Signal Transduction Inhibitors Research Articles

Photobiomodulation with 630-nm LED Inhibits M1 Macrophage Polarization via STAT1 Pathway Against Sepsis-Induced Acute Lung Injury.

Background: Sepsis-induced acute lung injury (ALI) is a clinical syndrome characterized by excessive uncontrolled inflammation. Photobiomodulation such as light-emitting diode (LED) irradiation has been used to attenuate inflammatory disease. Objective: The protective effect of 630 nm LED irradiation on sepsis-induced ALI remains unknown. The purpose of this study was to investigate the role of 630 nm LED irradiation in sepsis-induced ALI and its underlying mechanism. Methods and results: C57BL/6 mice were performed cecal ligation and puncture (CLP) for 12 h to generate experimental sepsis models. Histopathology analysis showed that alveolar injury, inflammatory cells infiltration, and hemorrhage were suppressed in CLP mice after 630 nm LED irradiation. The ratio of wet/dry weigh of lung tissue was significantly inhibited by irradiation. The number of leukocytes was reduced in bronchoalveolar lavage fluid. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) results and enzyme-linked immunosorbent assay showed that 630 nm LED irradiation significantly inhibited the mRNA and protein levels of M1 macrophage-related genes in the lung of CLP-induced septic mice. Meanwhile, LED irradiation significantly inhibited signal transducer and activator of transcription 1 (STAT1) phosphorylation in the lung of septic mice. In vitro experiments showed that 630 nm LED irradiation significantly inhibited M1 genes mRNA and protein expression in THP-1-derived M1 macrophages without affecting the cell viability. LED irradiation also significantly inhibited the level of STAT1 phosphorylation in THP-1-derived M1 macrophages. Conclusions: We concluded that 630 nm LED is promising as a treatment against ALI through inhibiting M1 macrophage polarization, which is associated with the downregulation of STAT1 phosphorylation.

Development and Verification of a Novel Three-Dimensional Aqueous Outflow Model for High-Throughput Drug Screening.

Distal outflow bleb-forming procedures in ophthalmic surgery expose subconjunctival tissue to inflammatory cytokines present in the aqueous humor, resulting in impaired outflow and, consequently, increased intraocular pressure. Clinically, this manifests as an increased risk of surgical failure often necessitating revision. This study (1) introduces a novel high-throughput screening platform for testing potential anti-fibrotic compounds and (2) assesses the clinical viability of modulating the transforming growth factor beta-SMAD2/3 pathway as a key contributor to post-operative outflow reduction, using the signal transduction inhibitor verteporfin. Human Tenon's capsule fibroblasts (HTCFs) were cultured within a 3D collagen matrix in a microfluidic system modelling aqueous humor drainage. The perfusate was augmented with transforming growth factor beta 1 (TGFβ1), and afferent pressure to the tissue-mimetic was continuously monitored to detect treatment-related pressure elevations. Co-treatment with verteporfin was employed to evaluate its capacity to counteract TGFβ1 induced pressure changes. Immunofluorescent studies were conducted on the tissue-mimetic to corroborate the pressure data with cellular changes. Introduction of TGFβ1 induced treatment-related afferent pressure increase in the tissue-mimetic. HTCFs treated with TGFβ1 displayed visibly enlarged cytoskeletons and stress fiber formation, consistent with myofibroblast transformation. Importantly, verteporfin effectively mitigated these changes, reducing both afferent pressure increases and cytoskeletal alterations. In summary, this study models the pathological filtration bleb response to TGFβ1, while demonstrating verteporfin's effectiveness in ameliorating both functional and cellular changes caused by TGFβ1. These demonstrate modulation of the aforementioned pathway as a potential avenue for addressing post-operative changes and reductions in filtration bleb outflow capacity. Furthermore, the establishment of a high-throughput screening platform offers a valuable pre-animal testing tool for investigating potential compounds to facilitate surgical wound healing.

Asymmetric Synthesis of Saturated and Unsaturated Hydroxy Fatty Acids (HFAs) and Study of Their Antiproliferative Activity.

Hydroxy fatty acids (HFAs) constitute a class of lipids, distinguished by the presence of a hydroxyl on a long aliphatic chain. This study aims to expand our insights into HFA bioactivities, while also introducing new methods for asymmetrically synthesizing unsaturated and saturated HFAs. Simultaneously, a procedure previously established by us was adapted to generate new HFA regioisomers. An organocatalytic step was employed for the synthesis of chiral terminal epoxides, which either by alkynylation or by Grignard reagents resulted in unsaturated or saturated chiral secondary alcohols and, ultimately, HFAs. 7-(S)-Hydroxyoleic acid (7SHOA), 7-(S)-hydroxypalmitoleic acid (7SHPOA) and 7-(R)- and (S)-hydroxymargaric acids (7HMAs) were synthesized for the first time and, together with regioisomers of (R)- and (S)-hydroxypalmitic acids (HPAs) and hydroxystearic acids (HSAs), whose biological activity has not been tested so far, were studied for their antiproliferative activities. The unsaturation of the long chain, as well as an odd-numbered (C17) fatty acid chain, led to reduced activity, while the new 6-(S)-HPA regioisomer was identified as exhibiting potent antiproliferative activity in A549 cells. 6SHPA induced acetylation of histone 3 in A549 cells, without affecting acetylated α-tubulin levels, suggesting the selective inhibition of histone deacetylase (HDAC) class I enzymes, and was found to inhibit signal transducer and activator of transcription 3 (STAT3) expression.

Hormone Metabolites and Herbal Bioactive Agents: Potential Drug Candidates for the Luminal A Breast Cancer subtype

Background: Hormone receptor positive, human epidermal growth factor receptor negative Luminal A breast cancer subtype responds to targeted endocrine therapy, signal transduction inhibitors and cyclin dependent kinase inhibitors. Estrogen and progesterone receptor mediated signal transduction involves receptor-DNA binding and transcriptional activation of downstream target genes. In addition to hormone receptor signaling, cellular metabolism of estradiol and progesterone exhibit distinct roles in cancer growth modulation. Targeted therapy is associated with systemic toxicity, therapy resistance and emergence of chemo-resistant cancer initiating stem cells. These limitations emphasize identification of testable drug candidates for therapy resistant breast cancer. Cellular metabolism of ovarian steroid hormones generates oxidative metabolites with distinct growth modulating effects. Anti-proliferative metabolites may represent potential drug candidates. Objectives: The objectives of the present review are to provide i) Systematic discussion of published evidence relevant to the role of ovarian steroid hormone metabolism in growth modulatory effects on cancer progression, ii) Evidence for applicability of Luminal A breast cancer and drug-resistant cancer stem cell models to identify mechanistic leads for efficacy of anti-proliferative hormone metabolites, and iii) Future research directions for clinical translatability of patient derived preclinical data. Conclusions: Collectively, present evidence validates experimental approaches to identify hormone metabolites as potential drug candidates for therapy-resistant breast cancer. .

Sodium dichloroacetate improves migration ability by suppressing LPS-induced inflammation in HTR-8/SVneo cells via the TLR4/NF-κB pathway.

Inadequate cytotrophoblast migration and invasion are speculated to result in preeclampsia, which is a pro-inflammatory condition. Sodium dichloroacetate (DCA) exerts anti-inflammatory actions. Thus,we sought to investigate the effect of DCA on the migration function of the lipopolysaccharide (LPS)-stimulated human-trophoblast-derived cell line (HTR-8/SVneo). HTR-8/SVneo cells were treated with LPS to suppress cell migration. Cell migration was examined by both scratch wound healing assay and transwell migration assay. Western blotting was used to analyze the expression levels of toll-like receptor-4 (TLR4), nuclear factor-κB (NF-κB), TNF-α, IL-1β, and IL-6 in the cells. DCA reversed LPS-induced inhibition of migration in HTR-8/SVneo cells. Furthermore, DCA significantly suppressed LPS-induced activation of TLR4, phosphorylation of NF-κB (p65), translocation of p65 into the nucleus, and the production of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6). Treatment with inhibitors of TLR4 signal transduction (CLI095 or MD2-TLR-4-IN-1) reduced LPS-induced overexpression of pro-inflammatory cytokines, and a synergistic effect was found between TLR4 inhibitors and DCA in HTR-8/SVneo cells. DCA improved trophoblast cell migration function by suppressing LPS-induced inflammation, at least in part, via the TLR4/NF-κB signaling pathway. This result indicates that DCA might be a potential therapeutic candidate for human pregnancy-related complications associated with trophoblast disorder.

Endogenous SIRT6 in platelets negatively regulates platelet activation and thrombosis.

Thromboembolism resulting from platelet dysfunction constitutes a significant contributor to the development of cardiovascular disease. Sirtuin 6 (SIRT6), an essential NAD+-dependent enzyme, has been linked to arterial thrombosis when absent in endothelial cells. In the present study, we have confirmed the presence of SIRT6 protein in anucleated platelets. However, the precise regulatory role of platelet endogenous SIRT6 in platelet activation and thrombotic processes has remained uncertain. Herein, we present compelling evidence demonstrating that platelets isolated from SIRT6-knockout mice (SIRT6-/-) exhibit a notable augmentation in thrombin-induced platelet activation, aggregation, and clot retraction. In contrast, activation of SIRT6 through specific agonist treatment (UBCS039) confers a pronounced protective effect on platelet activation and arterial thrombosis. Moreover, in platelet adoptive transfer experiments between wild-type (WT) and SIRT6-/- mice, the loss of SIRT6 in platelets significantly prolongs the mean thrombus occlusion time in a FeCl3-induced arterial thrombosis mouse model. Mechanistically, we have identified that SIRT6 deficiency in platelets leads to the enhanced expression and release of proprotein convertase subtilisin/kexin type 9 (PCSK9), subsequently activating the platelet activation-associated mitogen-activated protein kinase (MAPK) signaling pathway. These findings collectively unveil a novel protective role of platelet endogenous SIRT6 in platelet activation and thrombosis. This protective effect is, at least in part, attributed to the inhibition of platelet PCSK9 secretion and mitogen-activated protein kinase signaling transduction. Our study provides valuable insights into the intricate interplay between SIRT6 and platelet function, shedding light on potential therapeutic avenues for managing thrombotic disorders.

Identification of genes associated with gall bladder cell carcinogenesis: Implications in targeted therapy of gall bladder cancer.

Gall bladder cancer (GBC) is becoming a very devastating form of hepatobiliary cancer in India. Every year new cases of GBC are quite high in India. Despite recent advanced multimodality treatment options, the survival of GBC patients is very low. If the disease is diagnosed at the advanced stage (with local nodal metastasis or distant metastasis) or surgical resection is inoperable, the prognosis of those patients is very poor. So, perspectives of targeted therapy are being taken. Targeted therapy includes hormone therapy, proteasome inhibitors, signal transduction and apoptosis inhibitors, angiogenesis inhibitors, and immunotherapeutic agents. One such signal transduction inhibitor is the specific short interfering RNA (siRNA) or short hairpin RNA (shRNA). For developing siRNA-mediated therapy shRNA, although several preclinical studies to evaluate the efficacy of these key molecules have been performed using gall bladder cells, many more clinical trials are required. To date, many such genes have been identified. This review will discuss the recently identified genes associated with GBC and those that have implications in its treatment by siRNA or shRNA.

Epidermal growth factor potentiates EGFR(Y992/1173)-mediated therapeutic response of triple negative breast cancer cells to cold atmospheric plasma-activated medium

Cold atmospheric plasma (CAP) holds promise as a cancer-specific treatment that selectively kills various types of malignant cells. We used CAP-activated media (PAM) to utilize a range of the generated short- and long-lived reactive species. Specific antibodies, small molecule inhibitors and CRISPR/Cas9 gene-editing approaches showed an essential role for receptor tyrosine kinases, especially epidermal growth factor (EGF) receptor, in mediating triple negative breast cancer (TNBC) cell responses to PAM. EGF also dramatically enhanced the sensitivity and specificity of PAM against TNBC cells. Site-specific phospho-EGFR analysis, signal transduction inhibitors and reconstitution of EGFR-depleted cells with EGFR-mutants confirmed the role of phospho-tyrosines 992/1173 and phospholipase C gamma signaling in up-regulating levels of reactive oxygen species above the apoptotic threshold. EGF-triggered EGFR activation enhanced the sensitivity and selectivity of PAM effects on TNBC cells. The proposed approach based on the synergy of CAP and EGFR-targeted therapy may provide new opportunities to improve the clinical management of TNBC.

A First-in-Human Phase 1 Study of ABBV-525, a Small-Molecule MALT1 Inhibitor, in Patients with Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma

Background and Significance Many B-cell malignancies are characterized by chronic activation of the B-cell receptor (BCR) and nuclear factor kappa B (NF-κB) signaling pathways. In many non-Hodgkin lymphoma (NHL) subtypes, constitutive NF-κB activation results from genetic mutations and/or auto-antigen stimulation of the BCR pathway. While agents targeting the BCR pathway are effective treatments for many B-cell malignancies, patients (pts) often have progressive disease due to acquired resistance to BCR-targeted agents. Thus, there is an unmet medical need for novel therapeutic targets and treatment approaches. The mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is an enzymatic and scaffolding node in the BCR pathway and a key mediator of the BCR/NF-κB signal transduction pathway. Its action is downstream, or in some instances parallel to, resistance mechanisms to existing NHL therapies, including BTK C481S and PLCG2 mutations, which are known acquired mechanisms of resistance to covalent Bruton's tyrosine kinase (BTK) inhibitors in pts with chronic lymphocytic leukemia (CLL). MALT1 inhibition represents a novel therapeutic approach for malignancies with chronic activation of NF-κB, including those pts with acquired resistance to upstream targets. ABBV-MALT1 is a small-molecule, tool compound, MALT1 inhibitor. Preclinical studies of ABBV-MALT1 have demonstrated potent activity against MALT1-relevant biomarkers, including inhibition of BCR pathway signal transduction and reduced NF-κB gene activation in non-germinal center B-cell diffuse large B-cell lymphoma (non-GCB DLBCL) cell lines. ABBV-MALT1 has also shown activity in a range of preclinical lymphoma models as both monotherapy and in combination with venetoclax, including robust antitumor activity in malignant B-cell models that are resistant to BTK inhibitors. This phase 1 study evaluates the clinical candidate MALT1 inhibitor ABBV-525 as monotherapy in pts with relapsed or refractory (R/R) B-cell NHL. Study Design and Methods This is a first-in-human, phase 1, open-label, multicenter study of single-agent ABBV-525 in pts with R/R B-cell NHL (NCT05618028). Eligibility criteria are listed in Table 1. The primary objectives are to evaluate safety, tolerability, and pharmacokinetics (PK) of ABBV-525 and to determine the recommended phase 2 dose (RP2D). The secondary objective is to assess the preliminary efficacy of ABBV-525 in subsets of pts with R/R B-cell NHL. Exploratory objectives include evaluating biomarkers predictive of response and pharmacodynamic biomarkers, including the effects of ABBV-525 on BCR pathway signal transduction and NF-κB gene activation. This is a 3-part study (Figure 1): dose escalation (part 1), dose optimization (part 2), and dose expansion (part 3). Part 1 aims to establish the maximum administered dose/maximum tolerated dose of ABBV-525 and is primarily guided by a Bayesian optimal interval design. Part 2 aims to identify the RP2D of ABBV-525. Part 3 will further characterize the safety profile of ABBV-525 at the RP2D. Approximately 150 pts are planned for enrollment, including those with various R/R mature B-cell lymphomas in part 1, pts with documented diagnosis of R/R CLL in part 2, and pts with documented diagnosis of non-GCB DLBCL in part 3. ABBV-525 is orally administered until disease progression, intolerable toxicity, or other study discontinuation criteria are met. Safety assessments include dose-limiting toxicities, adverse events (per National Cancer Institute Common Terminology Criteria for Adverse Events v5.0), clinical laboratory parameters, vital signs, and electrocardiogram variables. PK parameters, including maximum observed plasma concentration (C max), time to C max, and area under the concentration-time curve will be analyzed using noncompartmental methods. Efficacy will be assessed through response per disease-specific criteria (including International Workshop on Chronic Lymphocytic Leukemia, International Workshop on Waldenstrom's Macroglobulinemia, and Lugano classification). Duration of response will be evaluated by Kaplan-Meier estimates. Biomarker data will be analyzed as change from baseline and summarized for each scheduled postbaseline visit. Pts are being enrolled in 25 sites across the USA, Australia, Belgium, France, Germany, Israel, Spain, and UK. As of August 1, 2023, 2 pts had been treated.

MALT1 Protease Inhibition Overcomes BTK Inhibitor Resistance and Shows Synergistic Activity with Venetoclax in Models of B Cell Lymphoma and Leukemia

Background Specific B cell malignancies, including the aggressive non-germinal center B cell-like (GCB) subtype of diffuse large B cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL), are driven by constitutive activation of the transcription factor NF-kB. Chronic signaling resulting from mutations or antigen-induced activation of the B cell receptor (BCR) pathway drives NF-kB activity in these tumors resulting in sustained proliferation and survival pathways. Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) represents a key mediator of the BCR/NF-kB signal transduction pathway responsible for maintaining survival and driving proliferation of NF-kB-addicted B cell tumors by proteolytically cleaving NF-kB antagonists. Aims Pharmacological inhibition of MALT1 protease activity may provide an attractive treatment option for patients with these cancers. Further, as combination therapy is often required for the treatment of aggressive B cell malignancies, the identification of therapies that synergistically combine with MALT1 inhibitors could afford additional and promising treatment options. Methods A highly potent and orally bioavailable MALT1 protease inhibitor (ABBV-MALT1) was used to test the hypothesis that MALT1 inhibition will abrogate the proliferation of preclinical models of B cell malignancies in vitro and in vivo. Tumors treated with ABBV-MALT1 were subjected to transcriptomic and functional proteomic assays to elucidate molecular mechanisms of action and rational combination partners. Results ABBV-MALT1 potently inhibits MALT1 activity in vitro while showing high selectivity against a panel of proteases, kinases and other types of receptors and enzymes. Mechanistic studies reveal that ABBV-MALT1 effectively inhibits signal transduction of the BCR pathway and reduces NF-kB gene activation in non-GCB DLBCL cell lines resulting in cell cycle arrest and diminished viability. In vivo, oral administration of this compound demonstrates robust tumor growth inhibition in several models of B cell tumors, including non-GCB DLBCL models that are resistant to Bruton's tyrosine kinase (BTK) inhibitors. NF-kB target genes include the pro-survival family members BCL-XL and BCL2-A1, which aid in regulation of the intrinsic apoptosis pathway. As ABBV-MALT1-induced inhibition of the NF-kB pathway resulted in downregulation of these genes, we hypothesized that the associated tumor models would become increasingly dependent on the pro-survival family member BCL-2. To test this hypothesis, combination studies of ABBV-MALT1 and the selective BCL-2 inhibitor venetoclax were performed in both cell line and patient-derived xenograft models of DLBCL. Herein we show that concomitant administration of ABBV-MALT1 and venetoclax results in dramatic antitumor activity in all models tested in vivo. This efficacy also translates to primary patient CLL cells in vitro where the combination confers greater levels of apoptosis compared to either agent alone. Summary/Conclusion: ABBV-MALT1 demonstrates robust single agent anti-tumor activity in malignant B cell models that are resistant to BTK inhibitors. Moreover, combination of ABBV-MALT1 with the BCL-2 inhibitor venetoclax shows synergistic cell killing of B cell tumors in vitro and dramatic tumor regression in vivo. Together, these data indicate that MALT1 inhibition may overcome BTK inhibitor resistance and combine with venetoclax to effectively treat patients with DLBCL, CLL and other B cell malignancies. Disclosures All authors are employees of AbbVie. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication.

Effects of SU5416 on angiogenesis and the ERK-VEGF/MMP-9 pathway in rat endometriosis.

SU5416 is a small molecule vascular endothelial growth factor (VEGF) receptor signal transduction inhibitor, which can block the VEGF re-ceptor autophosphorylation and inhibit receptor tyrosine kinase signal trans-duction, thereby reducing VEGF activity. However, there are few reports about the correlation of SU5416 to the occurrence and angiogenesis in endometrio-sis. In this study, we observed the effects of VEGF receptor inhibitor SU5416 on angiogenesis in endometriosis in rats. Thirty femalespecific-pathogen-free Sprague-Dawley rats were randomly divided into sham operation group (SOG), model group (MG), and SU5416 group (n=10 for each group). In the SOG, only the uterus was cut and sutured, and endometriosis models were established in the MG and SU5416 group by autologous transplantation. The SU5416 group was injected with 15 mg/kg SU5416 intraperitoneally, and the SOG and MG were intraperitoneally injected with an equal volume of normal saline for 6 weeks. The volume of ectopic lesions was lower in the SU5416 group at 42 d postoperatively thanin the MG (p<0.05). The proportion of CD31-positive cells in the endometrial tissue of the SU5416 group was lower than that of the MG (p<0.05); angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), laminin-5γ2 (LN-5γ2) and phosphorylation of ERK (P-ERK), VEGF, matrix metalloproteinase (MMP)-2, and MMP-9 protein expressions were lower in the SU5416 groupthan in the MG (p<0.05).VEGFreceptor inhibitor SU5416 can inhibit endometrio-sis angiogenesis and reduce inflammatory response in rats, and its mechanism of action may be related to the down-regulation of the ERK-VEGF/MMP-9 path-way expression.

Overexpression of SlCRF6 in tomato inhibits leaf development and affects plant morphology

Cytokinin response factors (CRFs) are transcription factors (TFs) that are specific to plants and have diverse functions in plant growth and stress responses. However, the precise roles of CRFs in regulating tomato plant architecture and leaf development have not been comprehensively investigated. Here, we identified a novel CRF, SlCRF6, which is involved in the regulation of plant growth via the gibberellin (GA) signaling pathway. SlCRF6-overexpressing (SlCRF6-OE) plants displayed pleiotropic phenotypic changes, including reduced internode length and leaf size, which caused dwarfism in tomato plants. This dwarfism could be alleviated by application of exogenous GA3. Remarkably, quantitative real-time PCR (qRTPCR), a dual luciferase reporter assay and a yeast one-hybrid (Y1H) assay revealed that SlCRF6 promoted the expression of SlDELLA (a GA signal transduction inhibitor) in vivo. Furthermore, transgenic plants displayed variegated leaves and diminished chlorophyll content, resulting in decreased photosynthetic efficiency and less starch than in wild-type (WT) plants. The results of transient expression assays and Y1H assays indicated that SlCRF6 suppressed the expression of SlPHAN (leaf morphology-related gene). Collectively, these findings suggest that SlCRF6 plays a crucial role in regulating tomato plant morphology, leaf development, and the accumulation of photosynthetic products.

Novel (-)-arctigenin derivatives inhibit signal transducer and activator of transcription 3 phosphorylation and P-glycoprotein function resensitizing multidrug resistant cancer cells in vitro and in vivo

Multidrug resistance (MDR) is considered one of the significant chemotherapy failures of cancer patients and resulting in tumor recurrence and refractory cancer. The collateral sensitivity phenomenon is suggested as a potential alternative therapy for coring multidrug resistance in cancer. To achieve better effects and reduce toxicity, a polypharmacology strategy was applied. Arctigenin has been reported as a signal transducer and activator of transcription 3 (STAT3) inhibitor as an anticancer drug with low toxicity. However, the effective dosage of arctigenin was too high for re-sensitization in MDR cell lines. Therefore, we have designed and synthesized arctigenin derivatives and have evaluated their chemoreversal effects in KBvin and KB cells. The results conveyed that compounds 9, 10, and 12 displayed significant collateral sensitivity effects on MDR cancer cells, and the corresponding calculated RF values were 32, 174, and 133, respectively. In addition, compounds 9, 10, and 12 were identified to influence the activation of STAT3 and the function of P-glycoprotein in KBvin cells. Combining the active compounds (9, 10, and 12) with paclitaxel significantly inhibits MDR tumor growth in a zebrafish xenograft tumor model without toxicity. Thus, this study provided novel effective arctigenin derivatives and is considered a potential co-treatment with paclitaxel for treating MDR tumors.

Overlapping Neuroimmune Mechanisms and Therapeutic Targets in Neurodegenerative Disorders.

Many potential immune therapeutic targets are similarly affected in adult-onset neurodegenerative diseases, such as Alzheimer's (AD) disease, Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD), as well as in a seemingly distinct Niemann-Pick type C disease with primarily juvenile onset. This strongly argues for an overlap in pathogenic mechanisms. The commonly researched immune targets include various immune cell subsets, such as microglia, peripheral macrophages, and regulatory T cells (Tregs); the complement system; and other soluble factors. In this review, we compare these neurodegenerative diseases from a clinical point of view and highlight common pathways and mechanisms of protein aggregation, neurodegeneration, and/or neuroinflammation that could potentially lead to shared treatment strategies for overlapping immune dysfunctions in these diseases. These approaches include but are not limited to immunisation, complement cascade blockade, microbiome regulation, inhibition of signal transduction, Treg boosting, and stem cell transplantation.

Hippophae rhamnoides reverses decreased CYP2D6 expression in rats with BCG-induced liver injury

In this study, we investigated the effect of Hippophae rhamnoides L. (HRP) on the activity of CYP2D6 via the CAMP/PKA/NF-κB pathway in rats with Bacille Calmette–Guerin (BCG)-induced immunological liver injury. BCG (125 mg/kg) was injected to establish the rat model of liver injury. HRP was administered intragastrically for one week as the intervention drug. Proteomics techniques were used to analyze protein expression levels, obtaining a comprehensive understanding of the liver injury process. ELISA or western blotting was used to detect specific protein levels. Dextromethorphan was detected using high-performance liquid chromatography to reflect the metabolic activity of CYP2D6. BCG downregulated the expression of CYP2D6, cAMP, PKA, IκB, and P-CREB and upregulated that of NF-κB, IL-1β, TNF-α, and CREB in the liver; HRP administration reversed these effects. Therefore, HRP may restore the metabolic function of the liver by reversing the downregulation of CYP2D6 through inhibition of NF-κB signal transduction and regulation of the cAMP/PKA/CREB/CYP2D6 pathway. These findings highlight the role of HRP as an alternative clinical drug for treating hepatitis B and other immune-related liver diseases.

The effects of berteroin on inflammatory mediators and antioxidant enzymes expression in human periodontal ligament cells.

Berteroin is a bioactive substance classified as an isothiocyanate found in cruciferous vegetables such as cabbage, arugula, and salad leaves. In this study, we aimed to determine whether berteroin exerts anti-inflammatory effects on human periodontal ligament cells (HPDLCs), a resident cells of periodontal tissue. Berteroin suppressed interleukin (IL)-1β or tumor necrosis factor (TNF)-α-induced chemokines (C-C motif chemokine ligand (CCL)2, CCL20, C-X-C motif chemokine ligand (CXCL)10, IL-8, and IL-6) production and intercellular adhesion molecule (ICAM)-1 expression in HPDLCs. In addition, berteroin inhibited phosphorylation of IκB kinase (IKK)- α/ β, nuclear factor (NF)- κB p65, and IκB- α and degradation of IκB- α in the NF-κB pathway induced by IL-1 β or TNF- α stimulation. Moreover, berteroin could inhibit signal transducer and activator of transcription (STAT)3 phosphorylation in TNF- α -stimulated HPDLC. Furthermore, berteroin increased the expression of the antioxidant enzymes, heme oxygenase (HO)-1 and NAD(P)H quinone dehydrogenase (NQO)1, in IL-1 β or TNF- α -stimulated HPDLCs. These results suggest that berteroin may decrease the production of inflammatory mediators in HPDLCs by suppressing the NF-κB pathway, and may also decrease the local reactive oxygen species (ROS) production in periodontal lesions by increasing the production of antioxidant enzymes.

A redox-responsive nanosystem to suppress chemoresistant lung cancer through targeting STAT3

Cancer stem cells (CSCs) have been demonstrated to be involved in tumor initiation and relapse, and the presence of CSCs in the tumor tissue often leads to therapeutic failure. BBI608 has been identified to eliminate CSCs by inhibiting signal transducer and activator of transcription 3 (STAT3). In this study, we confirm that BBI608 can efficiently suppress the proliferation and migration of non-small cell lung cancer (NSCLC) cells, and specifically kill the stemness-high population in chemoresistant NSCLC cells. To improve its bioavailability and tumor accumulation, BBI608 is successfully encapsulated into redox-responsive PEGylated branched N-(2-hydroxypropyl) methacrylamide (HPMA)-deoxy cholic acid (DA) polymeric nanoparticles (BBI608-SS-NPs). The BBI608-SS-NPs can release the drug in response to high concentrations of intracellular glutathione, and exhibit cytotoxicity against lung cancer cells and CSCs comparable to the free drug BBI608. Furthermore, the BBI608-SS-NPs preferentially accumulate in tumor sites, resulting in a superior anti-tumor efficacy in both cisplatin-resistant cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models of NSCLC. Mechanistic studies demonstrate that BBI608-SS-NPs not only directly inhibit the downstream genes of the STAT3 pathway, but also indirectly inhibit the Wnt pathway. Overall, this stimuli-responsive polymeric nanoformulation of BBI608 shows great potential in the treatment of chemoresistant NSCLC by targeting CSCs.

Top advances of the year: Myeloproliferative neoplasms.

The rapid pace of drug development in hematology has led to multiple approvals for myelofibrosis (MF) and polycythemia vera (PV) in recent years. Moreover, there are many innovative agents and combinations being explored for myeloproliferative neoplasms (MPNs). In the past year, there have been several advances in MF, PV, and essential thrombocythemia. In MF, investigational approaches are focusing on strategies to optimize inhibition of signal transduction (including JAK inhibition), modify epigenetics, enhance apoptosis, target DNA replication, transform host immunity, and/or alter the tumor microenvironment. In PV, ropeginterferon alfa-2b has been introduced to the market in the United States, and data continue to accumulate to support the safety and efficacy of this treatment. Hepcidin mimesis is also emerging as a novel way to treat erythrocytosis. In essential thrombocythemia, ropeginterferon alfa-2b is being evaluated, as are therapies to modify epigenetics and inhibit CALR. The enhanced focus on MPNs brings hope that our field can improve morbidity and mortality in this group of diseases.

Stimulation of Hemolysis and Eryptosis by α-Mangostin through Rac1 GTPase and Oxidative Injury in Human Red Blood Cells.

Chemotherapy-related anemia is prevalent in up to 75% of patients, which may arise due to hemolysis and eryptosis. Alpha-mangostin (α-MG) is a polyphenolic xanthonoid found in the mangosteen tree (Garcinia mangostana) whose antitumor medicinal properties are well-established. Nevertheless, the potential toxic effects of α-MG on red blood cells (RBCs) have, as of yet, not been as well studied. RBCs were exposed to 1-40 μM of α-MG for 24 h at 37 °C. Hemolysis and related markers were measured using colorimetric assays, eryptotic cells were identified through Annexin-V-FITC, Ca2+ was detected with Fluo4/AM, and oxidative stress was assessed through H2DCFDA using flow cytometry. The toxicity of α-MG was also examined in the presence of specific signal transduction inhibitors and in whole blood. α-MG at 10-40 μM caused dose-dependent hemolysis with concurrent significant elevation in K+, Mg2+, and LDH leakage, but at 2.5 μM it significantly increased the osmotic resistance of cells. A significant increase was also noted in Annexin-V-binding cells, along with intracellular Ca2+, oxidative stress, and cell shrinkage. Moreover, acetylcholinesterase activity was significantly inhibited by α-MG, whose hemolytic potential was significantly ameliorated by the presence of BAPTA-AM, vitamin C, NSC23766, and isosmotic sucrose but not urea. In whole blood, α-MG significantly depleted intracellular hemoglobin stores and was selectively toxic to platelets and monocytes. α-MG possesses hemolytic and eryptotic activities mediated through Ca2+ signaling, Rac1 GTPase activity, and oxidative injury. Also, α-MG leads to accelerated cellular aging and specifically targets platelet and monocyte populations in a whole blood milieu.

A novel bivalent anti-c-MET/PD-1 bispecific antibody exhibits potent cytotoxicity against c-MET/PD-L1-positive colorectal cancer.

Previously, we generated a novel bispecific antibody (BsAb) simultaneously targeting both c-MET and PD-1 (PDCD1), which can bridge T cells and c-MET positive tumor cells. However, the specific mechanisms and antitumor activities of the BsAb against c-MET/PD-L1 (CD274) positive colorectal cancer (CRC) is not completely understood. In this study, in addition to the tumor intrinsic mechanism investigation with molecular biology assay in vitro, a humanized mouse model was used to evaluate antitumor activity of the BsAb in vivo. The BsAb could inhibit c-MET/PD-L1+ CRC cell migration and show strong antitumor activity against HCT116 tumors in mice, potentially by inducing the degradation of c-MET protein in a dose and time-dependent manner. The BsAb could suppress the phosphorylation of c-MET downstream proteins GRB2-associated-binding protein 1 (Gab1) and focal adhesion kinase (FAK). Considering the tumor extrinsic mechanism, the BsAb may promote phagocytosis of macrophage. Furthermore, the level of plasma exosomal-c-MET/PD-L1 is able to distinguish CRC patients from healthy controls. In summary, the BsAb exhibited potent anti-tumor activities by two distinguished mechanisms: inhibition of c-MET signal transduction and promotion of macrophage-mediated phagocytosis. Our BsAb may provide a novel therapeutic agent for patients with c-MET/PD-L1+ CRC, and the status of exosomal-c-MET/PD-L1 can serve as a biomarker to predict responsiveness to treatment of our BsAb.