Search Results (341)

The emergence of SARS-CoV-2 variants highlights the urgent need for novel therapeutic strategies, particularly entry inhibitors that could efficiently prevent viral infection. Medicinal herbs and herbal combination formulas have long been recognized for their effects in treating infectious diseases and their antiviral properties, thus providing abundant resources for the discovery of antiviral candidates. While many candidates have been suggested to have antiviral activity against SARS-CoV-2 infection, few have been validated for their mechanisms, including possible effects on viral entry. This study aimed to identify SARS-CoV-2 entry inhibitors from medicinal herbs and herbal formulas that are known for heat-clearing and detoxifying properties and/or antiviral activities. A SARS-CoV-2 pseudoparticle (SARS-CoV-2pp) system was used to assess mechanism-specific entry inhibition. Our results showed that the methanol extract of Anemarrhena asphodeloides rhizome, as well as the water extracts of Cimicifuga foetida rhizome, Xiao Chai Hu Tang (XCHT), and Sheng Ma Ge Gen Tang (SMGGT), have substantial inhibitory effects on the entry of SARS-CoV-2pps into host cells. Given the observation that Cimicifuga foetida exhibited the most potent inhibition and is a constituent of SMGGT, we further investigated the major compounds of the herb and identified caffeic acid as a bioactive component for blocking SARS-CoV-2pp entry. Entry inhibition of Cimicifuga foetida and caffeic acid was validated on both wild-type and the currently dominant JN.1 strain SARS-CoV-2pp systems. Moreover, caffeic acid was able to both inactivate the pseudoparticles and prevent their entry into pretreated host cells. The results support the traditional use of these herbal medicines and underscore their potential as valuable resources for identifying active compounds and developing therapeutic entry inhibitors for the management of COVID-19. Full article

The C-kinase-activated protein phosphatase-1 (PP1) inhibitor of 17 kDa (CPI-17) is a specific inhibitor of the PP1 catalytic subunit (PP1c) and the myosin phosphatase (MP) holoenzyme. CPI-17 requires the phosphorylation of Thr38 in the peptide segment ³⁵ARV(P)TVKYDRREL⁴⁶ for inhibitory activity. CPI-17 regulates myosin phosphorylation in smooth muscle contraction and the tumorigenic transformation of several cell lines via the inhibition of MP. A phosphospecific antibody (anti-CPI-17^pThr38) against the phosphorylation peptide was used to determine the phosphorylation levels in cells. We found that phospho-CPI-17 and its closely related proteins are not present in HeLa and MCF7 cells after inducing phosphorylation by inhibiting phosphatases with calyculin A. In contrast, cross-reactions of proteins in the 40–220 kDa range with anti-CPI-17^pThr38 were apparent. Searching the protein database for similarities to the CPI-17 phosphorylation sequence revealed several proteins with 42–75% sequence identities. The LIMK2-1 isoform emerged as a possible PP1 inhibitor. Experiments with Flag-LIMK2-1 overexpressed in tsA201 cells proved that LIMK2-1 interacts with PP1c isoforms and is phosphorylated predominantly by protein kinase C. Phosphorylated LIMK2-1 inhibits PP1c and the MP holoenzyme with similar potencies (IC50 ~28–47 nM). In conclusion, our results suggest that LIMK2-1 is a novel phosphorylation-dependent inhibitor of PP1c and MP and may function as a CPI-17-like phosphatase inhibitor in cells where CPI-17 is present but not phosphorylated upon phosphatase inhibition. Full article

Background: Ambulatory blood pressure monitoring (ABPM) is increasingly recognized as a more reliable indicator of blood pressure status in children than clinic-based measurements, with superior predictive value for cardiovascular morbidity and mortality. However, evidence on the clinical utility of ABPM-derived indices, such as pulse pressure (PP), pulse pressure index (PPI), rate pressure product (RPP), ambulatory arterial stiffness index (AASI), and average real variability (ARV), remains underexplored in the pediatric population, particularly among children with chronic kidney disease (CKD). Objective: To evaluate the correlation between ABPM-derived indices in children, with a subgroup analysis comparing those with and without CKD. Secondary objectives included identifying factors associated with AASI and ARV and assessing their utility in cardiovascular risk stratification. Methods: In this bicentric cross-sectional study, 70 children (41 with CKD and 29 controls) were enrolled. ABPM indices (PP, PPI, RPP, AASI, and ARV) were calculated, and both descriptive and inferential statistical analyses, including linear regression, were performed. Results: Systolic and diastolic hypertension were significant predictors of elevated ARV (p < 0.05), while body mass index (BMI) and glomerular filtration rate (GFR) were positively associated with AASI (p < 0.05). Use of angiotensin-converting enzyme inhibitors (ACEIs) was associated with reduced arterial stiffness (p = 0.02). Significant differences were observed in weight, BMI, PP, and PPI between the CKD and non-CKD groups, with ABPM demonstrating greater sensitivity in detecting vascular health markers. Conclusions: ABPM-derived indices, particularly PP, PPI, and ARV, show promise in improving cardiovascular risk assessment in children. These findings support the broader use of ABPM metrics for refined cardiovascular evaluation, especially in pediatric CKD. Full article

Current systemic therapies for advanced colorectal cancer (CRC) have limited efficacy, so more effective strategies for the treatment and prevention of CRC are needed. The majority of colorectal cancers are initiated by mutations in Wnt signalling pathway genes, including mutations in the APC gene, which result in a truncated APC protein and lead to excess signalling from β-catenin and the formation of pre-cancerous adenomas. The aim of this study was to determine if targeting the Wnt pathway in combination with pro-apoptotic mimetics altered the proliferative capacity or viability of human colorectal adenoma cells. Patient-derived colorectal adenoma organoid cultures were established from colon adenoma tissue collected by colonoscopy and recapitulated the histopathology of primary colorectal adenoma tissue. The growth of colorectal adenoma organoids is inhibited by the Wnt-signalling antagonist pyrvinium pamoate (PP) and a pro-apoptotic inhibitor of BCL-XL but not BCL-2 (venetoclax) or MCL-1 inhibitors. At low concentrations, the PP and the BCL-XL inhibitor combination demonstrated potent synergy and induced apoptosis in APC-defective patient-derived adenoma organoids, even in the presence of oncogenic KRAS or BRAF mutations, providing a new strategy for colon cancer prevention. Full article

Ovarian cancer cells overexpress HDAC6, and selective HDAC6 inhibitors have been considered potential new drugs for ovarian cancer either alone or in combination with other anticancer agents. We screened 46 potential novel HDAC6 inhibitors in ES-2 ovarian cancer cells and showed that compound 25253 demonstrated the most potent anti-proliferative activity and effective synergy with paclitaxel, which was also validated in TOV21G ovarian cancer cells. The combination of 25253 and paclitaxel significantly induced subG1 and apoptotic cells, revealed by PI staining assay and Annexin V-FITC/PI double staining assay, respectively. Western blot analysis showed downregulation of Bcl-2 and Bcl-XL, and upregulation of Bax and Bak, indicating that apoptosis was mediated through the intrinsic pathway. The combination increased γ-H2AX and p-p53 protein levels, suggesting the induction of DNA damage. Furthermore, HDAC6 was downregulated and acetylated α-tubulin was profoundly increased. Compound 25253 enhanced the inhibitory effect of paclitaxel on cell migration and invasion, possibly due to the extensive accumulation of acetylated α-tubulin, which affected microtubule dynamics. Taken together, the combination of 25253 and paclitaxel synergistically inhibited the growth, migration, and invasion of ovarian cancer cells and induced apoptosis, providing supporting evidence that the combination of HDAC6 inhibitors and paclitaxel may be a promising treatment strategy for ovarian cancer. Full article

Yam (Dioscorea spp.) provides various nutritional and medicinal benefits, including a high starch content, dietary fiber, essential micronutrients, and bioactive compounds. The molecular mechanisms underlying tuber expansion have not yet been clarified. Rapid alkalinization factor (RALF) genes, which mediate various processes in plants, are thought to contribute to the regulation of tuber growth; however, their role in yam development, especially in gibberellin (GA)-mediated processes, remains unclear. Here, we characterized seven DrRALF genes in the yam genome. Analysis of gene duplication demonstrated that the expansion of DrRALF genes was primarily driven by whole-genome duplication or segmental duplication. Phylogenetic analysis revealed that DrRALF genes were concentrated in specific clusters, indicating that their functions are relatively conserved. DrRALF5 was specifically expressed in the roots, and DrRALF2, DrRALF3, DrRALF4, and DrRALF6 were highly expressed in flowers. DrRALF1, DrRALF2, DrRALF3, DrRALF4, DrRALF5, and DrRALF6 were shown to play a role in tuber expansion. Subsequent qRT-PCR validation of four selected DrRALF genes confirmed the regulation of DrRALF2, DrRALF4, DrRALF5, and DrRALF6 by GA and PP333 (paclobutrazol, a GA biosynthesis inhibitor). Yeast one-hybrid assays further showed that the DrRALF6 promoter region interacted with the GA-signaling protein, DrDELLA1. Our findings provide novel insights into the regulatory network controlling yam tuber expansion, especially through the interaction between DrRALF6 and GA signaling pathways. Our results clarify the molecular mechanisms involved in tuber growth and propose a promising strategy for improving yam production through genetic manipulation of the GA-RALF signaling pathway. Full article

The protozoan parasite Toxoplasma gondii transitions between acute (tachyzoite) and chronic (bradyzoite) stages, enabling lifelong persistence in hosts. Iron depletion triggers bradyzoite differentiation, with the phosphotyrosyl phosphatase activator (PTPA) identified as a key regulator. Here, we define PTPA’s role in T. gondii pathogenesis. PTPA forms a ternary complex with PP2A A/C subunits, validated by reciprocal pull-down assays. Depleting PTPA impaired tachyzoite proliferation, invasion, and gliding motility, while stress-induced bradyzoites exhibited defective cyst formation and vacuolar swelling. Metabolic dysregulation included amylopectin accumulation and lipid droplet proliferation. The PP2A inhibitor LB-100 phenocopied PTPA depletion, suppressing tachyzoite growth and bradyzoite differentiation. TgPTPA emerges as a linchpin coordinating PP2A activity, metabolic flux, and lifecycle transitions. Its dual roles in acute virulence and chronic persistence, combined with LB-100’s efficacy, position the PTPA–PP2A axis as a promising target for antitoxoplasmosis strategies. Full article

Busulfan (BU) is a widely used chemotherapy drug that has been shown to cause reproductive functional impairment in humans and model animals. However, the precise mechanisms underlying testicular injury induced by BU exposure have not been fully elucidated. Ferroptosis is a form of programmed cell death mediated by iron-dependent lipid peroxidation. The aim of the current study was to determine whether ferroptosis was involved in BU-induced testicular injury. We demonstrated that exposure to BU led to an increase in iron content in the testes of mice. Subsequent western blotting and reverse transcription quantitative PCR, as well as staining of testicular tissue sections, confirmed that ferroptosis mediated BU-induced testicular injury. Consistent with our in vivo findings, we found that ferroptosis, including iron metabolism and the solute carrier family 7 member 11/glutathione peroxidase 4 (xCT/GPX4) signaling pathway, may play a key role in mediating BU-induced injury to GC-1 spg cells in vitro. Treatment with ferroptosis inhibitors slowed cell death caused by BU exposure. Specifically, we found that the administration of zinc protoporphyrin IX (ZnPP), a heme oxygenase 1 (HO1) inhibitor, rescued BU-induced cell death. In conclusion, our in vivo and in vitro findings confirmed that BU exposure led to testicular ferroptosis in mice via the iron intake pathway and the HO1 signaling pathway. Full article

Introduction: The treatment of MBC patients is guided by receptor status, with re-biopsy at relapse recommended to reassess hormone receptor (HR) status. Various treatment options are available for HER2-veMBC, including CDK4/6 inhibitors, PARP inhibitors, and checkpoint inhibitors. The study highlights the importance of determining receptor subtype for guiding treatment choices. Patients and Methods: The GIM 13 AMBRA study is a longitudinal cohort study involving 42 centers in Italy. It includes data from 939 HER2- MBC patients enrolled between May 2015 and September 2020. The study analyzes the impact of HR expression changes on clinical outcomes using Kaplan–Meier survival curves and other statistical methods. Results: Among the 939 patients, 588 were rebiopsied at first relapse. The study found no significant differences in disease-free survival (DFS), progression-free survival (PFS), or overall survival (OS) between patients whose tumors changed molecular subtype and those who did not. However, post-progression survival from first-line treatment (PPS1) was different between the two groups. Discussion: The study confirms the phenomenon of receptor discordance between primary tumors and metastases. It emphasizes the need for re-biopsy in recurrent MBC to guide treatment strategies. The findings align with previous studies and highlight the importance of understanding receptor changes for improving patient outcomes. Conclusions: The GIM 13 AMBRA study provides valuable insights into the impact of molecular subtype changes on survival outcomes in Luminal MBC patients. It underscores the importance of re-biopsy and personalized treatment strategies in managing metastatic breast cancer. Full article

Background: Intestinal ischemia reperfusion injury (IRI) is a harmful process that occurs during intestinal infarction and intestinal transplantation (ITx). It is characterized by severe inflammation which disrupts the mucosal barrier, causing bacterial translocation and sepsis. Tranilast (N-[3,4-dimethoxycinnamoyl]-anthranilic acid) (TL) is a synthetic compound with powerful anti-inflammatory properties. Objective: To investigate the effect of pretreatment with TL in a validated rat model of intestinal IRI (60 min of ischemia). Methods: TL (650 mg/kg) was administered by oral gavage 24 and 2 h before the onset of ischemia. Experiment 1 examined 7-day survival in 3 study groups (sham, vehicle+IRI and TL+IRI, n = 10/group). In Experiment 2, the effects on the intestinal wall integrity and inflammation were studied after 60 min of reperfusion using 3 groups (sham, IRI and TL+IRI, n = 6/group). The following end-points were studied: L-lactate, intestinal fatty acid-binding protein (I-FABP), histology, intestinal permeability, endotoxin translocation, pro- and anti-inflammatory cytokines and heme oxygenase-1 (HO-1) levels. Experiment 3 examined the role of HO-1 upregulation in TL pretreatment, by blocking its expression using Zinc protoporphyrin (ZnPP) at 20 mg/kg vs. placebo (n = 6/group). Results: Intestinal IRI resulted in severe damage of the intestinal wall and a 10% 7-day survival. These alterations led to endotoxin translocation and upregulation of pro-inflammatory cytokines. TL pretreatment improved survival up to 50%, significantly reduced inflammation and protected the intestinal barrier. The HO-1 inhibitor ZnPP, abolished the protective effect of TL. Conclusions: TL pretreatment improves survival by protecting the intestinal barrier function, decreasing inflammation and endotoxin translocation, through upregulation of HO-1.This rat study of severe intestinal ischemia reperfusion injury demonstrates a novel role for Tranilast as a potential therapy. Administration of Tranilast led to a marked reduction in mortality, inflammation and intestinal permeability and damage. The study proved that Tranilast functions through upregulation of heme oxygenase-1. Full article

Corrosion inhibitors are substances that reduce or eliminate the corrosion of a metal in a certain environment. Corrosion inhibitors act by several mechanisms, including adsorption, film formation, passivation, and oxygen scavenging. Due to their toxicity, classic corrosion inhibitors affect the environment. Therefore, in recent years, more and more studies have focused on the development of eco-friendly inhibitors for the environment. In this study, ethanolic extract of Galium verum (GV) was tested for the inhibition of steel corrosion in 1 M HCl medium using electrochemical methods: open circuit potential (OCP), potentiodynamic polarization (PP), and electrochemical impedance spectroscopy (EIS). Reverse-phase liquid chromatography (HPLC) and gas chromatography mass spectrometry (MS-GC) previous studies state that GV extract contains polyphenols and other chemical species responsible for the inhibitory effect. Corrosion investigations have highlighted the influence of the concentration of the GV extract, in the range of 50 ÷ 400 ppm G.A.E./mL, as well as the influence of temperature in the range of 20 ÷ 50 °C. The corrosion inhibitory efficiency of the Galium verum ethanolic extract had a maximum value of 91.82% for a concentration of 400 ppm polyphenol content, demonstrating the inhibitory potential of this green product in an acidic environment for mild steel. Statistical calculus on the obtained values of EIS inhibitor efficiency showed that the effect of the extract becomes stronger at higher concentrations. Full article

The present Perspective analyzes the remarkable evolution of the Amyloid Cascade Hypothesis 2.0 (ACH2.0) theory of Alzheimer’s disease (AD) since its inception a few years ago, as reflected in the diminishing role of amyloid-beta (Aβ) in the disease. In the initial iteration of the ACH2.0, Aβ-protein-precursor (AβPP)-derived intraneuronal Aβ (iAβ), accumulated to neuronal integrated stress response (ISR)-eliciting levels, triggers AD. The neuronal ISR, in turn, activates the AβPP-independent production of its C99 fragment that is processed into iAβ, which drives the disease. The second iteration of the ACH2.0 stemmed from the realization that AD is, in fact, a disease of the sustained neuronal ISR. It introduced two categories of AD—conventional and unconventional—differing mainly in the manner of their causation. The former is caused by the neuronal ISR triggered by AβPP-derived iAβ, whereas in the latter, the neuronal ISR is elicited by stressors distinct from AβPP-derived iAβ and arising from brain trauma, viral and bacterial infections, and various types of inflammation. Moreover, conventional AD always contains an unconventional component, and in both forms, the disease is driven by iAβ generated independently of AβPP. In its third, the current, iteration, the ACH2.0 posits that proteolytic production of Aβ is suppressed in AD-affected neurons and that the disease is driven by C99 generated independently of AβPP. Suppression of Aβ production in AD seems an oxymoron: Aβ is equated with AD, and the later is inconceivable without the former in an ingrained Amyloid Cascade Hypothesis (ACH)-based notion. But suppression of Aβ production in AD-affected neurons is where the logic leads, and to follow it we only need to overcome the inertia of the preexisting assumptions. Moreover, not only is the generation of Aβ suppressed, so is the production of all components of the AβPP proteolytic pathway. This assertion is not a quantum leap (unless overcoming the inertia counts as such): the global cellular protein synthesis is severely suppressed under the neuronal ISR conditions, and there is no reason for constituents of the AβPP proteolytic pathway to be exempted, and they, apparently, are not, as indicated by the empirical data. In contrast, tau protein translation persists in AD-affected neurons under ISR conditions because the human tau mRNA contains an internal ribosomal entry site in its 5′UTR. In current mouse models, iAβ derived from AβPP expressed exogenously from human transgenes elicits the neuronal ISR and thus suppresses its own production. Its levels cannot principally reach AD pathology-causing levels regardless of the number of transgenes or the types of FAD mutations that they (or additional transgenes) carry. Since the AβPP-independent C99 production pathway is inoperative in mice, the current transgenic models have no potential for developing the full spectrum of AD pathology. What they display are only effects of the AβPP-derived iAβ-elicited neuronal ISR. The paper describes strategies to construct adequate transgenic AD models. It also details the utilization of human neuronal cells as the only adequate model system currently available for conventional and unconventional AD. The final alteration of the ACH2.0, introduced in the present Perspective, is that AβPP, which supports neuronal functionality and viability, is, after all, potentially produced in AD-affected neurons, albeit not conventionally but in an ISR-driven and -compatible process. Thus, the present narrative begins with the “omnipotent” Aβ capable of both triggering and driving the disease and ends up with this peptide largely dislodged from its pedestal and retaining its central role in triggering the disease in only one, although prevalent (conventional), category of AD (and driving it in none). Among interesting inferences of the present Perspective is the determination that “sporadic AD” is not sporadic at all (“non-familial” would be a much better designation). The term has fatalistic connotations, implying that the disease can strike at random. This is patently not the case: The conventional disease affects a distinct subpopulation, and the basis for unconventional AD is well understood. Another conclusion is that, unless prevented, the occurrence of conventional AD is inevitable given a sufficiently long lifespan. This Perspective also defines therapeutic directions not to be taken as well as auspicious ways forward. The former category includes ACH-based drugs (those interfering with the proteolytic production of Aβ and/or depleting extracellular Aβ). They are legitimate (albeit inefficient) preventive agents for conventional AD. There is, however, a proverbial snowball’s chance in hell of them being effective in symptomatic AD, lecanemab, donanemab, and any other “…mab” or “…stat” notwithstanding. They comprise Aβ-specific antibodies, inhibitors of beta- and gamma-secretase, and modulators of the latter. In the latter category, among ways to go are the following: (1) Depletion of iAβ, which, if sufficiently “deep”, opens up a tantalizing possibility of once-in-a-lifetime preventive transient treatment for conventional AD and aging-associated cognitive decline, AACD. (2) Composite therapy comprising the degradation of C99/iAβ and concurrent inhibition of the neuronal ISR. A single transient treatment could be sufficient to arrest the progression of conventional AD and prevent its recurrence for life. Multiple recurrent treatments would achieve the same outcome in unconventional AD. Alternatively, the sustained reduction/removal of unconventional neuronal ISR-eliciting stressors through the elimination of their source would convert unconventional AD into conventional one, preventable/treatable by a single transient administration of the composite C99/iAβ depletion/ISR suppression therapy. Efficient and suitable ISR inhibitors are available, and it is explicitly clear where to look for C99/iAβ-specific targeted degradation agents—activators of BACE1 and, especially, BACE2. Directly acting C99/iAβ-specific degradation agents such as proteolysis-targeting chimeras (PROTACs) and molecular-glue degraders (MGDs) are also viable options. (3) A circumscribed shift (either upstream or downstream) of the position of transcription start site (TSS) of the human AβPP gene, or, alternatively, a gene editing-mediated excision or replacement of a small, defined segment of its portion encoding 5′-untranslated region of AβPP mRNA; targeting AβPP RNA with anti-antisense oligonucleotides is another possibility. If properly executed, these RNA-based strategies would not interfere with the protein-coding potential of AβPP mRNA, and each would be capable of both preventing and stopping the AβPP-independent generation of C99 and thus of either preventing AD or arresting the progression of the disease in its conventional and unconventional forms. The paper is interspersed with “validation” sections: every conceptually significant notion is either validated by the existing data or an experimental procedure validating it is proposed. Full article

Type 1 protein phosphatases (PP1s) are crucial in various plant cellular processes. Their function is controlled by regulators known as PP1-interacting proteins (PIPs), often intrinsically disordered, such as Inhibitor 2 (I2), conserved across kingdoms. The durum wheat TdRL1 acts as a positive regulator of plant stress tolerance, presumably by inhibiting PP1 activity. In this work, co-immunoprecipitation and bimolecular fluorescence complementation (BiFC) assays demonstrate that the durum wheat TdPP1 interacts with both TdRL1 and At-I2 in vivo. YFP fluorescence restored after TdRL1-TdPP1 interaction decorated specifically the microtubular network of the tobacco co-infiltrated cells. In vitro phosphatase assays revealed that TdRL1 inhibited the activity of wild-type TdPP1 and two mutant forms (T243M and H135A) in a concentration-dependent manner, showing a novel and potent inhibition mechanism. Structural modeling of the TdPP1-inhibitor complexes suggested that both At-I2 and TdRL1 bind to TdPP1 by wrapping their flexible C-terminal tails around it, blocking access to the active site. Remarkably, the model showed that TdRL1 differs from At-I2 in its interaction with TdPP1 by trapping the phosphatase with its N-terminal tail. These findings provide important insights into the regulatory mechanisms governing the activity of PP1s in plants and highlight the potential for targeted inhibition to modulate plant stress responses. Full article

Background: Atopic dermatitis (AD) is a chronic pruritic inflammatory disease affecting children and adults. Upadacitinib and abrocitinib are selective Janus kinase 1 inhibitors approved for the treatment of moderate-to-severe AD. Although their efficacy and safety are described in phase 3 clinical trials, real-world data are limited. Objectives: We aimed to evaluate the effectiveness and safety of upadacitinib and abrocitinib treatment in a real-life adult population with moderate-to-severe AD throughout an extended observation period. Methods: This retrospective observational study was conducted by analyzing data from the electronic records of IRCCS Humanitas Research Hospital from January 2023 to December 2024. Patients were administered either upadacitinib (15 or 30 mg) or abrocitinib (100 or 200 mg). Effectiveness was evaluated by using clinician-reported scores (Investigator Global Assessment [IGA] and Eczema Area and Severity Index [EASI]) and patient-reported outcomes (peak pruritus numerical rating scale [PP-NRS]) at weeks 8, 16, 32 and 52. Statistical significance was set at a probability value (p-value) < 0.05. Adverse events were also collected. Results: In total, 129 patients were included in the study, and 84 of them reached 52 weeks. At week 52, the EASI 75, 90, and 100 responses were 88.9%, 70.8%, and 54.2% for upadacitinib, and 100%, 91.7%, and 75% for abrocitinib. An IGA score equal to 0 or 1 at 52 weeks was achieved by 84.7% of patients treated with upadacitinib and 100% of those receiving abrocitinib. A four-point reduction from baseline PP-NRS was reported by 86.1% for upadacitinib and by 83.3% of patients for abrocitinib after one year of follow-up. Conclusions: Our study showed comparable or even higher effectiveness outcomes in terms of EASI 75, EASI 90, and EASI 100 at week 52 compared to phase-3 clinical trials, with no new safety concerns, supporting the real-world effectiveness of abrocitinib and upadacitinib in moderate-to-severe AD. Full article

It is well-established that mitochondrial dysfunction plays a critical role in the development of pulmonary hypertension (PH). However, the molecular mechanisms and how the individual electron transport complexes (ETC) may be affected are poorly understood. In this study, we identified decreased ETC Complex I activity and assembly and linked these changes to disrupted mitochondrial bioenergetics in pulmonary arterial endothelial cells (PAECs) isolated from a lamb model of PH with increased pulmonary blood flow (Shunt). These derangements were associated with decreased mitochondrial activity of the protein tyrosine kinase, pp60^Src. Treating Control PAECs with either the Src family kinase inhibitor, PP2, or the siRNA-mediated knockdown of pp60^Src was able to recapitulate the adverse effects on ETC Complex I activity and assembly and mitochondrial bioenergetics. Conversely, restoring pp60^Src activity in lamb PH PAECs re-established ETC Complex I activity, improved ETC Complex I assembly and enhanced mitochondrial bioenergetics. Phosphoprotein enrichment followed by two-dimensional gel electrophoresis and tandem mass spectrometry was used to identify three ETC Complex I subunits (NDUFS1, NDUFAF5, and NDUFV2) as pp60^Src substrates. Finally, we demonstrated that the pY levels of NDUFS1, NDUFAF5, and NDUFV2 are decreased in lamb PH PAECs. Enhancing mitochondrial pp60^Src activity could be a therapeutic strategy to reverse PH-related mitochondrial dysfunction. Full article