Search Results (73)

Inflammation is a self-defense mechanism that controls the homeostasis of an organism, and its alteration by persistent noxious stimuli could lead to an imbalance in the regulation of inflammatory responses mediated by innate and adaptive immunity. During chronic inflammation, sustained exposure of myeloid cells to the various inflammatory signals derived from inflamed tissue could lead to the generation of myeloid cells with an immunosuppressive state, called myeloid-derived suppressor cells (MDSCs), which can exert protective or deleterious functions depending on the nature of signals and the specific inflammatory conditions created by different pathophysiological contexts. Initially identified in various tumor models and cancer patient samples, these cells have long been recognized as negative regulators of anti-tumor immunity. Consequently, researchers have focused on elucidating the molecular mechanisms underlying their potent immunosuppressive activity. As a key component of the signal transducing processes, protein kinases play a central role in regulating the signal transduction mechanisms of many cellular activities, including differentiation and immunosuppression. Over the past decade, at least a dozen kinases, including mechanistic target of rapamycin (mTOR), phosphoinositide 3-kinases (PI3Ks), TAM (Tyro3, Axl, Mer) family of receptor tyrosine kinases (TAM RTKs), mitogen-activated protein kinases (MAPKs), and others, have emerged as key contributors to the generation and differentiation of MDSCs. Here, we discuss the recent findings on these kinases that directly contribute to the immunosuppressive functions of MDSCs. Full article

Background/Objectives: Pregnancies complicated by red cell alloimmunization can progress to hemolytic disease of the fetus and newborn (HDFN), requiring close monitoring and timely intervention to prevent fetal/neonatal morbidity and mortality. This study investigated disease presentation, interventions, and outcomes in respondents with a history of alloimmunized pregnancy. Methods: This was a retrospective cross-sectional survey study administered online to alloimmunized patients between November 2022–February 2023. A total of 127 participants reported on 200 alloimmunized pregnancies. Distribution of pregnancy characteristics, antibodies and titers, monitoring, treatments and fetal outcomes were described and stratified where appropriate by fetal antigen status and disease severity. Outcomes and management practices in subsequent pregnancies following fetal loss to HDFN are reported. Results: Multiple antibodies were present in 42% of pregnancies with known antibody type (80/192). Titers reached critical levels (any titer for Anti-K; ≥16 for all other antibodies) in 71% (125/176) of pregnancies where titer was reported. Among fetal antigen positive pregnancies with critical titers, intrauterine transfusions were conducted in 40% (42/106), intravenous immunoglobulin was administered in 14% (15/106), plasmapheresis in 7% (7/106), and phenobarbital in 9% (9/106). Complications from transfusion were reported in 38% of pregnancies receiving intrauterine transfusion (17/45). Fetal death due to HDFN or complications from intrauterine transfusion was reported in 9% of antigen positive pregnancies with critical titers (10/106) and 16% of pregnancies receiving intrauterine transfusion (7/45). Conclusions: Disease presentation and severity complements previous research in this disease population, however, monitoring practices were diverse. Fetal death and intrauterine complication rates were higher than those previously reported in large international referral centers. Development of best practices and centralized referral centers may improve disease outcomes. Full article

Background: It has been demonstrated that levetiracetam can decrease absence epileptic activity in both human patients and different types of animal models of absence epilepsy, such as the genetically absence epileptic Wistar Albino Glaxo/Rijswijk (WAG/Rij) rat. It was also suggested previously that exogenous ketone supplements (EKSs)-evoked ketosis not only decreases the number of spike-wave discharges (SWDs) but also enhances the anti-absence epileptic effect of pyrimidine nucleoside uridine in WAG/Rij rats. These findings suggest that EKSs may enhance the efficacy of clinically used anti-epileptic drugs, such as levetiracetam. Methods: We investigated the effect of not only levetiracetam (intraperitoneal/i.p. 200 mg/kg) alone and KEKS supplemented food (containing 10% ketone ester/KE and 10% ketone salt/KS in a normal rat chow) alone, but also the combination of levetiracetam and KEKS supplemented food on SWD number and SWD time for 5 days in WAG/Rij rats. For evaluation of SWDs, electroencephalographic (EEG) recordings were performed every day. Moreover, for the measurement of blood glucose and R-beta-hydroxybutyrate (R-βHB) levels, the blood was taken from the tail vein of rats after EEG registration. Results: It was demonstrated that the administration of both levetiracetam alone and KEKS food alone decreased the SWD number and time spent in SWD, compared to control. Moreover, after combined administration of levetiracetam with KEKS food, enhanced anti-absence epileptic effect was observed, compared to levetiracetam alone. Blood R-βHB level significantly increased after administration of both KEKS food alone and KEKS food in combination with levetiracetam. Nevertheless, these treatments did not significantly change the blood glucose levels. Conclusions: We can conclude that EKSs may be able to enhance the anti-epileptic effect of different drugs, and this combined treatment method may represent a promising new approach and effective therapy against epileptic seizures, especially in treatment-resistant patients. Full article

Keratan sulfate (KS) is a negatively charged carbohydrate linked to proteins. Several KS-bearing structural glycosaminoglycans participate to maintain the homeostasis of a functional extracellular matrix. Dysfunction of its biochemical composition and structure might therefore lead to pathological situations. For this reason, imaging of KS in tissues is an important diagnostic tool. Here, we describe the identification of the KS paratope derived from the ancestral anti-KS IgG mAb MZ15, as well as the engineering, functional recombinant expression in E. coli, and purification of an anti-KS single-chain variable fragment (ScFv). The ScFv enabled in vitro imaging of KS in cryosections of rat cornea by immunofluorescence microscopy comparable to the ancestral IgG MZ15. Full article

In managing ulcerative colitis (UC), anti-tumour necrosis factor (TNF) agents are among the primary choices. Evidence suggests anti-TNF does not significantly increase malignancy risk (apart from lymphoma and melanoma), though uncertainties persist due to inconsistent long-term data. Kaposi’s sarcoma (KS), induced by human herpesvirus type-8 (HHV-8), is a multifocal neoplasm linked to immunosuppressive therapies, primarily affecting the skin and gastrointestinal tract. KS cases during anti-TNF therapy for UC are anecdotal. We report a rare occurrence of KS in the setting of the long-term use of the standard maintenance dose of infliximab (initiated in 2010) in a 56-year-old male patient with UC diagnosed in 2001. The patient underwent restorative proctocolectomy with ileal J-pouch-anal anastomosis in 2002 and subsequently developed chronic antibiotic-dependent pouchitis. Given the secondary loss of response to infliximab, a switch to vedolizumab was performed. In April 2024, the patient reported the presence of a skin lesion on the right leg. Following surgery, a rhomboid-shaped skin area was removed, encompassing the irregular, greyish KS lesion. The histopathological analysis confirmed the diagnosis of patch-like KS. We continued vedolizumab due to its gut-selective profile. The patient is in clinical remission and under dermatological follow-up with no lesion recurrence. Full article

Functional divergences of coding genes can be caused by divergences in their coding sequences and expression. However, whether and how expression divergences and coding sequence divergences coevolve is not clear. Gene expression divergences in differentiated cells and tissues recapitulate developmental models within a species, while gene expression divergences between analogous cells and tissues resemble traditional phylogenies in different species, suggesting that gene expression divergences are molecular traits that can be used for evolutionary studies. Using transcriptomes and evolutionary proxies to study gene expression divergences among differentiated cells and tissues in Arabidopsis, expression divergences of coding genes are shown to be strongly anti-correlated with phylostrata (gene ages), indicators of selective constraint Ka/Ks (nonsynonymous replacement rate/synonymous substitution rate) and indicators of positive selection (frequency of loci with Ka/Ks > 1), but only weakly or not correlated with indicators of neutral selection (Ks). Our results thus suggest that expression divergences largely coevolve with coding sequence divergences, suggesting that expression divergences of coding genes are selectively fixed by natural selection but not neutral selection, which provides a molecular framework for trait diversification, functional adaptation and speciation. Our findings therefore support that positive selection rather than negative or neutral selection is a major driver for the origin and evolution of Arabidopsis genes, supporting the Darwinian theory at molecular levels. Full article

Ibuprofen is one of the most commonly used anti-inflammatory drugs by humans, resulting in its appearance in the environment, which can negatively affect organisms living in it. The studies undertaken have shown that the immobilized Bacillus thuringiensis B1(2015b) strain can decompose this drug at a rate of q_max = 0.36 mg/L*h, with a K_s constant of 0.95 mg/L for this process. An analysis of the effect of ibuprofen on the metabolic profile of the immobilized strain B1(2015b) showed an increase in the consumption of carbon, nitrogen, phosphorus, and sulfur compounds by this strain compared to the free strain. Studies on the toxicity of ibuprofen against the B1(2015b) strain indicated a small protective effect of the carrier, manifested by a slightly higher EC₅₀ value = 1190 mg/L (for the free strain EC₅₀ = 1175 mg/L). A toxicity analysis of intermedia formed during ibuprofen degradation indicated that the increase in toxicity is positively correlated with the degree of hydroxylation of ibuprofen metabolites. A toxicity analysis of the post-culture fluid obtained after ibuprofen degradation by the immobilized and free strain indicated that the products formed due to this process are completely safe. Full article

Due to their inherent openness, wireless sensor networks (WSNs) are vulnerable to eavesdropping attacks. Addressing the issue of secure Internet Key Exchange (IKE) in the absence of reliable third parties like CA/PKI (Certificate Authority/Public Key Infrastructure) in WSNs, a novel key synchronization method named NDPCS-KS is proposed in the paper. Firstly, through an initial negotiation process, both ends of the main channels generate the same initial key seeds using the Channel State Information (CSI). Subsequently, negotiation keys and a negative database (NDB) are synchronously generated at the two ends based on the initial key seeds. Then, in a second-negotiation process, the NDB is employed to filter the negotiation keys to obtain the keys for encryption. NDPCS-KS reduced the risk of information leakage, since the keys are not directly transmitted over the network, and the eavesdroppers cannot acquire the initial key seeds because of the physical isolation of their eavesdropping channels and the main channels. Furthermore, due to the NP-hard problem of reversing the NDB, even if an attacker obtains the NDB, deducing the initial key seeds is computationally infeasible. Therefore, it becomes exceedingly difficult for attackers to generate legitimate encryption keys without the NDB or initial key seeds. Moreover, a lightweight anti-replay and identity verification mechanism is designed to deal with replay attacks or forgery attacks. Experimental results show that NDPCS-KS has less time overhead and stronger randomness in key generation compared with other methods, and it can effectively counter replay, forgery, and tampering attacks. Full article

Although niflumic acid (NA) is one of the most used non-steroidal anti-inflammatory drugs, it suffers from poor solubility, low bioavailability, and significant adverse effects. To address these limitations, the complexation of NA with cyclodextrins (CDs) is a promising strategy. However, complexing CDs with low molecular weight drugs like NA can lead to low CE. This study explores the development of inclusion complexes of NA with 2-hydroxypropyl-β-cyclodextrin (2HP-β-CD), including the effect of converting NA to its sodium salt (NAs) and adding hydroxypropyl methylcellulose (HPMC) on complex formation. Inclusion complexes were prepared using co-evaporation solvent and freeze-drying methods, and their CE and Ks were determined through a phase solubility study. The complexes were characterized using physicochemical analyses, including FT-IR, DSC, SEM, XRD, DLS, UV-Vis, ¹H-NMR, and ¹H-ROESY. The dissolution profiles of the complexes were also evaluated. The analyses confirmed complex formation for all systems, demonstrating drug–cyclodextrin interactions, amorphous drug states, morphological changes, and improved solubility and dissolution profiles. The NAs-2HP-β-CD-HPMC complex exhibited the highest CE and Ks values, a 1:1 host-guest molar ratio, and the best dissolution profile. The results indicate that the NAs-2HP-β-CD-HPMC complex has potential for delivering NA, which might enhance its therapeutic effectiveness and minimize side effects. Full article

Skin aging is characterized by reactive oxygen species (ROS) accumulation, principal players in triggering events associated with aging. Our recent data on the ability of an innovative poly-component formulation (KARISMA Rh Collagen^® FACE: K formulation) to suppress the biomolecular events associated with oxidative stress-induced aging prompted us to deepen the mechanisms underlying the observed effects on aged human dermal fibroblasts (HDFs). Here, we evaluated K’s ability to perform a direct free radical-scavenging action and modulate anti-oxidant systems by counteracting the inflammatory process in an H₂O₂-induced cellular senescence model. Standard methods were used to measure scavenging capacity and enzymatic anti-oxidant system activities. Nuclear factor E2-related factor 2 (Nrf2) and nuclear factor kappa-B (NF-κB) levels were analyzed by Western blot. We assessed pro-inflammatory cytokines, matrix metalloproteinases (MMPs), and advanced glycation end-products (AGEs). Our results show that K counteracted stress-induced aging in a dose-dependent manner by exerting a direct scavenging action and increasing anti-oxidant systems, such as superoxide dismutase (SOD) and catalase (CAT) up to control values. These findings could be associated with increased phospho-Nrf2 (p-Nrf2) expression, generally reduced in aged HDFs following exposure to different concentrations of K formulation. Moreover, K formulation caused a reduction of pro-inflammatory cytokines, interleukin-1β and -6, MMP-1 and -9, and AGE levels, events related to a downregulation of p-NF-κB level. The results indicate that K formulation re-established the normal physiology of HDFs by reducing p-NF-κB expression and restoring Nrf2 activation, thus supporting its efficacious reparative and regenerative action in treating skin aging. Full article

Background: Sickle cell disease (SCD) affects approximately 100,000 people in the United States and millions worldwide, with the highest prevalence of 70% of SCD being found in individuals of African ethnicity. Delayed hemolytic, alloimmunization, and anamnestic transfusion reactions in multiple transfusion patients need to be investigated and managed to avoid a worsening of the patient’s clinical status. Objective: This paper aims to investigate delayed transfusion reactions in SCD patients who were polytransfused in the Brazilian Amazon. Material and Methods: The clinical and laboratory indicators of SCD patients with more than four transfusions were investigated. The patients were treated at the Fundação Hospitalar de Hematologia e Hemoterapia do Estado do Amazonas, Brazil. Results: A total of 44 polytransfused patients with SCD were followed. Regarding Rh phenotype, it was possible to observe a frequency of 26.6% (12) patients with the RZRZ (DCE/DCE) phenotype, in addition to 4.5% (two) patients with RH and RHCE variants. It was also possible to observe 20.5% (nine) patients with an alloimmunization reaction, who presented the following alloantibodies: anti-RhD, anti-E, anti-K, anti-Jk^b, anti-N, anti-S, and anti-Di^a, two of which are unidentified. Of these, four (44.4%) patients also presented autoantibodies, anti-e, and three unidentified antibodies, and four (44.4%) patients presented an anamnestic reaction, with anti-RhD, K, and Jkb antibodies. Of the 44 patients monitored, 54.4% (24) had clinical and laboratory indicators of a delayed hemolytic reaction. Conclusion: Delayed transfusion reactions, often neglected, occur frequently. Therefore, transfusions need to be monitored for at least 28 days, with medical investigation of clinical and laboratory indicators to make greater use of this therapeutic resource. Full article

Concrete structures face significant challenges in sulfate-rich environments, where sulfate attack can affect their durability and structural integrity. This study explores innovative approaches to enhancing concrete performance by integrating hydrophobic and densification technologies. It emphasizes the critical role of anti-sulfate erosion inhibitors in mitigating sulfate-induced damage, reducing water absorption, and inhibiting corrosive reactions. This research addresses prevalent issues in Chinese engineering projects where high sulfate concentrations are common, necessitating robust solutions for sulfate resistance. Through rigorous testing, including wet–dry cycling tests with 5% and 10% Na₂SO₄ solutions following the GB/T 50082-2009 standard, concrete formulations achieved exceptional long-term sulfate resistance, meeting or exceeding KS200-grade requirements. These findings provide valuable insights into optimizing concrete durability in sulfate-rich environments, offering practical strategies to enhance infrastructure resilience and reduce maintenance costs. Full article

Kaposi sarcoma (KS) is an AIDS-defining angio-proliferative malignancy, with the Kaposi sarcoma-associated herpes virus (KSHV) as its etiologic agent. Upon treatment with chemotherapy, a proportion of HIV-associated KS patients experience disease recurrence within a few months of completing treatment. We aimed at determining whether KSHV-specific adaptive immune responses were associated with KS recurrence upon complete remission. We conducted a prospective cohort study. The primary outcome was the recurrence of HIV-associated KS. An immunofluorescence assay was used to determine anti-KSHV antibodies, an enzyme-linked immunospot was conducted for T cell responses, PCR was carried out to determine KSHV status, and flow cytometry was used for CD4 counting and immunophenotyping. KSHV detection in PBMCs was high and not associated with KS recurrence-free survival (p = 0.29). Anti-KSHV antibody titers were high and not associated with recurrence-free survival (p = 0.63). KSHV-specific T cell responses dropped from baseline levels among individuals with recurrence, but the drop was not statistically significant. Individuals experiencing KS recurrence had a significantly higher proportion of T cell subsets expressing PD1, while those with sustained remission had a significant increase in CD4 T cell counts from baseline levels during the follow-up period (p = 0.02). Anti-KSHV antibodies are not a good correlate of protection from KS recurrence. T cells in individuals experiencing KS recurrence hadhigh PD1 expression, while an increase in CD4 counts was associated with sustained KS remission. Full article

SARS-CoV, an RNA virus, is contagious and displays a remarkable degree of adaptability, resulting in intricate disease presentations marked by frequent genetic mutations that can ultimately give rise to drug resistance. Targeting its viral replication cycle could be a potential therapeutic option to counter its viral growth in the human body leading to the severe infectious stage. The M^pro of SARS-CoV-2 is a promising target for therapeutic development as it is crucial for viral transcription and replication. The derivatives of β-diketone and coumarin have already been reported for their antiviral potential and, thus, are considered as a potential scaffold in the current study for the computational design of potential analogs for targeting the viral replication of SARS-CoV-2. In our study, we used novel diketone-hinged coumarin derivatives against the SARS-CoV-2 M^Pro to develop a broad-spectrum antiviral agent targeting SARS-CoV-2. Through an analysis of pharmacokinetics and docking studies, we identified a list of the top 10 compounds that demonstrated effectiveness in inhibiting the SARS-CoV-2 MPro virus. On the basis of the pharmacokinetics and docking analyses, the top 5 novel coumarin analogs were synthesized and characterized. The thermodynamic stability of compounds KS82 and KS94 was confirmed by their molecular dynamics, and the stability of the simulated system indicated their inhibitory nature. Molecules KS82 and KS94 were further evaluated for their anti-viral potential using Vero E6 cells followed by RT-PCR assay against SARS-CoV-2. The test compound KS82 was the most active with the potential to inhibit SARS-CoV-2 replication in Vero E6 cells. These data indicate that KS82 prevents the attack of the virus and emerges as the primary candidate with promising antiviral properties. Full article

Seasonal coronaviruses (HCoVs) are known to contribute to cross-reactive antibody (Ab) responses against SARS-CoV-2. While these responses are predictable due to the high homology between SARS-CoV-2 and other CoVs, the impact of these responses on susceptibility to SARS-CoV-2 infection in cancer patients is unclear. To investigate the influence of prior HCoV infection on anti-SARS-CoV-2 Ab responses among COVID-19 asymptomatic individuals with cancer and controls without cancers, we utilized the VirScan technology in which phage immunoprecipitation and sequencing (PhIP-seq) of longitudinal plasma samples was performed to investigate high-resolution (i.e., epitope level) humoral CoV responses. Despite testing positive for anti-SARS-CoV-2 Ab in the plasma, a majority of the participants were asymptomatic for COVID-19 with no prior history of COVID-19 diagnosis. Although the magnitudes of the anti-SARS-CoV-2 Ab responses were lower in individuals with Kaposi sarcoma (KS) compared to non-KS cancer individuals and those without cancer, the HCoV Ab repertoire was similar between individuals with and without cancer independent of age, sex, HIV status, and chemotherapy. The magnitudes of the anti-spike HCoV responses showed a strong positive association with those of the anti-SARS-CoV-2 spike in cancer patients, and only a weak association in non-cancer patients, suggesting that prior infection with HCoVs might play a role in limiting SARS-CoV-2 infection and COVID-19 disease severity. Full article