Immune Modulatory Effects Research Articles

Development of Apoptotic-Cell-Inspired Antibody-Drug Conjugate for Effective Immune Modulation.

Apoptotic cells' phosphoserine (PS) groups have a significant immunosuppressive effect. They inhibit proinflammatory signals by interacting with various immune cells, including macrophages, dendritic cells, and CD4+ cells. Previously, we synthesized PS-group-immobilized polymers and verified their immunomodulatory effects. Despite its confirmed immunomodulatory potential, the PS group has not been considered as a payload for antibody-drug conjugates (ADCs) in a targeted anti-inflammatory approach. We conducted this research to introduce an apoptotic-cell-inspired antibody-drug conjugate for effective immunomodulation. Poly(2-hydroxyethyl methacrylate-co-2-methacryloyloxyethyl phosphorylserine) (p(HEMA-co-MPS)) was synthesized as a payload using RAFT polymerization, and goat anti-mouse IgG was selected as a model antibody, which was conjugated with the synthesized p(HEMA-co-MPS) via 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide/N-Hydroxysuccinimide (EDC/NHS) reaction. The antibody-binding affinity, anti-inflammatory potential, and cytotoxicity measurements were evaluated. We successfully synthesized ADCs with a significant anti-inflammatory effect and optimized the antibody-polymer ratio to achieve the highest antibody-binding affinity. We successfully introduced p(HEMA-co-MPS) to IgG without decreasing the anti-inflammatory potential of the polymer while maintaining its targeting ability. We suggest that the antibody-polymer ratio be appropriately adjusted for effective therapy. In the future, this technology can be applied to therapeutic antibodies, such as Tocilizumab or Abatacept.

Mezigdomide (MEZI) Plus Dexamethasone (DEX) and Daratumumab (DARA) or Elotuzumab (ELO) in Patients (pts) with Relapsed/Refractory Multiple Myeloma (RRMM): Results from the CC-92480-MM-002 Trial

Introduction : MEZI is a novel oral cereblon E3 ligase modulator (CELMoD ™) with enhanced tumoricidal and immune-modulatory effects compared with immunomodulatory drugs (IMiDs ®). In preclinical studies, MEZI showed synergy with anti-myeloma drugs including DEX, proteasome inhibitors (PIs), and anti-CD38 monoclonal antibodies (mAbs), and is being assessed in the phase 1/2 CC-92480-MM-002 (NCT03989414) trial with different treatment combinations in RRMM. Here we report the preliminary efficacy and safety of MEZI, DARA, and DEX (MeziDd) over 3 dosing schedules, as well as MEZI, ELO and DEX (MeziEd), in pts with RRMM. Methods : Eligible pts had: RRMM, received 2-4 prior lines of therapy, a minimal response or better to ≥ 1 prior regimen, and disease progression during or after their last therapy. In the MeziDd cohort, oral MEZI was given at escalating doses on days (D) 1-21 per 28-D cycle (C) (subcohort B1); on D1-14 per 21-D cycle from C1-8 and D1-21 per 28-D cycle ≥ C9 (subcohort B2); or on D1-7 and D15-21 per 28-D cycle from C1-6 and D1-21 per 28-D cycle ≥ C7 (subcohort B3). Intravenous (IV; 16 mg/kg) or subcutaneous (1800 mg) DARA was given weekly (C1-2), then biweekly (C3-6), and monthly (≥ C7) for subcohorts B1 and B3, and weekly (C1-3) then on D1 of each 21-D (C4-8) or 28-D (≥ C9) cycle for subcohort B2; with weekly oral/IV DEX (40 mg; 20 mg > 75 y or body mass index < 18.5 kg/m 2). In the MeziEd cohort, oral MEZI was given at escalating doses on D1-21 per 28-D cycle, with weekly (C1-2; 10 mg/kg) then monthly (≥ C3; 20 mg/kg) IV ELO, and oral/IV DEX on ELO dosing days (36 mg; 16 mg > 75 y) plus on D8, 15, and 22 of ≥ C3 (40 mg; 20 mg > 75 y). Thromboembolism (TE) prophylaxis was given within 48 hours of C1D1 and until 48 hours after last MEZI dose. Primary objectives were to determine the recommended dose and regimen and to assess safety and preliminary efficacy as overall response rate (ORR). Results : As of the May 25, 2023 data cut, 57 pts were enrolled and had received MeziDd (B1: n = 23; B2: n = 16; B3: n = 18) at the 0.3 mg or 0.6 mg dose. Median age was 67 (range, 45-83) y, median time since initial diagnosis was 8.2 (1.0-15.8) y, and median number of prior regimens was 2 (2-5). Prior therapies included stem cell transplantation (15.8%), IMiD agents (100%), PIs (98.2%), and anti-CD38 mAbs (8.8%); 82.5% of pts were refractory to IMiD agents and 61.4% to PIs. Extramedullary plasmacytomas were present in 4 (7.0%) pts. Forty-five of 57 (78.9%) pts continued treatment; the main reason for discontinuation was progressive disease (5 pts; 8.8%). In the safety population (n = 56), ORR was 75.0% overall, with 2 (3.6%) stringent complete responses, 8 (14.3%) complete responses, 16 (28.6%) very good partial responses, and 16 (28.6%) partial responses (Figure). Duration of response and progression-free survival data were not yet mature. Grade (Gr) 3/4 treatment-emergent adverse events (TEAEs) occurred in 43/56 (76.8%) pts and were mostly hematologic (Table). Gr 3/4 neutropenia occurred in 30 (53.6%) pts; Gr 3/4 thrombocytopenia occurred in 4 (7.1%) pts (3/4 pts were in subcohort B1-0.6 mg) and was not associated with bleeding. Gr 3/4 infections occurred in 11 (19.6%) pts and proved manageable in all cases (Table). Non-hematologic Gr 3/4 TEAEs were low. No Gr 3/4 TE or peripheral neuropathy was observed. MEZI dose reductions were needed for 7 (30.4%) pts in subcohort B1 (1 at 0.3 mg, 6 at 0.6 mg) and 1 (5.6%) pt in subcohort B3 (at 0.6 mg). In the evaluable population (n = 35), 5 (14.3%) pts had ≥ 1 dose-limiting toxicity. The maximum tolerated dose was not reached. MeziDd had pharmacodynamically active immune stimulation in T and NK cells in all 3 schedules and both doses. Twenty pts received MeziEd at 0.3 mg (n = 11) or 0.6 mg (n = 9); median prior lines of therapy was 3 (2-4) and 3 (2-5), and most pts (72.7% and 100%) had prior anti-CD38 mAb exposure. ORRs were 36% and 56%, respectively. The safety profile was consistent with known TEAEs and was generally well tolerated, although 2 Gr 3 pulmonary embolisms occurred. Conclusions : MeziDd showed promising efficacy and a manageable safety profile in pts with RRMM and 2-4 prior lines of therapy, as did MeziEd in pts with prior anti-CD38 mAb therapy. The immune activity of MEZI was consistent with previous preclinical reports. Improved safety and efficacy may be achieved by schedule and dose adjustments. These results support further evaluation of MEZI plus anti-myeloma mAbs in phase 1/2 and phase 3 studies. Updated results will be presented at the meeting.

New insights on the potential effect of progesterone in Covid-19: Anti-inflammatory and immunosuppressive effects.

Coronavirus disease 2019 (COVID-19) is a pandemic disease caused by severe acute respiratory syndrome CoV type 2 (SARS-CoV-2). COVID-19 is higher in men than women and sex hormones have immune-modulator effects during different viral infections, including SARS-CoV-2 infection. One of the essential sex hormones is progesterone (P4). This review aimed to reveal the association between P4 and Covid-19. The possible role of P4 in COVID-19 could be beneficial through the modulation of inflammatory signaling pathways, induction of the release of anti-inflammatory cytokines, and inhibition release of pro-inflammatory cytokines. P4 stimulates skew of naïve T cells from inflammatory Th1 toward anti-inflammatory Th2 with activation release of anti-inflammatory cytokines, and activation of regulatory T cells (Treg) with decreased interferon-gamma production that increased during SARS-CoV-2 infection. In addition, P4 is regarded as a potent antagonist of mineralocorticoid receptor (MR), it could reduce MRs that were activated by stimulated aldosterone from high AngII during SARS-CoV-2. P4 active metabolite allopregnanolone is regarded as a neurosteroid that acts as a positive modulator of γ-aminobutyric acid (GABAA ) so it may reduce neuropsychiatric manifestations and dysautonomia in COVID-19 patients. Taken together, the anti-inflammatory and immunomodulatory properties of P4 may improve central and peripheral complications in COVID-19.

Timed adoptive T cell transfer during chemotherapy in patients with recurrent platinum-sensitive epithelial ovarian cancer

BackgroundThe presence of T cells and suppressive myeloid cells in epithelial ovarian cancer (EOC) correlate with good and bad clinical outcome, respectively. This suggests that EOC may be sensitive to...

YuPingFeng (YPF) upregulates caveolin-1 (CAV1) to alleviate pulmonary fibrosis through the TGF-β1/Smad2 pathway

Ethnopharmacological relevanceTraditional Chinese medicine (TCM) is considered a valuable asset in China's medical tradition. YPF is a classic prescription that has been derived from the "Jiu Yuan Fang" formula and consists of three herbs: Huangqi (Astragalus membranaceus Bunge), Baizhu (Atractylodes rubra Dekker), and Fangfeng (Saposhnikovia divaricata (Turcz.) Schischk). This prescription is widely acclaimed for its exceptional pharmacological properties, including potent antioxidant effects, hormone regulation, and immune modulation effects. Aim of the studyPrevious research provides evidence suggesting that YPF may have therapeutic effects on pulmonary fibrosis. Further exploration is essential to confirm its effectiveness and elucidate the fundamental processes. Materials and methodsFirst, the active components and target genes of YPF were extracted from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database. Next, the GSE53845 dataset, which contains information on pulmonary fibrosis, was downloaded from the GEO database. Network informatics methods was then be utilized to identify target genes associated with pulmonary fibrosis. A YPF-based network of protein-protein interactions was constructed to pinpoint possible target genes for pulmonary fibrosis treatment. Additionally, an in vitro model of pulmonary fibrosis induced by bleomycin (BLM) was established to further investigate and validate the possible mechanisms underlying the effectiveness of YPF. ResultsIn this study, a total of 24 active ingredients of YPF, along with 178 target genes associated with the treatment, were identified. Additionally, 615 target genes related to pulmonary fibrosis were identified. Functional enrichment analysis revealed that 18 candidate genes (CGs) exhibited significant responses to tumor necrosis factor, NF-kB survival signaling, and positive regulation of apoptosis processes. Among these CGs, CAV1, VCAM1, and TP63 were identified as key target genes. Furthermore, cell experiments confirmed that the expression of CAV1 protein and RNA expression was increased in pulmonary fibrosis, but significantly decreased after treatment with YPF. Additionally, the expression of pSmad2, α-SMA, TGF-β1, and TNF-α was also decreased following YPF treatment. ConclusionsNetwork pharmacology analysis revealed that YPF exhibits significant potential as a therapeutic intervention for pulmonary fibrosis by targeting various compounds and pathways. This study emphasizes that the efficacy of YPF in treating pulmonary fibrosis may be attributed to its ability to up-regulate CAV1 expression and inhibiting pulmonary fibrosis via modulation of the TGF-β1/Smad2 signaling pathway. These findings underscore the promising role of YPF and its ability to potentially alleviate pulmonary fibrosis.

IINCIDENCE OF POST-OPERATIVE NAUSEA AND VOMITING IN LAPAROSCOPIC CHOLECYSTECTOMY WITH A SINGLE DOSE OF PREOPERATIVE DEXAMETHASONE

and vomiting (PONV). Dexamethasone, a synthetic glucocorticoid with potent anti-inflammatory, immune-modulating, analgesic, and anti-emetic effects, effectively reduces the incidence of PONV after laparoscopic cholecystectomy. In this double-blind, placebo-controlled study, we aimed to investigate the efficacy of a single 8 mg dose of dexamethasone in preventing PONV in patients undergoing laparoscopic cholecystectomy. Sixty patients were randomized into two groups: group A, who received an 8 mg dexamethasone injection in a 2-ml preparation, and group B, who received normal saline during induction. Both groups received standardized anesthesia. Post-operatively, the incidence of nausea and vomiting was observed in both groups. Our study's findings indicate that no substantial variances were observed between the two cohorts in terms of medical or demographic factors. However, a lower proportion of patients in group A exhibited post-operative nausea and vomiting (PONV), while group B had a higher demand for anti-emetic medications to alleviate PONV symptoms. Thus, we can infer that administering a solitary dose of dexamethasone before laparoscopic cholecystectomy can reduce the risk of post-operative complications in patients.

Differential Immune-Modulating Activities of Cell Walls and Secreted Metabolites from Probiotic Bacillus coagulans JBI-YZ6.3 under Normal versus Inflamed Culture Conditions.

Spore-forming probiotic bacteria, including Bacillus coagulans, are resilient and produce a variety of beneficial metabolites. We evaluated the immune-modulating effects of the novel probiotic strain Bacillus coagulans JBI-YZ6.3, where the germinated spores, metabolite fraction, and cell wall fraction were tested in parallel using human peripheral blood mononuclear cell cultures under both normal and lipopolysaccharide-induced inflamed culture conditions. The expression of CD25 and CD69 activation markers was evaluated via flow cytometry. Supernatants were tested for cytokines, interferons, chemokines, and growth factors using Luminex arrays. The germinated spores were highly immunogenic; both the cell wall and metabolite fractions contributed significantly. Under normal culture conditions, increased levels of immune activation were observed as increased expressions of CD25 and CD69 relative to natural killer cells, suggesting an increased ability to attack virus-infected target cells. On monocytes, a complex effect was observed, where the expression of CD25 increased under normal conditions but decreased under inflamed conditions. This, in combination with increased interleukin-10 (IL-10) and decreased monocyte chemoattractant protein-1 (MCP-1) production under inflamed conditions, points to anti-inflammatory effects. The production of the stem cell-related growth factor granulocyte colony-stimulating Factor (G-CSF) was enhanced. Further research is warranted to characterize the composition of the postbiotic metabolite fraction and document the characteristics of immunomodulating agents secreted by this probiotic strain.

Not only for Christmas: Prophylactic oral application of trans-cinnamaldehyde alleviates acute murine campylobacteriosis.

The prevalence of Campylobacter jejuni infections is increasing worldwide and responsible for significant morbidities and socioeconomic expenses. The rise in antimicrobial resistance of C. jejuni underscoresthe urge for evaluating antibiotics-independent compounds as therapeutic and preventive treatment options of human campylobacteriosis. Given its well-known anti-microbial and immune-modulatory properties we here surveyed the disease-modifying effects of trans-cinnamaldehyde pretreatment in experimental campylobacteriosis. Therefore, secondary abiotic IL-10-/- mice were orally challenged with trans-cinnamaldehyde starting 7 days prior C. jejuni infection. Whereas gastrointestinal colonization properties of the enteropathogens remained unaffected, trans-cinnamaldehyde pretreatment did not only improve clinical signs in infected mice, but also alleviated colonicepithelial cell apoptosis on day 6 post-infection. Furthermore, trans-cinnamaldehyde application resulted in less pronounced T cell responses in the colon that were accompanied bydampened proinflammatory mediator secretion in distinct intestinal compartments. Notably, theimmune-modulatory effects of trans-cinnamaldehyde were not restricted to the intestinal tract butcould also be observed in extra-intestinal organs such as the liver and kidneys. In conclusion, ourpreclinical placebo-controlled intervention study provides first evidence that due to its immune-modulatory effects, trans-cinnamaldehyde constitutes a promising prophylactic option to alleviate campylobacteriosis.

Structural determinants of sphingosine-1-phosphate receptor selectivity.

Fingolimod, the prodrug of fingolimod-1-phosphate (F1P), was the first sphingosine-1-phosphate receptor (S1PR) modulator approved for multiple sclerosis. F1P unselectively targets all five S1PR subtypes. While agonism (functional antagonism via receptor internalization) at S1PR1 leads to the desired immune modulatory effects, agonism at S1PR3 is associated with cardiac adverse effects. This motivated the development of S1PR3 -sparing compounds and led to a second generation of S1PR1,5 -selective ligands like siponimod and ozanimod. Our method combines molecular dynamics simulations and three-dimensional pharmacophores (dynophores) and enables the elucidation of S1PR subtype-specific binding site characteristics, visualizing also subtle differences in receptor-ligand interactions. F1P and the endogenous ligand sphingosine-1-phosphate bind to the orthosteric pocket of all S1PRs, but show different binding mode dynamics, uncovering potential starting points for the development of subtype-specific ligands. Our study contributes to the mechanistic understanding of the selectivity profile of approved drugs like ozanimod and siponimod and pharmaceutical tool compounds like CYM5541.

FRI530 Immune-Modulation By Rapamycin, Or Mycophenolic Acid, Of Th1 And Th2 Chemokines Secretion In Retro-orbital Cells Of Patients With Graves’ Ophthalmopathy

Abstract Disclosure: G. Elia: None. F. Ragusa: None. S. Paparo: None. V. Mazzi: None. A. Patrizio: None. P. Fallahi: None. A. Antonelli: None. S. Ferrari: None. Objectives: Cytokines and chemokines contribute to the inflammation of Graves’ ophthalmopathy (GO). Indeed cytokines stimulate the T helper (Th)1 and Th2 chemokines release from orbital cells (fibroblasts, preadipocytes and myocytes).We aim to investigate the effects of rapamycin or mycophenolic acid on the secretion of these chemokines in GO orbital cells. Methods: We obtained primary cultures of fibroblasts, preadipocytes and myoblasts from the orbits of GO patients, and we tested increasing concentrations of rapamycin and/or mycophenolic acid evaluating the secretion of the prototype Th1 [chemokine (C-X-C motif) ligand 10 (CXCL10)] and Th2 [chemokine (C-C motif) ligand 2 (CCL2)] chemokines. Results: We observed that CXCL10 secretion in the retro-orbital cells of GO was undetectable in the supernatants, whereas interferon (IFN)-gamma induce its release in a dose-dependently manner. No effect was observed under the tumor necrosis factor (TNF)-alpha stimuli, while the combination of both cytokines had a significant synergistic effect on CXCL10 secretion. As regards the effect on the CCL2 secretion, it was released in low amounts in basal condition; TNF-alpha dose-dependently induced its release, whereas IFN-gamma alone had no effect. The combination of TNF-alpha plus IFN-gamma had a significant synergistic effect on CCL2 secretion. By adding mycophenolic acid, or rapamycin, (in a pharmacological range) at the time of IFN-gamma and TNF-alpha stimulation, we observed a dose-dependently inhibitory effect on the chemokines release in the retro-orbital cells of GO. Furthermore, the combination of mycophenolic acid with rapamycin, have a synergistic inhibitory effect on the release of chemokines. Conclusion: Our data showed an immune-modulating effect of mycophenolic acid or rapamycin on the Th1 and Th2 chemokines secretion, in GO orbital cells. These findings suggest the therapeutic role of these drugs that could obtained, at least in part, through this mechanism. Presentation: Friday, June 16, 2023

1303P Immune-modulating effects on tumor draining lymph nodes following neoadjuvant chemoradiotherapy combined with immunotherapy in patients with T3-4N0-1 NSCLC

1303P Immune-modulating effects on tumor draining lymph nodes following neoadjuvant chemoradiotherapy combined with immunotherapy in patients with T3-4N0-1 NSCLC

Erucic acid improves the progress of pregnancy complicated with systemic lupus erythematosus by inhibiting the effector function of CD8+ Tcells.

Pathogenic CD8+ Tcells are pivotal contributors to the onset of systemic lupus erythematosus (SLE). Erucic acid (EA) has been proven to have anti-inflammatory activity. However, the capacity of EA to regulate pathogenic CD8+ Tcells in the context of pregnancy complicated with SLE (pSLE) remains unclear. In our investigation, we observed augmented CD8+ T cell effector function juxtaposed with diminished EA levels in pSLE patients relative to healthy pregnant controls. Significantly, plasma EA levels exhibited a negative correlation with the severity of pSLE-associated complications. In blood from patients with pSLE, EA inhibited the effector function of CD8+ Tcells, concurrently dampening the maintenance of stem cell-like memory CD8+ Tcells. Mechanistically, EA orchestrated the inhibition of CD8+ T cell effector function by impeding signal transducer and activator of transcription 3 phosphorylation and promoting ferroptosis. Moreover, EA supplementation in pregnant MRL/lpr mice manifested as the attenuation of uterine CD8+ T cell effector function, culminating in the mitigation of placental pathological damage. Our findings uncover the immune response modulatory effects of EA upon pathogenic CD8+ cells, thereby unveiling new perspectives for therapeutic strategies targeting pSLE patients.

Exploring Immune Modulatory Effects of Cyclotide-Enriched Viola tricolor Preparations.

Viola tricolor is a medicinal plant with documented application as an anti-inflammatory herb. The standard of care for the treatment of inflammatory bowel disease is immunosuppressive therapeutics or biologics, which often have undesired effects. We explored V.tricolor herbal preparations that are rich in an emerging class of phytochemicals with drug-like properties, so-called cyclotides. As an alternative to existing inflammatory bowel disease medications, cyclotides have immunomodulatory properties, and their intrinsic stability allows for application in the gastrointestinal tract, for instance, via oral administration. We optimized the isolation procedure to improve the yield of cyclotides and compared the cellular effects of violet-derived organic solvent-extracts, aqueous preparations, and an isolated cyclotide from this plant on primary human T lymphocytes and macrophages, i.e., cells that are crucial for the initiation and progression of inflammatory bowel disease. The hot water herbal decoctions have a stronger immunosuppressive activity towards proliferation, interferon-γ, and interleukin-21 secretion of primary human T cells than a DCM/MeOH cyclotide-enriched extract, and the isolated cyclotide kalata S appears as one of the active components responsible for the observed effects. This effect was increased by a longer boiling duration. In contrast, the DCM/MeOH cyclotide-enriched extract was more effective in reducing the levels of cytokines interleukin-6, interleukin-12, interleukin-23, tumor necrosis factor-α, and C - X-C motif chemokine ligand 10, secreted by human monocyte-derived macrophages. Defined cyclotide preparations of V.tricolor have promising pharmacological effects in modulating immune cell responses at the cytokine levels. This is important towards understanding the role of cyclotide-containing herbal drug preparations for future applications in immune disorders, such as inflammatory bowel disease.

Alpha-tocopherylquinone-mediated activation of the Aryl Hydrocarbon Receptor regulates the production of inflammation-inducing cytokines and ameliorates intestinal inflammation

This study investigated the role of Alpha-tocopherylquinone (TQ) in regulating the intestinal immune system and the underlying mechanisms. In the experimental dextran sodium sulfate and T cell-mediated colitis models, TQ significantly reduced the mRNA levels of interleukin (IL)-6, IL-1β, IL-17A, IL-23, and tumor necrosis factor (TNF)-α and the abundance of proinflammatory macrophages, T helper (Th)17 cells, and ILC3s in the colons of wild-type mice. TQ also prevented lipopolysaccharide (LPS)-induced activation of NFκB and signal transducer and activator of transcription (Stat)-3 pathways in the human macrophage U937 cells. Pharmacological inhibition or CRISPR-Cas-9-mediated knockout of Aryl hydrocarbon Receptor (AhR) prevented the anti-inflammatory effects of TQ in the LPS-treated U937 cells. Furthermore, TQ reduced the mRNA levels of the LPS-induced pro-inflammatory cytokines in the WT but not Ahr-/- mice splenocytes. TQ also reduced IL-6R protein levels and IL-6-induced Stat-3 activation in Jurkat cells and in vitro differentiation of Th17 cells from wild-type but not Ahr-/- mice naive T cells. Additionally, TQ prevented the pro-inflammatory effects of LPS on macrophages and stimulation of T cells in human PBMCs and significantly reduced the abundance of tumor necrosis factor-α, IL-1β, and IL-6hi inflammatory macrophages and Th17 cells in surgically resected Crohn's disease (CD) tissue. Our study shows that TQ is a naturally occurring, non-toxic, and effective immune modulator that activates AhR and suppresses the Stat-3-NFκB signaling.

Calcineurin Is a Universal Regulator of Vessel Function-Focus on Vascular Smooth Muscle Cells.

Calcineurin, a serine/threonine phosphatase regulating transcription factors like NFaT and CREB, is well known for its immune modulatory effects and role in cardiac hypertrophy. Results from experiments with calcineurin knockout animals and calcineurin inhibitors indicate that calcineurin also plays a crucial role in vascular function, especially in vascular smooth muscle cells (VSMCs). In the aorta, calcineurin stimulates the proliferation and migration of VSMCs in response to vascular injury or angiotensin II administration, leading to pathological vessel wall thickening. In the heart, calcineurin mediates coronary artery formation and VSMC differentiation, which are crucial for proper heart development. In pulmonary VSMCs, calcineurin/NFaT signaling regulates the release of Ca2+, resulting in increased vascular tone followed by pulmonary arterial hypertension. In renal VSMCs, calcineurin regulates extracellular matrix secretion promoting fibrosis development. In the mesenteric and cerebral arteries, calcineurin mediates a phenotypic switch of VSMCs leading to altered cell function. Gaining deeper insights into the underlying mechanisms of calcineurin signaling will help researchers to understand developmental and pathogenetical aspects of the vasculature. In this review, we provide an overview of the physiological function and pathophysiology of calcineurin in the vascular system with a focus on vascular smooth muscle cells in different organs. Overall, there are indications that under certain pathological settings reduced calcineurin activity seems to be beneficial for cardiovascular health.

Restoration of Foxp3+ Regulatory T Cells by HDAC-Dependent Epigenetic Modulation Plays a Pivotal Role in Resolving Pulmonary Arterial Hypertension Pathology.

Rationale: Immune dysregulation is a common feature of pulmonary arterial hypertension (PAH). Histone deacetylase (HDAC)-dependent transcriptional reprogramming epigenetically modulates immune homeostasis and is a novel disease-oriented approach in modern times. Objectives: To identify a novel functional link between HDAC and regulatory T cells (Tregs) in PAH, aiming to establish disease-modified biomarkers and therapeutic targets. Methods: Peripheral blood mononuclear cells were isolated from patients with idiopathic PAH (IPAH) and rodent models of pulmonary hypertension (PH): monocrotaline rats, Sugen5416-hypoxia rats, and Treg-depleted mice. HDAC inhibitor vorinostat (suberoylanilide hydroxamic acid, SAHA) was used to examine the immune modulatory effects invivo, ex vivo, and invitro. Measurements and Main Results: Increased HDAC expression was associated with reduced Foxp3+ Tregs and increased PD-1 (programmed cell death-1) signaling in peripheral blood mononuclear cells from patients with IPAH. SAHA differentially modified a cluster of epigenetic-sensitive genes and induced Foxp3+ Treg conversion in IPAH T cells. Rodent models recapitulated these epigenetic aberrations and T-cell dysfunction. SAHA attenuated PH phenotypes and restored FOXP3 transcription and Tregs in PH rats; interestingly, the effects were more profound in female rats. Selective depletion of CD25+ Tregs in Sugen5416-hypoxia mice neutralized the effects of SAHA. Furthermore, SAHA inhibited endothelial cytokine/chemokine release upon stimulation and subsequent immune chemotaxis. Conclusions: Our results indicated HDAC aberration was associated with Foxp3+ Treg deficiency and demonstrated an epigenetic-mediated mechanism underlying immune dysfunction in PAH. Restoration of Foxp3+ Tregs by HDAC inhibitors is a promising approach to resolve pulmonary vascular pathology, highlighting the potential benefit of developing epigenetic therapies for PAH.

Novel Kefir Exopolysaccharides (KEPS) Mitigate Lipopolysaccharide (LPS)-Induced Systemic Inflammation in Luciferase Transgenic Mice through Inhibition of the NF-κB Pathway.

A novel kefir exopolysaccharides (KEPS) derived from kefir grain fermentation were found to have a small molecular weight (12 kDa) compared to the traditionally high molecular weight (12,000 kDa) of kefiran (KE). KE has been shown to possess antioxidant, blood pressure-lowering, and immune-modulating effects. In this study, we characterized KEPS and KE and evaluated their anti-inflammatory properties in vitro using RAW264.7 macrophages. The main monosaccharide components were identified as glucose (98.1 ± 0.06%) in KEPS and galactose (45.36 ± 0.16%) and glucose (47.13 ± 0.06%) in KE, respectively. Both KEPS and KE significantly reduced IL-6 secretion in lipopolysaccharide (LPS)-stimulated macrophages. We further investigated their effects in LPS-induced systemic injury in male and female NF-κB-luciferase+/+ transgenic mice. Mice received oral KEPS (100 mg/kg) or KE (100 mg/kg) for seven days, followed by LPS or saline injection. KEPS and KE inhibited NF-κB signaling, as indicated by reduced luciferase expression and phosphorylated NF-κB levels. LPS-induced systemic injury increased luciferase signals, especially in the kidney, spleen, pancreas, lung, and gut tissues of female mice compared to male mice. Additionally, it upregulated inflammatory mediators in these organs. However, KEPS and KE effectively suppressed the expression of inflammatory mediators, including p-MAPK and IL-6. These findings demonstrate that KEPS can alleviate LPS-induced systemic damage by inhibiting NF-κB/MAPK signaling, suggesting their potential as a treatment for inflammatory disorders.

A phase III, multicenter, randomized study of olvimulogene nanivacirepvec followed by platinum-doublet chemotherapy and bevacizumab compared with platinum-doublet chemotherapy and bevacizumab in women with platinum-resistant/refractory ovarian cancer

BackgroundTreatment options for patients with platinum-resistant/refractory ovarian cancers are limited and only marginally effective. The development of novel, more effective therapies addresses a critical unmet medical need. Olvimulogene nanivacirepvec (Olvi-Vec),...

Statins, allies against antibiotic resistance?

Due to the ever-increasing rate of antibacterial resistance, the search for effective antibacterial agents has become imperative. Researchers have investigated the potential antimicrobial properties of various classes of nonantibiotic drugs. Statins are a group of antihyperlipidemic drugs with several cholesterol-independent effects, including anti-inflammatory, immune-modulating, antioxidant, and antibacterial effects. In vitro and in vivo studies have demonstrated the antibacterial properties of statins against various gram-positive and gram-negative bacteria. Simvastatin and atorvastatin are the most potent members of the family. Their antibacterial effect can be attributed to several direct and indirect mechanisms. Bacterial invasion, growth, and virulence are affected by statins. However, since in vitro minimum inhibitory concentrations (MICs) are significantly higher than serum concentrations at the lipid-lowering dosage, indirect mechanisms have been suggested to explain the positive clinical results, including reducing inflammation and improving immune response capacity. Further, statins have shown promising results when combined with antibiotics and other antibacterial agents, such as triazenes and silver nanoparticles. Despite this, the controversial aspects of statins have cast doubt on their efficacy as a possible solution for antibacterial resistance, and further research is required. Consequently, this review will examine in detail the current clinical and in vitro findings and controversies regarding statins' antibacterial properties and their relevance to antibacterial resistance.

Anti-Inflammatory and Immune Properties of Polyunsaturated Fatty Acids (PUFAs) and Their Impact on Colorectal Cancer (CRC) Prevention and Treatment.

Colorectal cancer (CRC) remains a leading cause of death from cancer worldwide, with increasing incidence in the Western world. Diet has become the focus of research as a significant risk factor for CRC occurrence, and the role of dietary polyunsaturated fatty acids (PUFAs) has become an area of interest given their potential role in modulating inflammation, particularly in the pro-carcinogenic inflammatory environment of the colon. This work reviews the main types of PUFAs, their characteristics, structure, and physiologic role. We then highlight their potential role in preventing CRC, their signaling function vis-à-vis tumorigenic signaling, and their subsequent potential role in modulating response to different treatment modalities. We review pre-clinical and clinical data and discuss their potential use as adjunct therapies to currently existing treatment modalities. Given our understanding of PUFAs' immune and inflammation modulatory effects, we explore the possible combination of PUFAs with immune checkpoint inhibitors and other targeted therapies.