Chronic hepatitis B virus (HBV) infection remains a significant global health challenge due to its link to severe conditions like HBV-related cirrhosis and hepatocellular carcinoma (HCC). Although current treatments effectively reduce viral levels, they have limited impact on certain HBV elements, namely hepatitis B surface antigen (HBsAg) and covalently closed circular DNA (cccDNA). This highlights the urgent need for innovative pharmaceutical and biological interventions that can disrupt HBsAg production originating from cccDNA. In this study, we identified a natural furanocoumarin compound, Imperatorin, which markedly inhibited the expression of HBsAg from cccDNA, by screening a library of natural compounds derived from Chinese herbal medicines using ELISA assay and qRT-PCR. The pharmacodynamics study of Imperatorin was explored on HBV infected HepG2-NTCP/PHHs and HBV-infected humanized mouse model. Proteome analysis was performed on HBV infected HepG2-NTCP cells following Imperatorin treatment. Molecular docking and bio-layer interferometry (BLI) were used for finding the target of Imperatorin. Our findings demonstrated Imperatorin remarkably reduced the level of HBsAg, HBV RNAs, HBV DNA and transcriptional activity of cccDNA both in vitro and in vivo. Additionally, Imperatorin effectively restrained the actions of HBV promoters responsible for cccDNA transcription. Mechanistic study revealed that Imperatorin directly binds to ERK and subsequently interfering with the activation of CAMP response element-binding protein (CREB), a crucial transcriptional factor for HBV and has been demonstrated to bind to the PreS2/S and X promoter regions of HBV. Importantly, the absence of ERK could nullify the antiviral impact triggered by Imperatorin. Collectively, the natural compound Imperatorin may be an effective candidate agent for inhibiting HBsAg production and cccDNA transcription by impeding the activities of HBV promoters through ERK-CREB axis.

Contradictory results are existed in the literature regarding the impact of trace elements on the pathogenesis of calcium oxalate (CaOx) stone patients. Therefore, the aim of our study was to investigate the effect of Cu and Zn on biochemical and molecular characteristics of CaOx stones. Plasma and urine concentrations of Cu and Zn in 30 CaOx stones patients and 20 controls were determined by flame atomic absorption spectrometry (FAAS). Urinary levels of citric acid and oxalate were measured by commercial spectrophotometric kits. Blood levels of glutathione reduced (GSH) and catalase (CAT) were determined as markers of antioxidant activity, while blood malondialdehyde (MDA) and urine level of nitric oxide (NO) were used to assess oxidative stress. Gene expression of MAPk pathway (ERK, P38, and JNK) were estimated. The plasma and urine levels of Cu were significantly increased in the patient group compared to those of controls, while the levels of Zn were decreased. Excessive urinary excretion of citric acid and oxalate were found among CaOx stone patients. The GSH and CAT concentration were significantly reduced in CaOx stones patients compared to healthy group. The plasma MDA and urine NO concentration were significantly increased in CaOx stones patients compared to control group. The expressions of the studied genes were significantly increased in CaOx stones patients. These findings suggest that alteration in Cu and Zn might contribute to pathogenesis of CaOx patients through oxidative stress and MAPK pathway genes (ERK, P38 and JNK).

Ulixertinib is a novel oral ERK inhibitor that has shown promising single-agent activity in a phase I clinical trial that included patients with RAS-mutant cancers.
We conducted a phase Ib trial combining ulixertinib with gemcitabine and nab-paclitaxel (GnP) for untreated metastatic pancreatic adenocarcinoma. The trial comprised a dose de-escalation part and a cohort expansion part at the recommended phase II dose (RP2D). Primary endpoint was to determine the RP2D of ulixertinib plus GnP and secondary endpoints were to assess toxicity and safety profile, biochemical and radiographic response, progression-free survival (PFS) and overall survival (OS).
Eighteen patients were enrolled. Ulixertinib 600 mg PO twice daily (BID) with GnP was initially administered but was de-escalated to 450 mg BID as RP2D early during dose expansion due to poor tolerability, which ultimately led to premature termination of the study. Common treatment-related adverse events (TRAEs) were anemia, thrombocytopenia, rash and diarrhea. For 5 response evaluable patients, one patient achieved a partial response and 2 patients achieved stable disease. For 15 patients who received the triplet, median PFS and OS were 5.46 and 12.23 months, respectively.
Ulixertinib plus GnP had similar frequency of grade ≥3 TRAEs and potentially efficacy as GnP, however was complicated by a high rate of all-grade TRAEs (ClinicalTrials.gov Identifier: NCT02608229).

Two-trial learning in Aplysia reveals nonlinear interactions between training trials: A single trial has no effect, but two precisely spaced trials induce long-term memory. Extracellularly regulated kinase (ERK) activity is essential for intertrial interactions, but the mechanism remains unresolved. A combination of immunochemical and optogenetic tools reveals unexpected complexity of ERK signaling during the induction of long-term synaptic facilitation by two spaced pulses of serotonin (5-hydroxytryptamine, 5HT). Specifically, dual ERK phosphorylation at its activating TxY motif is accompanied by dephosphorylation at the pT position, leading to a buildup of inactive, singly phosphorylated pY-ERK. Phosphorylation and dephosphorylation occur concurrently but scale differently with varying 5HT concentrations, predicting that mixed two-trial protocols involving both \"strong\" and \"weak\" 5HT pulses should be sensitive to the precise order and timing of trials. Indeed, long-term synaptic facilitation is induced only when weak pulses precede strong, not vice versa. This may represent a physiological mechanism to prioritize memory of escalating threats.

Lung cancer has a high mortality rate and is very common. One of the main reasons for the poor prognosis of patients with lung cancer is the high incidence of metastasis. Ginsenoside Rh3, a rare ginsenoside extracted from Panax notoginseng, exhibits excellent anti-inflammatory and anti-tumor effects. Nonetheless, the inhibitory potential of Rh3 against lung cancer remains unknown. The target genes of Rh3 were screened by the PharmMapper database; the proliferation of lung cancer cells was detected by MTT assay; the migration and invasion of cells were detected by the Transwell method; and the expression of extracellular signal-regulated kinase (ERK) and EMT-related proteins in vivo and in vitro were detected by Western blotting. In addition, we established a lung metastasis model in nude mice using A549 cells to assess the effect of Rh3 on NSCLC tumor metastasis in vivo. Our findings suggest that Rh3 significantly inhibited lung cancer metastasis both in vivo and in vitro. It was determined by flow cytometry analysis that Rh3 notably inhibited cell proliferation by blocking the G1 phase. In addition, Rh3 inhibited metastasis in lung cancer cells and regulated the expression of metastasis-related proteins under hypoxia. Mechanistic studies suggested that Rh3 targeted ERK to inhibit lung cancer metastasis. The ERK inhibitor U0126 or siRNA-mediated knockdown of ERK had an enhanced effect on Rh3\'s ability to inhibit lung cancer metastasis. The studies revealed that the inhibitory effect of Rh3 on the metastatic ability of lung cancer cells may be supported by ERK-related signaling pathways.

Combination of anti-EGFR monoclonal antibodies or immune checkpoint inhibitors with TKIs has shown minimal benefit in EGFR mutant (EGFR-mut) NSCLC patients. Consequently, new combination approaches are needed.
The EPICAL was a single arm, phase 1b study to evaluate safety, tolerability and anti-tumor activity of first line afatinib combined with anti-EGF vaccination in advanced EGFR-mut patients. EGFR status and mutations in liquid biopsies were determined by reverse transcriptase-polymerase chain reaction; serum biomarkers by ELISA and Western blotting analysis.
The assay enrolled 23 patients, 21 completed the anti-EGF immunization phase. Treatment was well tolerated and no serious adverse events (SAEs) related to the anti-EGF vaccine were reported. Objective response and disease control rates were 78.3% (95%CI = 53.6-92.5) and 95.7% (95%CI = 78.1-99.9), respectively. After a median follow-up of 24.2 months, median progression-free survival (PFS) was 14.8 months (95% CI = 9.5-20.1) and median overall survival (OS) 26.9 months (95% CI = 23.0-30.8). Among the 21 patients completing the immunization phase, PFS was 17.5 months (95% CI = 12.0-23.0) and OS 26.9 months (95% CI = 24.6-NR). At the end of the immunization phase, all 21 patients showed high serum titers of anti-EGF antibodies, while EGF levels had decreased significantly. Finally, treatment with fully immunized patient\'s sera inhibited the EGFR pathway in tumor cells growing in vitro.
Combination treatment with an anti-EGF vaccine is well tolerated; induces a sustained immunogenic effect and might enhance the clinical efficacy of EGFR TKIs.

Recently, the roles of inflammation and insulin resistance in neurodegeneration have become better appreciated. NE3107, an oral small molecule, blood-brain permeable anti-inflammatory insulin sensitizer that binds extracellular signal-regulated kinase, has been shown to selectively inhibit inflammation-driven ERK- and NF-κB-stimulated inflammatory mediators, including TNF-α, without inhibiting their homeostatic functions. We describe the rationale and design of NM101, the first randomized, multicenter Phase III clinical study to examine the safety and efficacy of 30 week treatment with NE3107 versus placebo in elderly adults with mild-to-moderate Alzheimer\'s disease. Patients (316) will be randomized in a 1:1 ratio. The co-primary end points measure cognitive function (ADAS Cog12), and functional and behavioral characteristics (ADCS CGIC). Trial registration number: NCT04669028 (Clinicaltrials.gov).
Lay abstract Diabetes and other inflammatory diseases increase the risk of Alzheimer’s disease. Insulin controls energy use in both the body and the brain. NE3107 is an oral pharmaceutical that has been shown to decrease inflammation and to improve insulin function in animals and in human subjects. We have designed a Phase III clinical trial to test the safety and activity of NE3107 in 316 elderly adults with Alzheimer’s disease, compared with a placebo capsule. After 30 weeks, assessments will be made to look for benefits in cognition, function and behavior compared with the control group.

As a prescription for promoting blood circulation and removing blood stasis, Taohong Siwu Decoction(THSWD) has certain effects in delaying the progression of renal fibrosis. However, as a traditional Chinese medicine compound containing many monomer components, it has been a research hotspot in the field of exploring the research methods and targets for the complex pathological process. The method of activating blood circulation and removing blood stasis has certain clinical effect in retarding the process of IgA nephropathy(IgAN) fibrosis, but the mechanism of action is still unclear. In this study, the network pharmacology method was used to investigate the active ingredients, targets and molecular mechanisms of THSWD in the intervention of IgAN fibrosis. On this basis, in vitro experiments were conducted to verify the effect of THSWD on the expression of ERK factor in BALB/c 3 T3 cells. The active ingredients and targets in THSWD were collected through the TCMSP. Sixty-one active ingredients and 240 targets including luteolin and quercetin were screened, and 185 targets were obtained by intersecting with CTD database to search IgAN related targets. Cytoscape software and STRING database were used to construct "THSWD-active ingredients-targets" network and protein-protein interaction network, and 69 core targets were screened. In DAVID\'s GO enrichment analysis and KEGG pathway analysis of the core targets and cell experiments, the results showed that ERK was an important factor for THSWD to interfere with IgAN fibrosis, and THSWD intervention could significantly decrease cell activity, ERK1/2 mRNA expression, and p-ERK1/2 protein expression. This study preliminarily revealed that THSWD may delay the growth of fibroblasts by affecting ERK factor and its phosphorylation level.

Increases in medial prefrontal cortex ERK have been linked to learning and memory processes. In the present study separate groups of rats initially underwent testing in an open-field paired with either 2.0 mg/kg apomorphine or vehicle injections. Subsequently, in a brief conditioning 5 min. test the paired apomorphine group manifested a conditioned hyperactivity response. The vehicle/apomorphine groups were then subdivided into two vehicle and two apomorphine subgroups matched for their activity scores in this conditioning test. Following another apomorphine/vehicle pairing in the test environment the groups received 3 additional 5 min. non-drug conditioning tests in which the groups received post-trial vehicle/apomorphine treatments. The vehicle groups received vehicle either immediately or 15 min. after the first two of the three conditioning tests and the apomorphine groups received 2.0 mg/kg either immediately or 15 min. after the first two of the three conditioning tests. In the first conditioning test both of the apomorphine groups exhibited equivalent conditioned responses. By the third test, the conditioned response of the immediate post-trial apomorphine group remained robust whereas conditioned response of the 15 min. apomorphine post-trial group was extinguished. Immediately following the third conditioning test, the animals were euthanized and ERK was measured in the medial prefrontal cortex and the nucleus accumbens. ERK was enhanced in both brain areas, selectively in the immediate apomorphine post-trial group. Increased ERK activity linked to the presence of the apomorphine conditioned response coupled with the absence of increased ERK activity following extinction of the apomorphine conditioned response suggests that ERK activity immediately following a conditioning test is an indicator of activity in brain systems with substantial dopaminergic input that are important in learning and memory. The facilitative effects of the immediate post-trial apomorphine treatment on the conditioned response are also consistent with the proposition that immediate post-trial dopaminergic drug treatments can modify the re-consolidation of conditioned behavior.

BACKGROUND: Little is known regarding oncoproteins other than platelet-derived growth factor subunit B in dermatofibrosarcoma protuberans (DFSP). Moreover, the risk factors for worse prognosis are controversial.
OBJECTIVE: We sought to determine the clinicopathologic features and key factors for adverse outcome in DFSP, including the implication of expression of protein kinase B (Akt)/mammalian target of rapamycin (mTOR), signal transducer and activator of transcription 3 (STAT3), extracellular signal regulated kinase (ERK), cyclin D1, and programmed death ligand 1 (PD-L1).
METHODS: Clinicopathologic and immunohistochemical analyses were performed for 44 DFSPs having wide local excision and 92 dermatofibromas as controls.
RESULTS: Compared with the 35 nonrecurrent DFSPs, the 9 recurrent DFSPs exhibited larger tumor size, deeper invasion beyond the subcutis, and more diverse histologic subtype. The fibrosarcomatous subtype revealed frequent mitotic figures and a high cyclin D1-positive index. The 2 metastatic DFSPs (1 each of the fibrosarcomatous and myxoid subtypes) demonstrated 4 and 11 instances of local recurrence, respectively, as well as larger tumor size, deeper invasion beyond the subcutis, and high expression of cyclin D1. Expression of Akt/mTOR, STAT3, ERK, and PD-L1 ranged from none or low in the primary skin lesions to high in the corresponding metastatic sites. Akt/mTOR and ERK were expressed more frequently in DFSP than in dermatofibroma.
CONCLUSIONS: Lack of information on patients before hospital evaluation.
CONCLUSIONS: Complex factors beyond fibrosarcomatous subtype may portend local recurrence or metastasis. Akt/mTOR, STAT3, ERK, and PD-L1 may be associated with development and/or progression of DFSP.