RESUMEN

Cervical cancer is a leading cause of cancer-related mortality in females worldwide, necessitating urgent solutions for effective treatment. Paclitaxel (PTX), a natural diterpene alkaloid compound, has the ability to inhibit mitosis and induce programmed apoptosis in tumor cells. However, its toxicity and drug resistance limit its efficacy in certain cervical cancer patients. ß-elemene (ß-ELE) can reverse multidrug resistance by inhibiting ATP-binding cassette transporters, thereby enhancing chemotherapy drug retention. Therefore, we propose a combination therapy using PTX/ß-ELE to improve chemotherapy sensitivity. To enhance targeted drug delivery, we developed M1-macrophage-membrane-coated nanoparticles (M1@PLGA/PTX/ß-ELE) for co-delivery of PTX&ß-ELE. Through both in vitro and in vivo cervical cancer models, we demonstrated that M1@PLGA/PTX/ß-ELE effectively suppressed tumor progression and polarization of tumor-associated macrophages. Furthermore, H&E staining confirmed the high therapeutic biosafety of M1@PLGA/PTX/ß-ELE as there was no significant damage observed in major organs throughout the entire therapeutic process. Overall, this study presents a targeted biomimetic nanoplatform and combinatorial strategy that synergistically enhances chemosensitivity in malignant tumors.

RESUMEN

Despite effective antiretroviral therapy (ART), 15-30% of people with HIV experience poor CD4+ T-cell recovery, termed immunologic non-responders (INR). This study aims to evaluate whether pre-ART plasma levels of interleukin-6 (IL-6), interferon gamma-induced protein-10 (IP-10), macrophage inflammatory protein-1-ß (MIP-1ß), and/or pentraxin-3 (PTX-3) could predict subsequent immunologic recovery. Seventy-four participants were enrolled and classified as INR and immunologic responders (IR) based on CD4+/CD8+ ratio increase over 24 months after starting ART. The results showed no significant differences in cytokine levels between INR and IR. Therefore, IL-6, IP-10, MIP-1ß, and PTX-3 were unsuitable as predictive markers of poor immune recovery.

Asunto(s)

Biomarcadores , Proteína C-Reactiva , Quimiocina CCL4 , Quimiocina CXCL10 , Infecciones por VIH , Interleucina-6 , Componente Amiloide P Sérico , Humanos , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Infecciones por VIH/sangre , Componente Amiloide P Sérico/metabolismo , Masculino , Femenino , Proteína C-Reactiva/análisis , Proteína C-Reactiva/metabolismo , Adulto , Quimiocina CCL4/sangre , Interleucina-6/sangre , Persona de Mediana Edad , Biomarcadores/sangre , Quimiocina CXCL10/sangre , Terapia Antirretroviral Altamente Activa , Resultado del Tratamiento , Antirretrovirales/uso terapéutico , Relación CD4-CD8 , Fármacos Anti-VIH/uso terapéutico

RESUMEN

Intercostal chest drain (ICD) insertion for pleural effusion or pneumothorax is one of the most routinely performed procedures. Patients with ICDs usually remain in a respiratory, medical, or cardiothoracic ward or a critical care unit. Despite it being a common procedure, there seems to be limited competency in troubleshooting chest drain when it is not functioning. From our daily experience working with junior doctors and doctors from specialties other than respiratory medicine, we feel there is a significant lack of training and troubleshooting skills to handle a non-functioning chest drain. This is a matter of grave concern, as inappropriate assessment can lead to the insertion of additional chest drains. In the current practice in the United Kingdom, we do not have out-of-hours respiratory cover, particularly in the district general hospitals, and the on-call medical team will not always have a registrar or any other team member with respiratory work experience. Therefore, we often fall short of managing ICD-related complications which results in the incorrect assessment of the patient's condition further leading to incorrect action plans, causing more harm to the patient. We present one such case, where a young pregnant lady in the respiratory ward who underwent thoracostomy with an ICD placement developed a near-tension pneumothorax secondary to block in the drain. The medical team's inexperience in troubleshooting led to a wrong treatment plan for the patient. Although ICD-related complications are frequent, very few reviews and guidelines are available in the literature which covers it comprehensively. Therefore, we aim to enlighten this less-explored area of clinical practice along with a review of literature.

RESUMEN

BACKGROUND: Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) that lasts a long time and has a variety of causes. AIM: The primary aim of this study was to evaluate pentoxifylline's (PTX) essential function in patients with UC. METHODS: Fifty-two mild to moderate UC patients who matched the eligibility requirements participated in this clinical study. One gram of mesalamine (t.i.d.) and a placebo were administered to the mesalamine group (n = 26) for a duration of 24 weeks. Mesalamine 1 g t.i.d. and PTX 400 mg two times daily were administered to the PTX group (n = 26) for 24 weeks. A gastroenterologist investigated patients at the start and 6 months after the medication was given to assess disease activity index (DAI) and numeric pain rating scale (NRS). Also, interleukin-6 (IL-6), sphingosine 1 phosphate (S1P), tumor necrosis factor-alpha (TNF-α), and fecal myeloperoxidase (MPO) were measured before and after therapy. Zonula occuldin-1 (ZO-1) and signal transducer and activator of transcription factor-3 (STAT-3) expression was assessed before and after therapy as well as histological assessment. Short Form 36 Health Survey (SF-36), was assessed for each patient before and after 6 months of treatment. RESULTS: The PTX group showed statistically lower levels of serum SIP, TNF-α, IL-6, faecal MPO, gene expression of STAT-3, and a significant increase of ZO-1 in comparison with the mesalamine group. DAI and NRS significantly decreased whereas SF-36 significantly increased in the PTX group. CONCLUSION: PTX could alleviate inflammation in patients with UC, so it might be promising adjunctive for patients with UC. TRIAL REGISTRATION IDENTIFIER: NCT05558761.

RESUMEN

Background: Existing research data indicates that albumin-bound paclitaxel (nab-ptx), anlotinib, and PD-1/L1 inhibitors have individually shown efficacy in second-line and subsequent treatments for advanced non-small cell lung cancer (NSCLC). This study seeks to investigate the potential of an optimized treatment regimen in this context by combining these three drugs and evaluating both efficacy and safety outcomes. Patients and Methods: Between January 2020 and January 2022, we collected data from pre-treated advanced NSCLC patients who received a combination therapy of nab-ptx, anlotinib, and PD-1/L1 inhibitors as a second-line or later treatment. The primary endpoints for the study included the objective response rate (ORR), progression-free survival (PFS), disease control rate (DCR) and overall survival (OS), while adverse events (AEs) were also recorded. Results: Our findings revealed that the ORR of this regimen in pretreated NSCLC patients was 35.71%, with mean PFS of 5.0 months and mean OS of 10.0 months. Further analysis suggested correlations between the efficacy of the regimen and factors such as PD-L1 expression levels, the occurrence of certain types of adverse events, and the status of NK cell activity. Additionally, the tolerable toxicity profile of this regimen indicates its potential applicability in the treatment of pretreated advanced NSCLC. Conclusion: Our study displayed that triple-drug combination of nab-ptx, anlotinib and PD-1/L1 inhibitors showed promising efficiency and tolerated cytotoxicity in the 2nd or above line treatment of advanced NSCLC, indicating the potential of such regimen as an important option for second-line treatment of advanced NSCLC. However, due to limitations in patient numbers, its actual clinical value awaits further research confirmation.

RESUMEN

OBJECTIVE AND DESIGN: Compelling evidence indicates that dysregulated macrophages may play a key role in driving inflammation in inflammatory bowel disease (IBD). Fibroblast growth factor (FGF)-19, which is secreted by ileal enterocytes in response to bile acids, has been found to be significantly lower in IBD patients compared to healthy individuals, and is negatively correlated with the severity of diarrhea. This study aims to explore the potential impact of FGF19 signaling on macrophage polarization and its involvement in the pathogenesis of IBD. METHODS: The dextran sulfate sodium (DSS)-induced mouse colitis model was utilized to replicate the pathology of human IBD. Mice were created with a conditional knockout of FGFR4 (a specific receptor of FGF19) in myeloid cells, as well as mice that overexpressing FGF19 specifically in the liver. The severity of colitis was measured using the disease activity index (DAI) and histopathological staining. Various techniques such as Western Blotting, quantitative PCR, flow cytometry, and ELISA were employed to assess polarization and the expression of inflammatory genes. RESULTS: Myeloid-specific FGFR4 deficiency exacerbated colitis in the DSS mouse model. Deletion or inhibition of FGFR4 in bone marrow-derived macrophages (BMDMs) skewed macrophages towards M1 polarization. Analysis of transcriptome sequencing data revealed that FGFR4 deletion in macrophages significantly increased the activity of the complement pathway, leading to an enhanced inflammatory response triggered by LPS. Mechanistically, FGFR4-knockout in macrophages promoted complement activation and inflammatory response by upregulating the nuclear factor-κB (NF-κB)-pentraxin3 (PTX3) pathway. Additionally, FGF19 suppressed these pathways and reduced inflammatory response by activating FGFR4 in inflammatory macrophages. Liver-specific overexpression of FGF19 also mitigated inflammatory responses induced by DSS in vivo. CONCLUSION: Our study highlights the significance of FGF19-FGFR4 signaling in macrophage polarization and the pathogenesis of IBD, offering a potential new therapeutic target for IBD.

Asunto(s)

Colitis , Sulfato de Dextran , Factores de Crecimiento de Fibroblastos , Macrófagos , Receptor Tipo 4 de Factor de Crecimiento de Fibroblastos , Animales , Masculino , Ratones , Colitis/inducido químicamente , Colitis/patología , Colitis/inmunología , Colon/patología , Colon/metabolismo , Sulfato de Dextran/toxicidad , Modelos Animales de Enfermedad , Factores de Crecimiento de Fibroblastos/genética , Factores de Crecimiento de Fibroblastos/metabolismo , Hígado/patología , Hígado/metabolismo , Macrófagos/metabolismo , Macrófagos/inmunología , Ratones Endogámicos C57BL , Ratones Noqueados , Receptor Tipo 4 de Factor de Crecimiento de Fibroblastos/genética , Receptor Tipo 4 de Factor de Crecimiento de Fibroblastos/metabolismo

RESUMEN

Oral administration of BCS class IV anticancer agents has always remained challenging and frequently results in poor oral bioavailability. The goal of the current study was to develop hybrid nanoparticles (HNPs) employing cholesterol and poloxamer-407 to boost paclitaxel's (PTX) oral bioavailability. A series of HNPs with different cholesterol and poloxamer-407 ratios were developed utilizing a single-step nanoprecipitation technique. The PTX loaded HNPs were characterized systematically via particle size, zeta potential, polydispersity index, surface morphology, in vitro drug release, FTIR, DSC, XRD, acute oral toxicity analysis, hemolysis evaluation, accelerated stability studies, and in vivo pharmacokinetic analysis. The HNPs were found within the range of 106.6±55.60 - 244.5±88.24 nm diameter with the polydispersity index ranging from 0.20±0.03 - 0.51±0.11. SEM confirmed circular, nonporous, and smooth surfaces of HNPs. PTX loaded HNPs exhibited controlled release profile. The compatibility between the components of formulation, thermal stability, and amorphous nature of HNPs were confirmed by FTIR, DSC, and XRD, respectively. Acute oral toxicity analysis revealed that developed system have no deleterious effects on the animals' cellular structures. HNPs demonstrated notable cytotoxic effects and were hemocompatible at relatively higher concentrations. In vivo pharmacokinetic profile (AUC0-∞, AUMC0-∞, t1/2, and MRT0-∞) of the PTX loaded HNPs was improved as compared to pure PTX. It is concluded from our findings that the developed HNPs are hemocompatible, biocompatible and have significantly enhanced the oral bioavailability of PTX.

Asunto(s)

Disponibilidad Biológica , Portadores de Fármacos , Nanopartículas , Paclitaxel , Paclitaxel/farmacocinética , Paclitaxel/administración & dosificación , Paclitaxel/química , Paclitaxel/farmacología , Animales , Administración Oral , Portadores de Fármacos/química , Nanopartículas/química , Materiales Biocompatibles/química , Ratas , Tamaño de la Partícula , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/farmacocinética , Antineoplásicos Fitogénicos/farmacología , Masculino , Poloxámero/química , Hemólisis/efectos de los fármacos , Liberación de Fármacos , Colesterol/química

RESUMEN

Cementum is a vital component of periodontium, yet its regeneration remains a challenge. Pentraxin 3 (PTX3) is a multifunctional glycoprotein involved in extracellular matrix remodeling and bone metabolism regulation. However, the role of PTX3 in cementum formation and cementoblast differentiation has not been elucidated. In this study, we initially observed an increase in PTX3 expression during cementum formation and cementoblast differentiation. Then, overexpression of PTX3 significantly enhanced the differentiation ability of cementoblasts. While conversely, PTX3 knockdown exerted an inhibitory effect. Moreover, in Ptx3-deficient mice, we found that cementum formation was hampered. Furthermore, we confirmed the presence of PTX3 within the hyaluronan (HA) matrix, thereby activating the ITGB1/FAK/YAP1 signaling pathway. Notably, inhibiting any component of this signaling pathway partially reduced the ability of PTX3 to promote cementoblast differentiation. In conclusion, our study indicated that PTX3 promotes cementum formation and cementoblast differentiation, which is partially dependent on the HA/ITGB1/FAK/YAP1 signaling pathway. This research will contribute to our understanding of cementum regeneration after destruction.

Asunto(s)

Proteínas Adaptadoras Transductoras de Señales , Diferenciación Celular , Cemento Dental , Transducción de Señal , Proteínas Señalizadoras YAP , Animales , Cemento Dental/metabolismo , Proteínas Señalizadoras YAP/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Ratones , Proteína C-Reactiva/metabolismo , Integrina beta1/metabolismo , Componente Amiloide P Sérico/metabolismo , Componente Amiloide P Sérico/genética , Ratones Endogámicos C57BL , Quinasa 1 de Adhesión Focal/metabolismo , Quinasa 1 de Adhesión Focal/genética , Cementogénesis

RESUMEN

Endometriosis is characterized by the ectopic implantation of a functional uterine lining outside of the uterus. Commonly, it occurs in the fallopian tubes, ovaries, uterosacral ligaments, and gastrointestinal tract. Less commonly, it may occur in the pericardium, pleura, and central nervous system. Thoracic endometriosis syndrome includes multiple presentations, most commonly catamenial pneumothorax. We present a case of a catamenial pneumothorax that was incidentally found on imaging after the patient presented with complaints of abdominal pain and weight loss.

Asunto(s)

Proteína C-Reactiva , Humanos , Proteína C-Reactiva/metabolismo , Proteína C-Reactiva/inmunología , Biomarcadores , Animales

RESUMEN

Sepsis is a intricate pathological process characterized by life-threatening organ dysfunction resulting from a dysregulated host response to infection. It stands as a prominent cause of mortality among critically ill patients globally. The pivotal focus in sepsis management lies in the early identification and prompt administration of antimicrobial agents. Owing to the constraints of current diagnostic methodologies, marked by insufficient sensitivity and delayed outcomes, extensive research has been undertaken to ascertain novel biomarkers for sepsis. In this review, we provide an overview discussing the latest advancements in the study of PTX-3 as a biomarker for sepsis. We acknowledge pivotal discoveries from preceding research and engage in discourse regarding the challenges and limitations confronted by PTX-3 as a sepsis biomarker.

RESUMEN

BACKGROUND: COVID-19 clinical course is highly variable and secondary infections contribute to COVID-19 complexity. Early detection of secondary infections is clinically relevant for patient outcome. Procalcitonin (PCT) and C-reactive protein (CRP) are the most used biomarkers of infections. Pentraxin 3 (PTX3) is an acute phase protein with promising performance as early biomarker in infections. In patients with COVID-19, PTX3 plasma concentrations at hospital admission are independent predictor of poor outcome. In this study, we assessed whether PTX3 contributes to early identification of co-infections during the course of COVID-19. METHODS: We analyzed PTX3 levels in patients affected by COVID-19 with (n = 101) or without (n = 179) community or hospital-acquired fungal or bacterial secondary infections (CAIs or HAIs). FINDINGS: PTX3 plasma concentrations at diagnosis of CAI or HAI were significantly higher than those in patients without secondary infections. Compared to PCT and CRP, the increase of PTX3 plasma levels was associated with the highest hazard ratio for CAIs and HAIs (aHR 11.68 and 24.90). In multivariable Cox regression analysis, PTX3 was also the most significant predictor of 28-days mortality or intensive care unit admission of patients with potential co-infections, faring more pronounced than CRP and PCT. INTERPRETATION: PTX3 is a promising predictive biomarker for early identification and risk stratification of patients with COVID-19 and co-infections. FUNDING: Dolce & Gabbana fashion house donation; Ministero della Salute for COVID-19; EU funding within the MUR PNRR Extended Partnership initiative on Emerging Infectious Diseases (Project no. PE00000007, INF-ACT) and MUR PNRR Italian network of excellence for advanced diagnosis (Project no. PNC-E3-2022-23683266 PNC-HLS-DA); EU MSCA (project CORVOS 860044).

Asunto(s)

Biomarcadores , Proteína C-Reactiva , COVID-19 , Coinfección , SARS-CoV-2 , Componente Amiloide P Sérico , Humanos , COVID-19/sangre , COVID-19/diagnóstico , Proteína C-Reactiva/metabolismo , Proteína C-Reactiva/análisis , Componente Amiloide P Sérico/metabolismo , Biomarcadores/sangre , Masculino , Femenino , Anciano , Persona de Mediana Edad , SARS-CoV-2/aislamiento & purificación , Infecciones Bacterianas/sangre , Infecciones Bacterianas/diagnóstico , Polipéptido alfa Relacionado con Calcitonina/sangre , Pronóstico , Micosis/sangre , Micosis/diagnóstico , Anciano de 80 o más Años

RESUMEN

BACKGROUND: Paclitaxel (PTX) treatment resistance is an important factor leading to poor prognosis in triple-negative breast cancer (TNBC), therefore there is an urgent need to identify new target for combination therapy. Neddylation is a post-translational process that introduces a ubiquitin-like protein called neural precursor cell expressed developmentally downregulated protein 8 (NEDD8). Previous studies have found that neddylation is activated in multiple tumors, but its relationship with PTX chemotherapy sensitivity has not been reported. METHODS: Differences in UBC12 and NEDD8 expression levels between PTX-sensitive and PTX-insensitive TNBC tissues were validated using public databases and immunohistochemistry. The in vitro and in vivo functional experiments were used to observe the effect of neddylation inhibition combined with PTX therapy on tumor progression. Co-IP, western blot and PCR assays were used to investigate the molecular mechanisms. Molecular docking was used to simulate the protein binding of UBC12 and TRIM25. Molecular dynamics simulation was used to observe the changes in TRIM25 protein conformation. RESULTS: We found that in TNBC that is insensitive to PTX, NEDD8 and NEDD8 conjugating enzyme UBC12 are highly expressed. Treatment with the NEDD8-activating enzyme (NAE) inhibitor mln4924 or knockdown of UBC12 significantly increased the sensitivity of the tumor to PTX, and this increase in sensitivity is related to UBC12-mediated autophagy activation. Mechanistically, UBC12 can transfer NEDD8 to E3 ubiquitin ligase tripartite motif containing 25 (TRIM25) at K117. Molecular dynamics simulations indicate that the neddylation modification of TRIM25 reduces steric hindrance in its RING domain, facilitating the binding of TRIM25 and ubiquitylated substrates. Subsequently, TRIM25 promotes the nuclear translocation of transcription factor EB (TFEB) and transcription of autophagy related genes by increasing K63-polyubiquitination of TFEB, thereby reducing tumor sensitivity to PTX. CONCLUSIONS: Neddylation is activated in PTX-insensitive TNBC. Specifically, autophagy gene transcriptional activation mediated by the UBC12/TRIM25/TFEB axis reduces TNBC sensitivity to PTX. Neddylation suppression combination with PTX treatment shows a synergistic anti-tumor effect.

Asunto(s)

Autofagia , Proteína NEDD8 , Paclitaxel , Proteínas de Motivos Tripartitos , Neoplasias de la Mama Triple Negativas , Ubiquitina-Proteína Ligasas , Humanos , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/patología , Paclitaxel/farmacología , Paclitaxel/uso terapéutico , Femenino , Ratones , Animales , Autofagia/efectos de los fármacos , Proteína NEDD8/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Proteínas de Motivos Tripartitos/metabolismo , Proteínas de Motivos Tripartitos/genética , Línea Celular Tumoral , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Ciclopentanos/farmacología , Resistencia a Antineoplásicos , Ensayos Antitumor por Modelo de Xenoinjerto , Enzimas Ubiquitina-Conjugadoras/metabolismo , Enzimas Ubiquitina-Conjugadoras/genética

RESUMEN

Several clinical studies reported that the elevated expression of Chitinase-3-like 1 (CHI3L1) was observed in patients suffering from a wide range of diseases: cancer, metabolic, and neurological diseases. However, the role of CHI3L1 in AD is still unclear. Our previous study demonstrated that 2-({3-[2-(1-Cyclohexen-1-yl)ethyl]-6,7-dimethoxy-4-oxo-3,4-dihydro-2-quinazolinyl}culfanyl)-N-(4-ethylphenyl)butanamide, a CHI3L1 inhibiting compound, alleviates memory and cognitive impairment and inhibits neuroinflammation in AD mouse models. In this study, we studied the detailed correlation of CHI3L1 and AD using serum from AD patients and using CHI3L1 knockout (KO) mice with Aß infusion (300 pmol/day, 14 days). Serum levels of CHI3L1 were significantly elevated in patients with AD compared to normal subjects, and receiver operating characteristic (ROC) analysis data based on serum analysis suggested that CHI3L1 could be a significant diagnostic reference for AD. To reveal the role of CHI3L1 in AD, we investigated the CHI3L1 deficiency effect on memory impairment in Aß-infused mice and microglial BV-2 cells. In CHI3L1 KO mice, Aß infusion resulted in lower levels of memory dysfunction and neuroinflammation compared to that of WT mice. CHI3L1 deficiency selectively inhibited phosphorylation of ERK and IκB as well as inhibition of neuroinflammation-related factors in vivo and in vitro. On the other hand, treatment with recombinant CHI3L1 increased neuroinflammation-related factors and promoted phosphorylation of IκB except for ERK in vitro. Web-based gene network analysis and our results showed that CHI3L1 is closely correlated with PTX3. Moreover, in AD patients, we found that serum levels of PTX3 were correlated with serum levels of CHI3L1 by Spearman correlation analysis. These results suggest that CHI3L1 deficiency could inhibit AD development by blocking the ERK-dependent PTX3 pathway.

Asunto(s)

Enfermedad de Alzheimer , Proteína 1 Similar a Quitinasa-3 , Humanos , Ratones , Quinazolinas/administración & dosificación , Modelos Animales de Enfermedad , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Encéfalo/patología , Enfermedades Neuroinflamatorias/metabolismo , Enfermedades Neuroinflamatorias/patología , Microglía/metabolismo , Microglía/patología , Componente Amiloide P Sérico/metabolismo , Proteína C-Reactiva/metabolismo , Proteína 1 Similar a Quitinasa-3/sangre , Proteína 1 Similar a Quitinasa-3/genética , Biomarcadores/sangre

RESUMEN

Background: This study aimed to investigate the effect and mechanism of Pentraxin 3 (PTX3) on myocardial injury in sepsis. Methods: Thirty male C57BL/6 mice were randomly assigned to Groups A, B, or C. Mice in Groups A and B were injected with unloaded lentivirus, while mice in Group C were injected with lentivirus encoding PTX3 overexpression. Seven days after injection, septic myocardial injury mouse models were constructed following intraperitoneal injection with LPS in Groups B and C, and mice in Group A were intraperitoneally injected with normal saline. Cardiac function was examined using echocardiography; pathological variation of myocardial cells was measured through HE staining, transmission electron microscopy, and TUNEL staining; and Western blot was used to measure the expression of PI3K/AKT/mTOR pathway-related, autophagy-related, and apoptosis-related proteins in mice myocardial cells. Results: PTX3 significantly improved cardiac function and structure in sepsis-stricken mice, and PTX3 alleviated cardiac damage caused by sepsis. PTX3 reduced the relative protein expression of p-PI3K, p-AKT, mTOR, LC3I/II, Beclin, ATG5, Bax, Caspase-3, and Caspase-9 in septic mouse cardiomyocytes and increased the relative protein expression of Bcl-2. Conclusion: PTX3 can attenuate myocardial injury in sepsis due to the down-regulation of apoptosis and autophagy induced by the PI3K/AKT/mTOR pathway.

Asunto(s)

Apoptosis , Autofagia , Proteína C-Reactiva , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Sepsis , Serina-Treonina Quinasas TOR , Animales , Masculino , Ratones , Proteína C-Reactiva/metabolismo , Proteína C-Reactiva/genética , Modelos Animales de Enfermedad , Regulación hacia Abajo , Ratones Endogámicos C57BL , Miocardio/patología , Miocardio/metabolismo , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Sepsis/metabolismo , Sepsis/genética , Componente Amiloide P Sérico/genética , Componente Amiloide P Sérico/metabolismo , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismo

RESUMEN

A trio of spontaneous pneumomediastinum, pneumopericardium, and pneumothorax is a highly unusual presentation. The majority of reported cases are due to trauma, while the remaining cases are iatrogenic. Among infections, this trio has so far been reported in COVID-19 pneumonia and pneumocystis pneumonia in HIV-positive patients. There are case reports on pneumothorax and pneumomediastinum in tuberculosis, but the trio is not reported. Here, we present a case of a recently diagnosed HIV-positive patient with complaints of cough and shortness of breath whose initial workup was negative for Mycobacterium. The patient was, however, started on antitubercular drugs based on clinical radiological evidence. He developed spontaneous pneumothorax, pneumomediastinum, and pneumopericardium, and repeat bronchoalveolar lavage (BAL) came positive for Mycobacterium. The patient, however, could not be revived and succumbed to obstructive and septic shock.

RESUMEN

The wastewater industry and the energy system are undergoing significant transformations to address climate change and environmental pollution. Green hydrogen, which will be mainly obtained from renewable electricity water electrolysis (Power-to-Hydrogen, PtH), has been considered as an essential energy carrier to neutralize the fluctuations of renewable energy sources. PtH, or Power-to-X (PtX), has been allocated to multiple sectors, including industry, transport and power generation. However, considering its large potential for implementation in the wastewater sector, represented by Water Resource Recovery Facilities (WRRFs), the PtX concept has been largely overlooked in terms of planning and policymaking. This paper proposes a concept to implement PtX at WRRFs, where sourcing of water, utilization of the oxygen by-product, and PtX itself can be sustainable and diversified strategies. Potential value chains of PtX are presented and illustrated in the frame of a WWRF benchmark simulation model, highlighting the applications of oxygen from PtX through pure oxygen aeration and ozone disinfection. Opportunities and challenges are highlighted briefly, and so is the prospective outlook to the future. Ultimately, it is concluded that 'coupling PtX to WRRFs' is a promising solution, which will potentially bring sustainable opportunities for both WRRFs and the energy system. Apart from regulatory and economic challenges, the limitations in coupling PtX to WRRFs mainly come from energy efficiency concerns and the complexity of the integration of the water framework and the energy system.

Asunto(s)

Aguas Residuales , Aguas Residuales/química , Recursos Hídricos , Purificación del Agua , Eliminación de Residuos Líquidos/métodos , Oxígeno , Conservación de los Recursos Hídricos

RESUMEN

Human cytochrome P450 1B1 enzyme (hCYP1B1), a member of hCYP1 subfamily, plays a crucial role in multiple diseases by participating in many metabolic pathways. Although a suite of potent hCYP1B1 inhibitors have been previously reported, most of them also act as aryl hydrocarbon receptor (AhR) agonists that can up-regulate the expression of hCYP1B1 and then counteract their inhibitory potential in living systems. This study aimed to develop novel efficacious hCYP1B1 inhibitors that worked well in living cells but without AhR agonist effects. For these purposes, a series of 1,8-naphthalimide derivatives were designed and synthesized, and their structure-activity relationships (SAR) as hCYP1B1 inhibitors were analyzed. Following three rounds SAR studies, several potent hCYP1B1 inhibitors were discovered, among which compound 3n was selected for further investigations owing to its extremely potent anti-hCYP1B1 activity (IC50 = 0.040 nM) and its blocking AhR transcription activity in living cells. Inhibition kinetic analyses showed that 3n potently inhibited hCYP1B1 via a mix inhibition manner, showing a Ki value of 21.71 pM. Docking simulations suggested that introducing a pyrimidine moiety to the hit compound (1d) facilitated 3n to form two strong interactions with hCYP1B1/heme, viz., the C-Br⋯π halogen bond and the N-Fe coordination bond. Further investigations demonstrated that 3n (5 µM) could significantly reverse the paclitaxel (PTX) resistance in H460/PTX cells, evidenced by the dramatically reduced IC50 values, from 632.6 nM (PTX alone) to 100.8 nM (PTX plus 3n). Collectively, this study devised a highly potent hCYP1B1 inhibitor (3n) without AhR agonist effect, which offered a promising drug candidate for overcoming hCYP1B1-associated drug resistance.

Asunto(s)

Citocromo P-450 CYP1B1 , Diseño de Fármacos , Naftalimidas , Humanos , Relación Estructura-Actividad , Naftalimidas/farmacología , Naftalimidas/química , Naftalimidas/síntesis química , Citocromo P-450 CYP1B1/antagonistas & inhibidores , Citocromo P-450 CYP1B1/metabolismo , Estructura Molecular , Relación Dosis-Respuesta a Droga

RESUMEN

Several studies indicate that observation alone is sufficient for the management of stable pneumothorax. To compare clinical efficacy, tolerability, and safety outcomes for treating hemodynamically stable adult patients with pneumothorax, the present review compared observation alone versus interventional procedures. We searched PubMed and Google Scholar from inception until June 24, 2020, for randomized controlled trials (RCTs) comparing observational therapy with conventional therapy for the treatment of adult pneumothorax. The pediatric age group and patients with tension pneumothorax were not included. Four hundred and forty-six patients were enrolled in three RCTs. The failure rate (relative risk (RR) 4.30; 95% CI = 0.23-81.82, p = 0.33) and mortality (RR 1.01; 95% CI = 0.31-3.33, p = 0.98) of observation were comparable to those of the chest tube. Chest tube and observation both carried comparable risks of complications, including tension pneumothorax and empyema (RR 3.15; 95% CI = 0.67-1) and (RR 1.55; 95% CI = 0.21-11.56, p = 0.67), respectively. Between chest tubes and observation, there was no statistically significant difference in the duration of hospital stay. We conclude that observation is as safe and effective at treating adult patients with stable pneumothorax as a chest tube.

RESUMEN

Periprosthetic joint infections (PJIs) are serious complications of prosthetic surgery. The criteria for the diagnosis of PJI integrate clinical and laboratory findings in a complex and sometimes inconclusive workflow. Host immune factors hold potential as diagnostic biomarkers in bone and joint infections. We reported that the humoral pattern-recognition molecule long pentraxin 3 (PTX3) predicts PJI in total hip and knee arthroplasty (THA and TKA, respectively). If and how genetic variation in PTX3 and inflammatory genes that affect its expression (IL-1ß, IL-6, IL-10, and IL-17A) contributes to the risk of PJI is unknown. We conducted a case-control study on a Caucasian historic cohort of THA and TKA patients who had prosthesis explant due to PJI (cases) or aseptic complications (controls). Saliva was collected from 93 subjects and used to extract DNA and genotype PTX3, IL-1ß, IL-6, IL-10, and IL-17A single-nucleotide polymorphisms (SNPs). Moreover, the concentration of IL-1ß, IL-10, and IL-6 was measured in synovial fluid and plasma. No association was found between PTX3 polymorphisms and PJI; however, the AGG haplotype, encompassing rs2853550, rs1143634, and rs1143627 in IL-1ß, was linked to the infection (p = 0.017). Also, synovial levels of all inflammatory markers were higher in cases than in controls, and a correlation emerged between synovial concentration of PTX3 and that of IL-1ß in cases only (Spearman r = 0.67, p = 0.004). We identified a relationship between rs2853550 and the synovial concentration of IL-1ß and PTX3. Our findings suggest that IL-1ß SNPs could be used for the early identification of THA and TKA patients with a high risk of infection.

Asunto(s)

Artroplastia de Reemplazo de Cadera , Artroplastia de Reemplazo de Rodilla , Predisposición Genética a la Enfermedad , Interleucina-1beta , Polimorfismo de Nucleótido Simple , Infecciones Relacionadas con Prótesis , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Artroplastia de Reemplazo de Cadera/efectos adversos , Artroplastia de Reemplazo de Rodilla/efectos adversos , Proteína C-Reactiva/genética , Proteína C-Reactiva/metabolismo , Estudios de Casos y Controles , Marcadores Genéticos , Interleucina-1beta/genética , Infecciones Relacionadas con Prótesis/genética , Componente Amiloide P Sérico/genética , Componente Amiloide P Sérico/metabolismo