Search Results (4,303)

Trastuzumab is the first humanised monoclonal antibody (Mab) developed for breast cancer (BC) therapy. The high affinity of Trastuzumab Fab-domain binding to the human epidermal growth factor receptor 2 (HER2) receptor, with a K_d value of <1 nM, is also accompanied by Fc domain interaction with Fc-receptors in natural killer cells and leukocytes, enabling the killing of tumour cells through antibody-directed cellular cytotoxicity (ADCC). Trastuzumab blocks the over-expressed HER2 receptor-mediated dimerization and consequent intracellular signalling, leading to cancerous growth. However, the trastuzumab resistance (TR) became the major problem within 1 year of treatment. The mutation in phosphatidylinositol 3′-kinase (PI3K) pathway, cross-talk with estrogen receptors, over-expression of Mucin 1 (MUC1) protein, insulin-like growth factor I receptor, etc., are key pathways involved in TR. In this review, we have provided a molecular view of TR and the possible remedies for overcoming TR using BC stem cell (BCSC)-based therapy, PI3K pathway inhibitors, MUC1-based treatment, etc. We have also analysed the patents and clinical trials from the pre-TR and post-TR era to rationalise the possible steps to overcome TR. Our analysis implies that Trastuzumab monotherapy no longer applies to HER2+ BC treatment. Further, combination therapy using other antibodies like pertuzumab and protein kinase inhibitors and targeting pathways like the ubiquitin proteasome pathway will be the future option for BC Treatment. Overall, this review provides a detailed summary of the molecular mechanisms involving TR and its potential ways of evasion, based on updated information from published research articles, clinical trial outcomes, and patent data. Full article

Neutrophils constitute the largest fraction of total circulating leukocytes in humans and mediate early innate immune responses. Although they are often considered a uniform population of short-lived immune cells, emerging evidence from single-cell RNA sequencing and high-dimensional flow cytometry has revealed that neutrophils are functionally and phenotypically heterogeneous in both healthy and pathological conditions. However, a critical gap is how molecularly defined neutrophil states translate into distinct spatiotemporal behaviors in vivo. This review summarizes our current understanding of the molecular signatures underlying neutrophil heterogeneity and explores the functional in vivo behaviors in various diseases, including cancer, sepsis, and ischemic stroke. We also discuss the potential of intravital imaging to bridge the gap between static molecular profiling and dynamic cellular behavior, offering a comprehensive view of the functional heterogeneity of neutrophils. Full article

Background: Liver inflammation and fibrosis are directly associated with non-alcoholic fatty liver disease (NAFLD). Dysregulation of the potent pro-inflammatory cytokine interleukin-1 beta (IL-1β), inducible nitric oxide synthase (iNOS), and tissue leukocyte infiltration (CD45 +ve) are connected with multiorgan injury and fibrosis. We investigated whether the induction of NAFLD can cause dysregulation in the hepatic IL-1β/iNOS and IL-1β/CD45 axes of inflammation and fibrosis, as well as in endogenous metabolites (lipids, glucose, and insulin) and apoptosis, in the presence and absence of the flavonoid quercetin. Methods: The model group of rats was fed with a high-fat and high-carbohydrate diet (HFCD) for 4 weeks. The protective group of rats was given both quercetin (50 mg/kg) and HFCD for 4 weeks. All rats were sacrificed on day 29. Results: NAFLD was induced in rats as demonstrated by dyslipidemia, hyperglycemia, insulin resistance, liver inflammation, and elevation of liver injury enzymes. NAFLD was also associated with the upregulation of hepatic IL-1β, iNOS, CD45, and apoptosis (p53). Biomarkers of fibrosis (TIMP-1 and α-SMA) were also elevated, and fibrosis was confirmed in the model group by increased collagen deposition and elevated stages of fibrosis score (Stage 1 to 2 of Brunt’s NASH classification). All these parameters were significantly (p < 0.01) modulated by quercetin treatment. Additionally, a significant (p < 0.001) correlation between IL-1β and hepatic injury parameters was observed. Conclusions: These findings suggest a potential association between NAFLD and the IL-1β/iNOS and IL-1β/CD45 axes of liver injury and fibrosis, as well as dyslipidemia, glycemia, and apoptosis, with quercetin exhibiting beneficial hepatic pleiotropic effects. Full article

Titanium and its alloys are used in dental and orthopedic implants. However, long-term stability remains a clinical challenge. To overcome this limitation, surface modification has been investigated to improve surface properties. Our previous study demonstrated that the immobilization of secretory leukocyte protease inhibitor (SLPI) on the titanium surface promotes osteoblast adhesion, proliferation, and differentiation in vitro. The current study demonstrated the first in vivo evaluation of SLPI as a bioactive coating for medical implants. Grade 5 titanium screws were coated with 10 µg/mL of recombinant human SLPI (rhSLPI) for 24 h via simple physical adsorption, and the results were preliminarily validated via FE-SEM and ELISA. These SLPI-coated titanium screws (TiSs) were then placed in the tibia of Sprague–Dawley rats for 4 and 8 weeks. The hematological and biochemical parameters (BUN, Creatinine, AST, and Troponin I) demonstrated no acute systemic alterations within the 8-week period across all groups. Moreover, micro-computed tomography (micro-CT) and histological analysis revealed significantly higher bone volume fraction (%BV/TV) at 4 weeks compared to uncoated controls (20.64% ± 2.452% vs. 11.73% ± 0.524%). Finally, the biomechanical stability of implants, assessed using the removal torque test, showed that TiSs showed higher strength compared to Ti at both 4 and 8 weeks. In conclusion, this study represents a novel approach to transitioning rhSLPI-coated titanium evaluation from in vitro models to an in vivo rat model. rhSLPI surface functionalization enhances early-stage osseointegration and improves implant mechanical stability without acute hematological and biochemical alterations. These proof-of-concept findings suggest the potential of SLPI as a bioactive coating strategy. Full article

Platelet-rich plasma (PRP) is widely used as a second-line treatment for chronic tendinopathy that persists despite structured conservative care, yet outcomes and imaging correlates remain heterogeneous. This review outlines PRP biology and preparation, summarises quantitative imaging techniques for monitoring tendon response, and presents the experience of a single centre integrating these methods into routine supraspinatus and lateral elbow PRP workflows. PRP is described as an autologous platelet concentrate with variable leukocyte and fibrin content, with leukocyte-rich formulations commonly selected for chronic tendinopathy. Quantitative approaches—including ultrasound shear-wave elastography and radiomics, MRI T2/T2* mapping, CT-based bone metrics, PET/CT, and optical techniques—offer numerical biomarkers of tendon structure, mechanics, and inflammation but are rarely implemented in PRP trials. At the authors’ centre, leukocyte-rich PRP is injected under ultrasound guidance after failed physiotherapy, and follow-up combines validated questionnaires with grey-level run-length matrix texture analysis of ultrasound and 3.0 T MRI T2 distribution profiling. A pilot ultrasound study in supraspinatus and common extensor tendinosis showed uniform short-term clinical improvement and significant changes in most texture features, with selected parameters correlating with symptom relief. A prospective supraspinatus cohort demonstrated significant six-month clinical gains in both tendinosis and small partial-thickness tears, whereas only the tendinosis group exhibited T2 profile convergence toward asymptomatic patterns. These data indicate that quantitative ultrasound radiomics and whole-length T2 profiling are feasible imaging biomarkers that capture PRP-induced tendon remodelling beyond qualitative imaging and may help tailor PRP protocols to specific tendon phenotypes. Full article

Background: Intracavernosal platelet-rich plasma (PRP) is increasingly used for erectile dysfunction (ED), despite the absence of standardized biological characterization and clear dose definitions. This systematic review evaluates the clinical efficacy of PRP in ED while integrating emerging immune-centric mechanistic evidence. Methods: Following PRISMA 2020 guidelines, randomized controlled trials (RCTs) and prospective studies (2020–2025) investigating intracavernosal PRP in adult men with ED were identified across major databases. Validated outcomes included International Index of Erectile Function (IIEF-EF or IIEF-5), Erection Hardness Score (EHS), Sexual Encounter Profile (SEP), and penile Doppler parameters. Preclinical data were narratively integrated to contextualize biological plausibility. Results: Fourteen clinical studies met the inclusion criteria (six RCTs, eight prospective cohorts). Across most studies, PRP produced clinically relevant within-patient improvements, and three RCTs demonstrated minimal clinically important difference (MCID) responder rates compared with placebo. However, other trials showed comparable improvements in placebo arms, underscoring substantial contextual effects. Safety was consistently favourable. Marked heterogeneity in blood volume processed (10–120 mL), injected PRP volume (3–12 mL), preparation systems, and session protocols precluded cross-study comparability. Critically, no study reported platelet dose, leukocyte subsets, peripheral blood mononuclear cell (PBMNC) content, or red blood cell contamination. Preclinical models consistently demonstrate that PRP restores erectile function through angiogenic, neuroprotective, and immunomodulatory mechanisms, including CXCL5-mediated monocyte recruitment and M1-to-M2 macrophage polarization. Conclusions: Intracavernosal PRP shows promising short-term efficacy signals and a favourable short-term safety profile in mild-to-moderate vasculogenic ED, but current evidence is limited by profound biological and methodological heterogeneity. PRP should be reconsidered as an immune-regenerative intervention requiring dose-defined, composition-defined, and mechanistically informed randomized trials. Interpretation of these findings is constrained by the absence of formal risk-of-bias assessment for non-randomized studies, substantial clinical and biological heterogeneity across trials, and the lack of standardized PRP characterization. Full article

A novel ocellatin-P1 isoform was isolated and purified from the skin secretion of the pepper frog Leptodactylus labyrinthicus. The crude skin secretion was fractionated by reversed-phase high-performance liquid chromatography (RP-HPLC) using a C₈ column and the peptide was subsequently purified on a reversed-phase C₁₈ column. Ocellatin-LB3 (as this isoform was named) was chemically sequenced by Edman degradation. This peptide is a linear C-terminally amidated molecule composed of 25 amino acid residues: ¹GLLDTLKGAAKNVVGGLASKVMEKL²⁵-NH₂. Synthetic ocellatin-LB3 was active against Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa and inactive against Staphylococcus aureus, Staphylococcus epidermidis and Enterococcus faecalis. In addition, the peptide reduced the Trypanosoma cruzi infection in L6 cells. At 64 µM it did not reduce erythrocytes or polymorphonuclear leukocytes, but did reduce mononuclear leukocyte counts, as detected by flow cytometry. No hemolytic activity was observed in red blood cells even at 128 µM. The peptide exhibited limited antiproliferative activity against MCF-7 and HeLa tumor cells at 128 µM. Pre-incubation with the peptide appeared to enhance N-formylmethionine-leucyl-phenylalanine (fMLP)-induced migration, indicating a potential additive or synergistic effect on human neutrophils. The three-dimensional structure of ocellatin-LB3 was investigated by circular dichroism (CD) and nuclear magnetic resonance (NMR). In the presence of sodium dodecyl sulfate (SDS), the peptide adopts an α-helical structure spanning residues Leu³–Lys²⁴, which remains largely preserved even at 95 °C. NMR Hydrogen/Deuterium (H/D) exchange experiments suggest that ocellatin-LB3 adopts a preferential orientation when interacting with SDS micelles. Based on the similarity among ocellatins, and on the physicochemical and structural properties of this peptide, a possible membrane-mediated mode of action is proposed, although this remains to be experimentally validated. Full article

Integrins and other cell adhesion molecules play a critical role in the migration and homing of leukocytes. This study investigates whether metastatic tumor cells can exploit leukocyte-like rolling and arrest mechanisms during early vascular steps of metastatic dissemination. B16 melanoma cell adhesion to activated bEnd.3 endothelial monolayers or immobilized VCAM-1 were analyzed under defined shear flow using a parallel-plate chamber. Function-blocking antibodies, divalent cation modulation, pertussis toxin, and low-temperature conditions were used as classical controls. B16-BL6 melanoma cells exhibited robust VLA-4-dependent rolling and arrest on activated endothelial monolayers and on immobilized VCAM-1 under physiological shear stresses (0.7–2 dyn/cm²), independent of chemokine-related Gαi signaling. These findings identify a chemokine-independent mechanism of VLA-4-mediated vascular capture by melanoma cells under shear flow, providing a potential mechanistic basis for early steps in metastatic dissemination. Full article

Background and Objectives: Tamoxifen, a cornerstone selective estrogen receptor modulator in breast cancer therapy, is increasingly recognized to be associated with retinal toxicity characterized by mitochondrial dysfunction, oxidative stress, lipid peroxidation, and oxidative DNA injury. By targeting mitochondrial bioenergetic dysfunction and redox disequilibrium, adenosine triphosphate (ATP) emerges as a biologically plausible candidate for retinal cytoprotection. This study aimed to evaluate the protective effect of ATP against tamoxifen-induced retinal toxicity in a rat model. Materials and Methods: Twenty-four male albino Wistar rats were randomly assigned to four groups: healthy control (HG), ATP-alone (ATPG, 4 mg/kg, intraperitoneally), tamoxifen-alone (TAMG, 5 mg/kg, orally), and tamoxifen plus ATP-treated (ATAG; ATP, 4 mg/kg, intraperitoneally; tamoxifen, 5 mg/kg, orally). Treatments were administered once daily for 30 days. Oxidative stress markers (malondialdehyde, total glutathione), antioxidant enzyme activities (superoxide dismutase, catalase), and oxidative DNA damage (8-hydroxy-2′-deoxyguanosine) were assessed in ocular tissues. Retinal histopathological evaluation included hematoxylin–eosin staining with semiquantitative assessment of edema, vascular congestion, polymorphonuclear leukocyte infiltration, and cytoplasmic vacuolization, together with quantitative measurements of retinal layer thicknesses and ganglion cell layer (GCL) cell counts. Results: Tamoxifen administration induced marked oxidative stress, antioxidant depletion, and increased oxidative DNA damage in ocular tissues, accompanied by significant thickening of retinal layers, reduced GCL cell counts, and pronounced disruption of retinal architecture. By comparison, ATP co-administration significantly suppressed lipid peroxidation and restored antioxidant defenses, thereby reducing oxidative DNA damage and preserving retinal structural integrity, as reflected by partial normalization of retinal layer thicknesses, preservation of GCL cell counts, and the presence of only mild residual edema. Conclusions: These findings indicate that ATP attenuates tamoxifen-induced retinal toxicity by supporting mitochondrial energy balance and redox homeostasis. Accordingly, ATP administration may represent a promising protective approach for reducing retinal injury associated with long-term tamoxifen therapy. Full article

Background/Objective: This study evaluated the analgesic and anti-inflammatory effects of ambroxol in an experimental model of endometriosis. Methods: Ambroxol was administered at doses of 10, 50, and 100 mg/kg (Abx 10, Abx 50, and Abx 100) by daily gavage for 21 days. A medroxyprogesterone-treated group (Progesterone) was included as a positive control. Pain was assessed using validated behavioral tests, including the Rat Grimace Scale (RGS), the von Frey test, and the rotarod test. Additionally, interleukin-1β (IL-1β) levels and total leukocyte counts were measured in peritoneal lavage fluid. The volumetric reduction in endometriotic implants was evaluated by ultrasonography, while histopathological analysis characterized inflammatory infiltrate and epithelial layer integrity using a standardized scoring system. Results: All ambroxol doses reduced spontaneous pain manifestations throughout the treatment. The mechanical withdrawal threshold significantly increased from the second week onward, and motor quality improved over the course of the study. A significant reduction in IL-1β levels compared with the negative control (Control(−)) was observed on day 21. Abx 50 and Abx 100 significantly reduced implant volumes (48.2% and 56.2%, respectively) and promoted marked disruption of the endometriotic epithelial layer. When compared with Progesterone, higher doses—particularly 100 mg/kg—demonstrated comparable efficacy. Conclusions: Taken together, these pleiotropic effects support the potential for drug repurposing in endometriosis. Full article

Diabetes mellitus (DM) is a chronic metabolic disorder characterized by persistent low-grade inflammation and a markedly increased risk of cardiovascular diseases (CVD). Leukocytes play an important role not only in host defense but are also increasingly recognized as key contributors to haemostasis and thromboinflammatory processes. In DM, chronic hyperglycaemia, oxidative stress and inflammation lead to leukocyte dysfunction, including enhanced cell activation, impaired mitochondrial function, and dysregulated interactions with platelets and endothelial cells. These alterations promote the thromboinflammatory state that contributes to vascular complications in DM. Thus, the modulation of oxidative stress and inflammation are important. Polyphenols are a class of plant secondary metabolites widely studied for their antioxidant and anti-inflammatory properties. This review comprehensively explores leukocyte dysfunction in DM, its contribution to thromboinflammation, and the mechanistic role of polyphenols in modulating these processes. The evidence presented suggests that polyphenols may contribute to the modulation of thromboinflammatory pathways. Further research in this area is required to enhance our understanding of thromboinflammation in DM and to translate these findings into effective adjunctive strategies, alongside standard pharmacological therapies to reduce CVD risk in individuals with DM. Full article

Feed nutrition and rise in antibiotic resistance are growing global challenges in aquaculture, with Aeromonas hydrophila causing significant losses in the carp family. This 60-day study evaluated the potential of combining herbal seed extract (Achyranthes aspera and Ricinus communis) with inactivated vaccine (A. hydrophila) to enhance growth and immunity in Labeo rohita. A total of 540 fish were randomly assigned in six groups (T0-untreated control, T1-A. aspera seed extract (ASE), T2-R. communis seed extract (RSE), T3-vaccinated control, T4-vaccine plus ASE, T5-vaccine plus RSE). Results revealed that herbal–vaccine combinations, particularly T4, showed highest growth performance (p < 0.05). Furthermore, this group showed improved metabolic profiles, indicated by reduced serum cholesterol, triglycerides, and glucose, along with significantly elevated albumin and globulin concentrations. In terms of immune response, neutrophil counts were significantly higher in T4 and T5. Crucially, following a challenge with A. hydrophila, survival rates were higher in T4:90% and T5:85% compared with positive control’s meager 20% survival. Post-challenge hematology confirmed that groups T4 and T5 maintained an enhanced immune status. These findings suggest that combining medicinal plants extract with vaccine effectively enhances growth, immunity, and disease resistance in L. rohita, presenting an environment friendly alternative to traditional antibiotics in aquaculture. Full article

Invasive candidiasis is a fungal infection characterized by a high mortality rate. Carcinoembryonic antigen-related cell adhesion molecule (CEACAM) family receptors play a crucial role in regulating innate responses of both leukocytes and epithelia. Human CEACAM3, CEACAM5 and CEACAM6 receptors recognize Candida albicans and are expressed in transgenic CEABAC10 mice. In a murine C. albicans infection model, CEABAC10 mice exhibited a shortened survival period attributed to an early cytokine storm, an exacerbated acute phase response, and heightened systemic inflammation compared to their wild-type littermates. The livers and kidneys of CEABAC10 mice displayed intensified purulent necrotizing inflammation, accompanied by increased infiltration of neutrophils and macrophages. Our in vivo and in vitro data indicated that the expression of CEACAM6 on monocytes of CEABAC10 mice caused the elevated cytokine levels and the subsequent exacerbation of the acute phase response upon C. albicans infection, resulting in decreased survival. Full article

Introduction: Periprosthetic joint infections (PJI) are among the most serious and costly complications in orthopedic surgery, significantly affecting patient prognosis and healthcare systems. Despite rigorous aseptic measures, intraoperative contamination of sterile fields, instruments, and air remains a persistent source of potential infection. This study investigates the relationship between the microbial contamination of sterile fields during arthroplasty and postoperative inflammatory markers, with the objective of determining whether the contamination of sterile fields correlates with the presence of periprosthetic joint infection (PJI). Material and Methods: This prospective observational study included 33 patients undergoing total hip or knee arthroplasty in a university-affiliated orthopedic center. Intraoperative samples were collected from sterile fields and equipment to detect microbial contamination, while postoperative monitoring involved the C-reactive protein (CRP); erythrocyte sedimentation rate (ESR); leukocyte count; temperature; and wound assessment on days 1, 3 and 7. All patients received 48 h of prophylactic cefuroxime. Statistical analysis was conducted using the International Business Machines (IBM) Statistical Product and Service Solutions (SPSS) software for Windows, version 30.0 (IBM Corporation, Armonk, New York, United States of America) with significance set at p ≤ 0.05. Results: Postoperative inflammatory markers showed distinct patterns depending on the isolated microorganism, with Proteus vulgaris and Staphylococcus hominis ssp. consistently associated with higher CRP and leukocyte values, indicating a more intense systemic response. Staphylococcus epidermidis was the most frequently isolated species but showed moderate inflammatory profiles, suggesting its potential role in subclinical colonization. A strong correlation between CRP on day 3 and leukocyte count (r = 0.81) confirms their combined utility in the early detection of infectious complications, while ESR appeared less dynamic and more complementary in nature. Discussion: This study highlights the significant role of intraoperative contamination and microbial virulence in shaping the postoperative inflammatory response after arthroplasty. Elevated CRP and leukocyte levels, particularly on day 3, were closely associated with pathogens known for biofilm formation and chronic infections. Despite prophylactic antibiotic use, confirmed infections still occurred, suggesting the need to reassess current protocols and enhance intraoperative contamination control. Conclusions: Pathogen presence in sterile fields during arthroplasty increases the risk of periprosthetic joint infections, often without early clinical symptoms. CRP on day 3 and leukocyte count were the most reliable early indicators of persistent inflammation. Full article

(1) Objective. To conduct a comparative bioinformatics analysis of the transcriptomic profiles of peri-implantitis and periodontitis to identify common and specific molecular signatures underlying their pathogenesis, as well as molecular parallels with atherosclerosis. (2) Methods: We used datasets from the Gene Expression Omnibus (GEO) database: dataset GSE223924 (30 gingival tissue samples from patients with peri-implantitis, periodontitis, and healthy subjects) and GSE100927 (atherosclerotic and control tissue; n = 104). Differentially expressed genes (DEGs) were identified based on the criteria: |logFC| > 1 and FDR < 0.05. To quantitatively assess the relative abundance of immune cells, we used the xCell deconvolution algorithm. (3) Results: In the peri-implantitis group, 3669 DEGs with upregulated expression and 3106 with downregulated expression were identified; in the periodontitis group, 1968 and 1250 DEGs, respectively. Functional analysis of the upregulated DEGs revealed activation of inflammatory processes, cell adhesion, and angiogenesis in both diseases. Key differences lay in the activation of adaptive immune mechanisms in peri-implantitis (enrichment of the “graft rejection” and “T-cell receptor signaling”) and innate immunity in periodontitis (enrichment of the “lipopolysaccharide response” and “Toll-like receptors (TLR) signaling” pathways). Analysis of downregulated DEGs revealed more profound disruptions in cytoskeletal organization and epithelial differentiation in periodontitis, as well as suppression of xenobiotic and lipid metabolism in both diseases. xCell deconvolution confirmed a significant increase in B cells, neutrophils, monocytes, M1 macrophages, and dendritic cells in peri-implantitis, and also revealed a trend toward an increase in these cells in periodontitis (p > 0.05), which is consistent with the activation of TLR signaling. In periodontitis, a significant increase in M2 macrophages and a decrease in Th1 cells were observed. Comparison with atherosclerosis revealed 272 common DEGs with peri-implantitis and 173 common DEGs with periodontitis. Functional analysis of the common genes confirmed their role in leukocyte transendothelial migration, cytokine production, and the “Lipids and Atherosclerosis” pathway. (4) Conclusions: Functional analysis and immune deconvolution consistently demonstrate that peri-implantitis is characterized by statistically significant activation of both adaptive and innate immunity, whereas in periodontitis, the activation of innate immunity manifests primarily at the level of signaling pathways. The significant overlap found between the transcriptional profiles of both diseases and atherosclerosis may indicate the presence of common pathogenetic links. Full article