The Natural Occurring Compounds Targeting Endoplasmic Reticulum Stress

ER stress has been implicated in pathophysiological development of many diseases. Persistent overwhelming stimuli trigger ER stress to initiate apoptosis, autophagy, and cell death. IRE1-JNK and eIF2α-CHOP signaling pathways are the two important players of ER stress, which is also modulated by ROS production, calcium disturbance, and inflammatory factors. ER stress has been developed as a novel strategy for diseases management. Recently, a vast of research focuses on the natural occurring compounds targeting ER stress, which results in medical benefits to human diseases. These small reported molecules mainly include polyphenols, alkaloids, and saponins. Many of them have been developed for use in clinical applications. To better understand the pharmacological mechanism of these molecules in ER stress in diseases, efforts have been made to discover and deliver medical merits. In this paper, we will summarize the natural occurring compounds targeting ER stress

Melittin promotes dexamethasone in the treatment of adjuvant rheumatoid arthritis in rats

Background: Rheumatoid arthritis (RA) is an erosive-destructive inflammation of the joints, and the chronic, long-term stiffness and deformation induced by RA are some of the symptoms of arthritis that are difficult to treat. Dexamethasone (DEX) and melittin (MLT) are two interesting anti-inflammatory substances, both of which possess anti-inflammatory effects exerted through the suppression of the immune system. The purpose of this study was to explore the role of MLT in the treatment of RA by DEX as well as to clarify the influence of MLT on the efficacy and side effects of DEX.Method: The rats were injected with Complete Freund’s Adjuvant (CFA) to induce arthritis, followed by treatment with different doses of DEX and/or MLT. The relevant indexes of paw inflammation were determined, and the appetite, growth status, arthritis status, cytokine levels, and organ coefficient of the rats were evaluated. In addition, the paraffin sections of the joint tissues were prepared to analyze the pathological changes.Result: DEX exhibited side effects, notably hindering feed intake and growth, and inducing immune organ lesions in the rats. MLT significantly reduced the side effects of DEX and promoted its efficacy. DEX in combination with MLT demonstrated a synergistic efficacy in RA treatment, showing advantages in detumescence reduction, pro-inflammatory cytokine inhibition, and joint internal pathological improvement.Conclusion: Thus, MLT promoted the efficacy of DEX in adjuvant RA treatment in rats, offering an approach to reduce the use dosage and side effects of DEX

The Multifunctional Effects of Nobiletin and Its Metabolites In Vivo

Nobiletin (NOB) chemically known as 5,6,7,8,3′,4′-hexamethoxyflavone is a dietary polymethoxylated flavonoid found in Citrus fruits. Recent evidences show that NOB is a multifunctional pharmaceutical agent. The various pharmacological activities of NOB include neuroprotection, cardiovascular protection, antimetabolic disorder, anticancer, anti-inflammation, and antioxidation. These events may be underpinned by modulation of signaling cascades, including PKA/ERK/MEK/CREB, NF-κB, MAPK, Ca2+/CaMKII, PI3K/Akt1/2, HIF-1α, and TGFβ signaling pathways. The metabolites may exhibit stronger beneficial effects than NOB on diseases pathogenesis. The biological activities of NOB have been clarified on many systems. This review aims to discuss the pharmacological effects of NOB with specific mechanisms of actions. NOB may become a promising candidate for potential drug development. However, further investigations of NOB on specific intracellular targets and clinical trials are still needed, especially for in vivo medical applications

Identification of serum biomarkers of hepatocarcinoma through liquid chromatography/mass spectrometry-based metabonomic method

Late diagnosis of hepatocarcinoma (HCC) is one of the most primary factors for the poor survival of patients. Thereby, identification of sensitive and specific biomarkers for HCC early diagnosis is of great importance in biological medicine to date. In the present study, serum metabolites of the HCC patients and healthy controls were investigated using the improved liquid chromatography–mass spectrometry (LC/MS). A wavelet-based method was utilized to find and align peaks of LC–MS. The characteristic peaks were selected by performing a two-sample t test statistics (p value <0.05). Clustering analysis based on principal component analysis showed a clear separation between HCC patients and healthy individuals. The serum metabolite, namely 1-methyladenosine, was identified as the characteristic metabolite for HCC. Moreover, receiver–operator curves were calculated with 1-methyladenosine and/or alpha fetal protein (AFP). The higher area under curve value was achieved in 1-methyladenosine group than AFP group (0.802 vs. 0.592), and the diagnostic model combining 1-methyladenosine with AFP exhibited significant improved sensitivity, which could identify those patients who missed the diagnosis of HCC by determining serum AFP alone. Overall, these results suggested that LC/MS-based metabonomic study is a potent and promising strategy for identifying novel biomarkers of HCC

Research on the Boundary Identification Method of Concealed Geological Bodies Based on Non-seismic Geophysical Data—— Taking Benxi-Xiuyan Area as an Example

In the process of deep geological structure research, gravity and aeromagnetic anomaly data are often used to invert the distribution law of concealed geological bodies. In order to reveal the boundaries of concealed geological bodies and divide structural divisions, this paper adopts fuzzy control simulated annealing genetic algorithm () to superimpose the gravity and aeromagnetic anomaly data in Benxi-Xiuyan area and classify the patterns, and identify the main geological body boundaries and fractures. Comparing the relationship with known geological maps, the two have a higher degree of matching. Experiments show that the application of SAGAFcm algorithm can quickly identify the boundaries of concealed geological bodies and provide a new means for field geological mapping

The Long-Term Effects of Barren Land Afforestation on Plant Productivity, Soil Fertility, and Soil Moisture in China: A Meta-Analysis

As global ecological degradation intensifies, the long-term impacts of afforestation on productivity and soil fertility in barren lands have become critical in improving global ecological security and productivity. Through meta-analysis, this study integrates data from 109 barren land afforestation sites across China, aiming to comprehensively analyze the effects on plant productivity and soil fertility while identifying the key environmental drivers of these changes. We found that afforestation consistently enhances plant productivity across 60 years. However, soil fertility and moisture initially surged significantly after afforestation but gradually declined after the first decade, indicating the limited long-term benefits. Climatic factors, namely precipitation and humidity index, are crucial in enhancing plant productivity, while geographic factors, specifically lower elevations and gentler slopes, are associated with greater increases in soil fertility. Elevation and slope are two key factors that influence soil moisture after afforestation. These findings highlight the need for ongoing soil management and ecological maintenance in afforestation projects to sustain the soil fertility benefits. Our study provides a robust scientific foundation for afforestation strategies aimed at barren land restoration and offers valuable insights for policy formulation in barren land afforestation

The pharmacodynamic and differential gene expression analysis of PPAR α/δ agonist GFT505 in CDAHFD-induced NASH model.

Peroxisome proliferator-activated receptor α/δ (PPAR α/δ), regulating glucolipid metabolism and immune inflammation, has been identified as an effective therapeutic target in non-alcoholic steatohepatitis (NASH). Dual PPAR α/δ agonist, such as GFT505 (also known as elafibranor), demonstrated potential therapeutic effect for NASH in clinical trials. To profile the regulatory network of PPAR α/δ agonist in NASH, the choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) induced NASH model was used to test the pharmacodynamics and transcriptome regulation of GFT505 in this study. The results showed that GFT505 ameliorated hepatic steatosis, inflammation and fibrosis in CDAHFD mice model. RNA-sequencing yielded 3995 up-regulated and 3576 down-regulated genes with GFT505 treatment. And the most significant differentialy expressed genes involved in glucolipid metabolism (Pparα, Acox1, Cpt1b, Fabp4, Ehhadh, Fabp3), inflammation (Ccl6, Ccl9, Cxcl14) and fibrosis (Timp1, Lamc3, Timp2, Col3a1, Col1a2, Col1a1, Hapln4, Timp3, Pik3r5, Pdgfα, Pdgfβ, Tgfβ1, Tgfβ2) were confirmed by RT-qPCR. The down-regulated genes were enriched in cytokine-cytokine receptor interaction pathway and ECM-receptor interaction pathway, while the up-regulated genes were enriched in PPAR signaling pathway and fatty acid degradation pathway. This study provides clues and basis for further understanding on the mechanism of PPAR α/δ agonist on NASH

Insights into the Action Mechanisms of Traditional Chinese Medicine in Osteoarthritis

Osteoarthritis (OA) is a chronic degenerative joint disease characterized by articular cartilage destruction, synovial inflammation, and osteophyte formation. No effective treatments are available. The current pharmacological medications such as nonsteroidal anti-inflammatory drugs (NSAIDs) and analgesics, accompanied by possible adverse effects, might ameliorate OA symptoms. But they do not arrest the progression of OA. Traditional Chinese medicine (TCM) provides medical value by modification of disease and symptoms in OA. Valuable work on exploring TCM merits for OA patients has been investigated using modern technologies, although the complicated interacting network among the numerous components indicates the uncertainty of target specification. This review will provide an overview of the action mechanism of TCM in the last 5 years, discussing the TCM activities of anti-inflammation, antiapoptosis, antioxidation, anticatabolism, and proliferation in OA. TCM is a proposed medical option for OA treatment

<i>In Situ</i> Polymerization of Zwitterions on Therapeutic Proteins to Enable Their Effective Oral Delivery

Oral administration of protein drugs has always been challenging owing to various intestinal barriers. Herein, we developed an efficient oral protein delivery strategy by using in situ polymerization of zwitterions to encapsulate proteins, which were then loaded into enteric coated capsules for oral feeding. After oral administration of such capsules, the enteric coating would be degraded once the capsule enters the intestine, releasing polyzwitterion/protein nanocomplexes. With the help of polyzwitterion modification, such nanocomplexes were able to pass through the mucus and cellular barriers, likely by the proton-assisted amino acid transporter 1 (PAT1) pathway. Such a polyzwitterion-based protein encapsulation strategy could allow for effective oral delivery of different proteins, including bovine serum albumin (BSA), insulin, and antibodies. Using this strategy, the oral bioavailabilities of insulin and immunoglobin G (IgG) were measured to be as high as 16.9% and 12.5%, respectively. Notably, oral feeding of polyzwitterion/insulin capsules could effectively lower the blood glucose level of diabetic animals (mice, rats, and pigs). Moreover, polyzwitterion/antiprogramed death-1 (αPD-1) capsules were able to induce efficient antitumor immune responses, showing significant tumor inhibition effects toward B16F10- and 4T1-tumor bearing mouse models after oral administration. No significant toxic effect was observed for such oral protein formulations in the treated animals. Our work presents a strategy for the efficient oral delivery of protein drugs, including those with large molecular weights (e.g., antibodies) that can hardly be orally delivered using existing technologies