Impact of low-level laser therapy as an adjunct to non-surgical periodontal treatment on the levels of tissue plasminogen activator and plasminogen activator inhibitor 1 in Stage 3-4, Grade C periodontitis patients: a split-mouth, randomized control study.

AIM: To investigate the effects of low-level laser therapy (LLLT) as an adjunct to non-surgical periodontal treatment (NSPT) on the plasminogen-activating system. MATERIALS AND METHODS: Stage 3-4 Grade C periodontitis and age-gender-matched healthy individuals participated in the split-mouth study (ClinicalTrials.gov identifier, NCT05233501). The study groups were Periodontitis/NSPT (Sham); Periodontitis/NSPT + LLLT (LLLT); Healthy (Control). Following NSPT, LLLT was applied on Days 0, 2 and 7. Clinical parameters were recorded at baseline and on Day 30. Gingival crevicular fluid (GCF) was collected at baseline, on days 7, 14, and 30; tissue-type plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) levels were measured with ELISA. RESULTS: Clinical parameters, total GCF tPA (tPAt) and PAI-1 (PAI-1t) levels significantly reduced in LLLT and Sham groups (< 0.001). GCF tPAt levels in LLLT were significantly lower (< 0.05) than Sham on Day 7. GCF tPAt levels in periodontitis groups were significantly higher than the Control at baseline, on Days 7 and 14 (< 0.01). By Day 30, both groups decreased to control levels (> 0.05). GCF PAI-1t levels were significantly lower in LLLT than the Sham on day 30 (< 0.01), comparable to healthy controls (> 0.05). CONCLUSION: Adjunctive LLLT modulates the plasminogen activating system in severe periodontitis by altering GCF tPA and PAI-1 levels. CLINICAL RELEVANCE: LLLT as an adjunct to non-surgical periodontal treatment in patients with Stage 3-4 Grade C leads to reduced plasminogen activation.

The Perspective of Vitamin D on suPAR-Related AKI in COVID-19.

The coronavirus disease 2019 (COVID-19) pandemic has claimed the lives of millions of people around the world. Severe vitamin D deficiency can increase the risk of death in people with COVID-19. There is growing evidence that acute kidney injury (AKI) is common in COVID-19 patients and is associated with poorer clinical outcomes. The kidney effects of SARS-CoV-2 are directly mediated by angiotensin 2-converting enzyme (ACE2) receptors. AKI is also caused by indirect causes such as the hypercoagulable state and microvascular thrombosis. The increased release of soluble urokinase-type plasminogen activator receptor (suPAR) from immature myeloid cells reduces plasminogen activation by the competitive inhibition of urokinase-type plasminogen activator, which results in low plasmin levels and a fibrinolytic state in COVID-19. Frequent hypercoagulability in critically ill patients with COVID-19 may exacerbate the severity of thrombosis. Versican expression in proximal tubular cells leads to the proliferation of interstitial fibroblasts through the C3a and suPAR pathways. Vitamin D attenuates the local expression of podocyte uPAR and decreases elevated circulating suPAR levels caused by systemic inflammation. This decrease preserves the function and structure of the glomerular barrier, thereby maintaining renal function. The attenuated hyperinflammatory state reduces complement activation, resulting in lower serum C3a levels. Vitamin D can also protect against COVID-19 by modulating innate and adaptive immunity, increasing ACE2 expression, and inhibiting the renin-angiotensin-aldosterone system. We hypothesized that by reducing suPAR levels, appropriate vitamin D supplementation could prevent the progression and reduce the severity of AKI in COVID-19 patients, although the data available require further elucidation.

Aplicación tópica de ácido tranexámico en urología: ¿Una alternativa de manejo? / Topical Application of Tranexamic Acid in Urology: An Alternative Management?

Los agentes antifibrinolíticos, como el ácido tranexámico, por medio de su administración endovenosa se usan en distintos procedimientos quirúrgicos para prevenir la pérdida de sangrado perioperatorio.[1] Este medicamento es un derivado sintético análogo de la lisina que bloquea los sititos de unión de la lisina en el plasminógeno, inhibiendo su conversión a plasmina e interfiriendo en la fibrinólisis.[2] La aplicación del ácido tranexámico para disminuir el riesgo de sangrado ha sido utilizado en procedimientos urológicos como la resección transuretral prostática (RTUP), prostatectomía radical y nefrolitotomía percutánea (NLP),[3] [4] [5] también se emplea para disminuir las hematurias persistentes en pacientes con poliquistosis renal y en otras hematurias macroscópicas de origen urológico.

Antifibrinolytic agents, such as tranexamic acid, by intravenous administration are used in various surgical procedures to prevent perioperative bleeding loss.[1] This drug is a synthetic lysine analog derivative that blocks the lysine binding sites on plasminogen, inhibiting its conversion to plasmin and interfering with fibrinolysis.[2] The application of tranexamic acid to reduce the risk of bleeding has been used in urological procedures such as transurethral resection of the prostate (TURP), radical prostatectomy and nephrolithotomy. The application of tranexamic acid to reduce the risk of bleeding has been used in urological procedures such as transurethral resection of the prostate (TURP), radical prostatectomy and percutaneous nephrolithotomy (PNL),[3] [4] [5] it is also used to reduce persistent hematuria in patients with polycystic kidney disease and other macroscopic hematuria of urological origin.

[Pharmaceutical supply of human plasminogen replacement therapy for the treatment of ligneous conjunctivitis: Logistics for a university hospital]. / Approvisionnement hospitalier en plasminogène humain substitutif pour le traitement de la conjonctivite ligneuse : comment faire en pratique ?

In order to treat a pediatric patient with ligneous conjunctivitis secondary to congenital plasminogen deficiency, a supply of topically administered replacement human plasminogen has been required. In the absence of market approval, this blood-derived drug is managed by a temporary authorisation for nominative use, allowing monthly hospital dispensations. To ensure regulatory compliance and proper use of the drug, it took two years of interactions between various hospital departments and the laboratory to define the pharmaceutical supply chain in our hospital and allow the patient to receive treatment. The main difficulties lie in respecting the cold chain of this drug stored frozen in the bottles not ready for use. Transportation from the laboratory to the patient's home via the hospital pharmacy is carried out in calibrated conditions, ensuring a temperature below -20°C for 72h. Reception and dispensing steps were combined into a single pharmaceutical service in order to optimise transport time while ensuring the safety and traceability of the drug lots. Each month, a date is scheduled between the hospital pharmacy, the laboratory and the family to ensure that delivery and dispensing take place on the same day. Appropriate use and handling are explained to the family. However, two issues remain to be addressed by the manufacturer to facilitate future use of human plasminogen: the thermostability problem, which does not allow stays away from home longer than three days, and self-administration by the child, which is unlikely to be feasible due to handling difficulties.

Treatment of ligneous conjunctivitis with fresh frozen plasm in twin babies.

Ligneous conjunctivitis is a rare form of chronic conjunctivitis. Mostly seen in childhood, it is characterized by the formation of fibrin-rich pseudomembranes in the tarsal conjunctiva. Plasminogen deficiency plays an important role in its etiology. There is no standart treatment protocol for managing this challenging condition, which can, with corneal involvement, lead to blindness. We present twin babies with ligneous conjunctivitis managed with fresh frozen plasma, topical heparin, and topical cyclosporine, without surgical excision of membranes.

Proteomic and mechanistic study of Qingxuan Tongluo formula and curcumin in the treatment of Mycoplasma pneumoniae pneumonia.

OBJECTIVE: Mycoplasma pneumoniae (MP) is the only pathogen in the Mycoplasma family that can cause respiratory symptoms, including acute upper respiratory tract infection and bronchitis, which are often attributed to Mycoplasma pneumoniae pneumonia (MPP). MPP is one of the diseases that commonly affects the pediatric respiratory system, but its pathogenesis is unclear. This study investigated the therapeutic effects and mechanisms of Qingxuan Tongluo formula and its main component, curcumin, on MPP. METHODS: A mouse model of MPP was obtained by nasal drip of the MP strain. The effects of Qingxuan Tongluo formula and curcumin on the treatment of MPP were studied. The proteomic profiles of the alveolar lavage fluid of mice in the model group, Qingxuan Tongluo formula group and curcumin group were evaluated by LC-MS/MS. ELISA and immunohistochemistry were used to verify the possible presence of MP infection biomarkers and drug target proteins. RESULTS: Compared with the mice in the model group, the MPP mice in the Qingxuan Tongluo formula group had significantly reduced fever and cough and prolonged the cough incubation period. Moreover, the pulmonary pathology of the MPP mice was significantly improved, and the lung histopathological score was decreased. After treatment with Qingxuan Tongluo formula and curcumin, the functional and pathway abnormalities caused by MP were mainly inhibited. Levels of HSP90AA1, GRP94, ENO1 and PLG expression were verified by ELISA and immunohistochemistry. CONCLUSION: Qingxuan Tongluo formula significantly reduced fevers and cough and prolonged the cough incubation period of MPP mice. Qingxuan Tongluo formula and curcumin significantly improved the pathological changes in lung tissue caused by MP infection. Proteomics analyses indicated that Qingxuan Tongluo formula and curcumin may have therapeutic effects on MPP by regulating energy metabolism, relieving oxidative stress and activating the fibrinolytic system. ENO1 and PLG were found to be potential drug targets.

Prevention of Anastomotic Leak Via Local Application of Tranexamic Acid to Target Bacterial-mediated Plasminogen Activation: A Practical Solution to a Complex Problem.

OBJECTIVE: To investigate the role of bacterial- mediated plasminogen (PLG) activation in the pathogenesis of anastomotic leak (AL) and its mitigation by tranexamic acid (TXA). BACKGROUND: AL is the most feared complication of colorectal resections. The pathobiology of AL in the setting of a technically optimal procedure involves excessive submucosal collagen degradation by resident microbes. We hypothesized that activation of the host PLG system by pathogens is a central and targetable pathway in AL. METHODS: We employed kinetic analysis of binding and activation of human PLG by microbes known to cause AL, and collagen degradation assays to test the impact of PLG on bacterial collagenolysis. Further, we measured the ability of the antifibrinolytic drug TXA to inhibit this process. Finally, using mouse models of pathogen-induced AL, we locally applied TXA via enema and measured its ability to prevent a clinically relevant AL. RESULTS: PLG is deposited rapidly and specifically at the site of colorectal anastomoses. TXA inhibited PLG activation and downstream collagenolysis by pathogens known to have a causal role in AL. TXA enema reduced collagenolytic bacteria counts and PLG deposition at anastomotic sites. Postoperative PLG inhibition with TXA enema prevented clinically and pathologically apparent pathogen-mediated AL in mice. CONCLUSIONS: Bacterial activation of host PLG is central to collagenolysis and pathogen-mediated AL. TXA inhibits this process both in vitro and in vivo. TXA enema represents a promising method to prevent AL in high-risk sites such as the colorectal anastomoses.

Type 1 Plasminogen Deficiency With Pulmonary Involvement: Novel Treatment and Novel Mutation.

Type 1 plasminogen deficiency is a rare genetic disorder. Type 1 plasminogen deficiency is characterized by fibrin-rich pseudomembrane formation on mucosal surfaces, particularly the conjunctiva. Tracheobronchial tree involvement is a less common reported manifestation of type 1 plasminogen deficiency. Pseudomembranes in the tracheobronchial tree may result in respiratory compromise and ultimately fail if not recognized and treated. Currently, there is no specific replacement therapy approved for the treatment of congenital plasminogen deficiency. In the present paper, we report that type 1 plasminogen deficiency with novel frameshift mutation and pulmonary involvement was treated initially with systemic fresh frozen plasma followed by pulmonary lavage with fresh frozen plasma and tissue plasminogen activator.

Anterior Segment Surgeries Under Topical Fresh Frozen Plasma Treatment in Ligneous Conjunctivitis.

PURPOSE: To evaluate the efficacy of topical fresh frozen plasma (FFP) therapy on clinical symptoms, findings, and prognosis after anterior segment surgeries in patients with ligneous conjunctivitis (LC). METHODS: Retrospective case note review. RESULTS: Eleven eyes of 7 cases whose remission was not achieved after medical treatment such as topical corticosteroids, cyclosporine A, and heparin were included in the study. The median age of admission was 19 (1-49) years, median duration of FFP treatment was 48 (15-79) months, median follow-up period was 62 (16-114) months, and median age at symptom onset was 12 (4-252) months. Diagnosis was made according to clinical presentations, plasminogen activities, and response to treatment. Topical FFP that was prepared in our clinic was used in all cases. Surgeries (membrane excision, eyelid surgery, deep anterior lamellar keratoplasty, and cataract surgery) were performed after at least 1 month of FFP treatment. Prosthetic contact lens was applied to one eye. During the follow-up period, recurrences requiring membrane excision and side effects from topical FFP were not observed. CONCLUSIONS: LC is a rare membranous conjunctivitis that proceeds with remissions and recurrences. When it was shown that the etiology of LC is plasminogen deficiency, FFP became the only treatment option targeting the etiology. In this study, we observed that the topical FFP is an effective treatment method that prevents recurrence and ensures regression of membranes and safer anterior segment surgeries in LC.

Preventing Candida albicans from subverting host plasminogen for invasive infection treatment.

Candida albicans is a common fungal pathogen in humans that colonizes the skin and mucosal surfaces of the majority healthy individuals. How C. albicans disseminates into the bloodstream and causes life-threatening systemic infections in immunocompromised patients remains unclear. Plasminogen system activation can degrade a variety of structural proteins in vivo and is involved in several homeostatic processes. Here, for the first time, we characterized that C. albicans could capture and "subvert" host plasminogen to invade host epithelial cell surface barriers through cell-wall localized Eno1 protein. We found that the "subverted" plasminogen system plays an important role in development of invasive infection caused by C. albicans in mice. Base on this finding, we discovered a mouse monoclonal antibody (mAb) 12D9 targeting C. albicans Eno1, with high affinity to the 254FYKDGKYDL262 motif in α-helices 6, ß-sheet 6 (H6S6) loop and direct blocking activity for C. albicans capture host plasminogen. mAb 12D9 could prevent C. albicans from invading human epithelial and endothelial cells, and displayed antifungal activity and synergistic effect with anidulafungin or fluconazole in proof-of-concept in vivo studies, suggesting that blocking the function of cell surface Eno1 was effective for controlling invasive infection caused by Candida spp. In summary, our study provides the evidence of C. albicans invading host by "subverting" plasminogen system, suggesting a potential novel treatment strategy for invasive fungal infections.

Treatment of ligneous conjunctivitis with heterologous serum.

Ligneous conjunctivitis is a rare form of chronic and recurrent bilateral conjunctivitis, in which thick membranes develop on the tarsal conjunctiva and on other mucosae. We report the case of a 55-year old female patient with bilateral ligneous conjunctivitis who was successfully treated with 50% heterologous serum. There was no recurrence or side effects after one-year follow-up. We suggest the use of 50% heterologous serum should be further studied to better determine its efficacy as a treatment option for ligneous conjunctivitis.

Treatment of ligneous conjunctivitis with heterologous serum / Tratamento de conjuntivite lenhosa com soro heterólogo

ABSTRACT Ligneous conjunctivitis is a rare form of chronic and recurrent bilateral conjunctivitis, in which thick membranes develop on the tarsal conjunctiva and on other mucosae. We report the case of a 55-year old female patient with bilateral ligneous conjunctivitis who was successfully treated with 50% heterologous serum. There was no recurrence or side effects after one-year follow-up. We suggest the use of 50% heterologous serum should be further studied to better determine its efficacy as a treatment option for ligneous conjunctivitis.

RESUMO A conjuntivite lenhosa é uma forma rara de conjuntivite bilateral crônica e recorrente, na qual há formação de membranas espessas na conjuntiva tarsal e em outras mucosas. Relatamos o caso de uma paciente de 55 anos com conjuntivite lenhosa bilateral, que obteve sucesso no tratamento com soro heterólogo em concentração de 50%. Não houve recorrência após um ano de seguimento e nem efeitos colaterais ao tratamento. Dessa forma, o uso de soro heterólogo a 50% poderia ser mais estudado para melhor avaliação de sua eficácia como opção de tratamento para a conjuntivite lenhosa.

Ligneous conjunctivitis due to plasminogen deficit: Diagnostic and therapeutic approach. With literature review.

Ligneous conjunctivitis is a rare and poorly understood pathology. Infections and repeated microtraumas are often involved in acute disease flare-ups. This masquerade may lead to misdiagnosis and delayed treatment. We report two cases of ligneous conjunctivitis, describing various presentations of its natural history and focusing on the treatment of this rare disease.

Treatment of Ligneous Conjunctivitis Using Topical Plasminogen Therapy in an 8-Week-Old Female Infant.

An 8-week-old female infant presented with bilateral eyelid swelling and conjunctival membranes. She was diagnosed as having ligneous conjunctivitis. The membranes were excised but recurred despite topical cyclosporine, heparin, fresh frozen plasma, and systemic fresh frozen plasma transfusions. Topical plasminogen prevented membrane recurrence and intravenous plasminogen therapy treated systemic manifestations of the disease. [J Pediatr Ophthalmol Strabismus. 2018;55:e30-e32.].

(-)-Epigallocatechin gallate derivatives reduce the expression of both urokinase plasminogen activator and plasminogen activator inhibitor-1 to inhibit migration, adhesion, and invasion of MDA-MB-231 cells.

Urokinase plasminogen activator (uPA) and its inhibitor plasminogen activator inhibitor-1 (PAI-1) are established independent biomarkers for high metastasis risk in breast cancer. In this study, we investigated the regulatory activity of (-)-epigallocatechin-3-gallate (EGCG) and its derivatives on uPA and PAI-1 expression and thereby their anti-metastatic potential. EGCG showed only marginal effects on the uPA system and on the metastatic behavior of breast cancer cells (MDA-MB-231). However, the EGCG derivative 3e with a methyl-substituted carbonate substituent at the 4″-position showed potent inhibition of PAI-1 (62%) and uPA (50%) expression. The Ras-extracellular-signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (MAPK), and phosphatidylinositol-3-kinase (PI3K)/Akt/NF-κB pathways, which regulate uPA and PAI-1 expression, were also affected by 3e (25%, 45%, and 25% reduction, respectively). In line with these findings, substantial reduction in metastatic behavior of MDA-MB-231 cells, such as adhesion (40%), invasion (56%), and migration (40%), was observed in the presence of 3e. It is also noteworthy that, in MDA-MB-231 cells, 3e did not exert any beneficial effect on the expression of matric metalloprotein (MMP) 2 and 9, which indicates that the anti-metastatic activity of 3e in MDA-MB-231 cells is not related to its regulation of the expression of MMPs. Taken together, we have shown that the EGCG derivative 3e could suppress the metastatic behavior of MDA-MB-231 cells through regulation of uPA and PAI-1.

Treatment of plasminogen deficiency patients with fresh frozen plasma.

Congenital plasminogen (Plg) deficiency leads to the development of ligneous membranes on mucosal surfaces. Here, we report our experience with local and intravenous fresh frozen plasma (FFP). We retrospectively reviewed medical files of 17 patients and their eight first-degree relatives. Conjunctivitis was the main complaint. Thirteen patients were treated both with intravenous and conjunctival FFP. Venous thrombosis did not develop in any. Genetic evaluation revealed heterogeneous mutations as well as polymorphisms. Diagnosis and treatment of Plg deficiency is challenging; topical and intravenous FFP may be an alternative treatment.

High-fat diet-induced plasma protein and liver changes in obese rats can be attenuated by melatonin supplementation.

Obesity triggers changes in protein expression in various organs that might participate in the pathogenesis of obesity. Melatonin has been reported to prevent or attenuate such pathological protein changes in several chronic diseases. However, such melatonin effects on plasma proteins have not yet been studied in an obesity model. Using a proteomic approach, we investigated the effect of melatonin on plasma protein profiles after rats were fed a high-fat diet (HFD) to induce obesity. We hypothesized that melatonin would attenuate abnormal protein expression in obese rats. After 10weeks of the HFD, animals displayed increased body weight and fat accumulation as well as increased glucose levels, indicating an obesity-induced prediabetes mellitus-like state. Two-dimensional gel electrophoresis and liquid chromatography-mass spectrometry/mass spectrometry revealed 12 proteins whose expression was altered in response to the HFD and the melatonin treatment. The altered proteins are related to the development of liver pathology, such as cirrhosis (α1-antiproteinase), thrombosis (fibrinogen, plasminogen), and inflammation (mannose-binding protein A, complement C4, complement factor B), contributing to liver steatosis or hepatic cell death. Melatonin treatment most probably reduced the severity of the HFD-induced obesity by reducing the amplitude of HFD-induced plasma protein changes. In conclusion, we identified several potential biomarkers associated with the progression of obesity and its complications, such as liver damage. Furthermore, our findings reveal melatonin's beneficial effect of attenuating plasma protein changes and liver pathogenesis in obese rats.