown to act as a prooxidant and induce DNA lesions in normal cells. We were interested in whether curcumin induces DNA damage and the DNA damage response (DDR) signalling pathway leading to apoptosis in normal resting human T cells. To this end, we analysed DNA damage after curcumin treatment of resting human T cells (CD3(+)) and of proliferating leukaemic Jurkat cells by the fluorimetric detection of alkaline DNA unwinding (FADU) assay and immunocytochemical detection of γ-H2AX foci. We showed that curcumin-treated Jurkat cells and resting T cells showed neither DNA lesions nor did they activate key proteins in the DDR signalling pathway, such as phospho-ATM and phospho-p53. However, both types of cell were equally sensitive to curcumin-induced apoptosis and displayed activation of caspase-8 but not of DNA damage-dependent caspase-2. Altogether, our results revealed that curcumin can induce apoptosis of normal resting human T cells that is not connected with DNA damage.