Inhibition Of Energy Metabolism Research Articles

The rheumatoid arthritis drug auranofin exerts potent anti-lymphoma effect by stimulating TXNRD-mediated ROS generation and inhibition of energy metabolism

Since the survival of lymphoma patients who experience disease progression or relapse remains very poor, new therapeutic approaches and effective drugs are urgently needed. Here we show that auranofin (AF), an anti-rheumatoid drug thought to inhibit thioredoxin reductases (TXNRDs) as its mechanism of action, exhibited potent activity against multiple cancer types, especially effective against B cell lymphoma. Surprisingly, a knockdown of TXNRD1 and TXNRD2 did not cause significant cytotoxicity, suggesting that abrogation of TXNRD enzyme per se was insufficient to cause cancer cell death. Further mechanistic study showed that the interaction of AF with TXNRD could convert this antioxidant enzyme to a ROS-generating molecule via disrupting its electron transport, leading to a leak of electrons that interact with molecular oxygen to form superoxide. AF also suppressed energy metabolism by inhibiting both mitochondria complex II and the glycolytic enzyme GAPDH, leading to a significant depletion of ATP and inhibition of cancer growth in vitro and in vivo. Importantly, we found that the AF-mediated ROS stress could induce PD-L1 expression, revealing an unwanted effect of AF in causing immune suppression. We further showed that a combination of AF with anti-PD-1 antibody could enhance the anticancer activity in a syngeneic immune-competent mouse B-cell lymphoma model. Our study suggests that AF could be a potential drug for lymphoma treatment, and its combination with immune checkpoint inhibitors would be a logical strategy to increase the therapeutic activity.

Chaga mushroom extract suppresses oral cancer cell growth via inhibition of energy metabolism

Oral cancer stands as a prevalent maligancy worldwide; however, its therapeutic potential is limited by undesired effects and complications. As a medicinal edible fungus, Chaga mushroom (Inonotus obliquus) exhibits anticancer effects across diverse cancers. Yet, the precise mechanisms underlying its efficacy remain unclear. We explored the detailed mechanisms underlying the anticancer action of Chaga mushroom extract in oral cancer cells (HSC-4). Following treatment with Chaga mushroom extracts, we analyzed cell viability, proliferation capacity, glycolysis, mitochondrial respiration, and apoptosis. Our findings revealed that the extract reduced cell viability and proliferation of HSC-4 cells while arresting their cell cycle via suppression of STAT3 activity. Regarding energy metabolism, Chaga mushroom extract inhibited glycolysis and mitochondrial membrane potential in HSC-4 cells, thereby triggering autophagy-mediated apoptotic cell death through activation of the p38 MAPK and NF-κB signaling pathways. Our results indicate that Chaga mushroom extract impedes oral cancer cell progression, by inhibiting cell cycle and proliferation, suppressing cancer cell energy metabolism, and promoting autophagy-mediated apoptotic cell death. These findings suggest that this extract is a promising supplementary medicine for the treatment of patients with oral cancer.

Antifungal mechanism of phenyllactic acid against Mucor investigated through proteomic analysis

The primary inhibitory targets of phenyllactic acid (PLA, including D-PLA and L-PLA) on Mucor were investigated using Mucor racemosus LD3.0026 isolated from naturally spoiled cherry, as an indicator fungi. The results demonstrated that the minimum inhibitory concentration (MIC) of PLA against Mucor was 12.5 mmol·L−1. Results showed that the growing cells at the tip of the Mucor were not visibly deformed, and there was no damage to the cell wall following PLA treatment; however, PLA damaged the cell membrane and internal structure. The results of isobaric tags for relative and absolute quantification (iTRAQ) indicated that the Mucor mitochondrial respiratory chain may be the target of PLA, potentially inhibiting the energy supply of Mucor. These results indicate that the antifungal mechanism of PLA against mold is independent of its molecular configuration. The growth of Mucor is suppressed by PLA, which destroys the organelle structure in the mycelium and inhibits energy metabolism.

Co-delivery of Paclitaxel/Atovaquone/Quercetin to regulate energy metabolism to reverse multidrug resistance in ovarian cancer by PLGA-PEG nanoparticles

Ovarian cancer is a malignant tumor that seriously endangers the lives of women, with chemotherapy being the primary clinical treatment. However, chemotherapy encounters the problem of generating multidrug resistance (MDR), mainly due to drug efflux induced by P-glycoprotein (P-gp), which decreases intracellular accumulation of chemotherapeutic drugs. The drugs efflux mediated by P-gp requires adenosine triphosphate (ATP) hydrolysis to provide energy. Therefore, modulating energy metabolism pathways and inhibiting ATP production may be a potential strategy to reverse MDR. Herein, we developed a PTX-ATO-QUE nanoparticle (PAQNPs) based on a PLGA-PEG nanoplatform capable of loading the mitochondrial oxidative phosphorylation (OXPHOS) inhibitor atovaquone (ATO), the glycolysis inhibitor quercetin (QUE), and the chemotherapeutic drug paclitaxel (PTX) to reverse MDR by inhibiting energy metabolism through multiple pathways. Mechanistically, PAQNPs could effectively inhibit the OXPHOS and glycolytic pathways of A2780/Taxol cells by suppressing the activities of mitochondrial complex III and hexokinase II (HK II), respectively, ultimately decreasing intracellular ATP levels in tumor cells. Energy depletion can effectively inhibit cell proliferation and reduce P-gp activity, increasing the chemotherapeutic drug PTX accumulation in the cells. Moreover, intracellular reactive oxygen species (ROS) is increased with PTX accumulation and leads to chemotherapy-resistant cell apoptosis. Furthermore, PAQNPs significantly inhibited tumor growth in the A2780/Taxol tumor-bearing NCG mice model. Immunohistochemical (IHC) analysis of tumor tissues revealed that P-gp expression was suppressed, demonstrating that PAQNPs are effective in reversing MDR in tumors by inducing energy depletion. In addition, the safety study results, including blood biochemical indices, major organ weights, and H&E staining images, showed that PAQNPs have a favorable in vivo safety profile. In summary, the results suggest that the combined inhibition of the two energy pathways, OXPHOS and glycolysis, can enhance chemotherapy efficacy and reverse MDR in ovarian cancer.

FATP2 regulates Osteoclastogenesis by increasing lipid metabolism and ROS production.

Lipid metabolism plays a crucial role in maintaining bone homeostasis, particularly in osteoclasts (OCs) formation. Here, we found the expression level of FATP2, a transporter for long-chain and very-long-chain fatty acids, was significantly upregulated during OC differentiation and in the bone marrow of mice fed a high-fat diet (HFD). Notably, the use of FATP2 siRNA or a specific inhibitor (Lipofermata) resulted in significant inhibition of OC differentiation while only slightly affecting osteoblasts (OBs). In pathological models of bone loss induced by LPS or OVX, in vivo treatment with Lipofermata was able to rescue the loss of bone mass by inhibiting OC differentiation. RNA sequencing (RNA-seq) revealed that Lipofermata reduced fatty acid β-oxidation and inhibited energy metabolism, while regulating reactive oxygen species (ROS) metabolism to decrease ROS production, ultimately inhibiting OC differentiation. Treatment with Lipofermata, either in vivo or in vitro, effectively rescued the overactivation of OCs, indicating that FATP2 regulated OC differentiation by modulating fatty acid uptake and energy metabolism. These findings suggested that targeting FATP2 may represent a promising therapeutic approach for pathological osteoporosis.

Inducing vulnerability to InhA inhibition restores isoniazid susceptibility in drug-resistant Mycobacterium tuberculosis.

Of the approximately 10 million cases of Mycobacterium tuberculosis (Mtb) infections each year, over 10% are resistant to the frontline antibiotic isoniazid (INH). INH resistance is predominantly caused by mutations that decrease the activity of the bacterial enzyme KatG, which mediates the conversion of the pro-drug INH to its active form INH-NAD. We previously discovered an inhibitor of Mtb respiration, C10, that enhances the bactericidal activity of INH, prevents the emergence of INH-resistant mutants, and re-sensitizes a collection of INH-resistant mutants to INH through an unknown mechanism. To investigate the mechanism of action of C10, we exploited the toxicity of high concentrations of C10 to select for resistant mutants. We discovered two mutations that confer resistance to the disruption of energy metabolism and allow for the growth of Mtb in high C10 concentrations, indicating that growth inhibition by C10 is associated with inhibition of respiration. Using these mutants as well as direct inhibitors of the Mtb electron transport chain, we provide evidence that inhibition of energy metabolism by C10 is neither sufficient nor necessary to potentiate killing by INH. Instead, we find that C10 acts downstream of INH-NAD synthesis, causing Mtb to become particularly sensitive to inhibition of the INH-NAD target, InhA, without changing the concentration of INH-NAD or the activity of InhA, the two predominant mechanisms of potentiating INH. Our studies revealed that there exists a vulnerability in Mtb that can be exploited to render Mtb sensitive to otherwise subinhibitory concentrations of InhA inhibitor.IMPORTANCEIsoniazid (INH) is a critical frontline antibiotic to treat Mycobacterium tuberculosis (Mtb) infections. INH efficacy is limited by its suboptimal penetration of the Mtb-containing lesion and by the prevalence of clinical INH resistance. We previously discovered a compound, C10, that enhances the bactericidal activity of INH, prevents the emergence of INH-resistant mutants, and re-sensitizes a set of INH-resistant mutants to INH. Resistance is typically mediated by katG mutations that decrease the activation of INH, which is required for INH to inhibit the essential enzyme InhA. Our current work demonstrates that C10 re-sensitizes INH-resistant katG-hypomorphs without enhancing the activation of INH. We furthermore show that C10 causes Mtb to become particularly vulnerable to InhA inhibition without compromising InhA activity on its own. Therefore, C10 represents a novel strategy to curtail the development of INH resistance and to sensitize Mtb to sub-lethal doses of INH, such as those achieved at the infection site.

Inhibition of high sulfur on functional microorganisms and genes in slightly contaminated soil by cadmium and chromium

It is generally accepted that sulfur can passivate the bioavailability of heavy metals in soil, but it is not clear whether high sulfur in cadmium (Cd) and chromium (Cr) contaminated soil has negative effect on soil microbial community and ecological function. In this study, total sulfur (TS) inhibited the Chao 1, Shannon, Phylogenetic diversity (Pd) of bacterial and Pd of fungi in slightly contaminated soil by Cd and Cr around pyrite. TS, total potassium, pH, total chromium, total cadmium, total nitrogen, soil organic matter were the predominant factors for soil microbial community; the contribution of TS in shaping bacterial and fungal communities ranked at first and fifth, respectively. Compared with the low sulfur group, the abundance of sulfur sensitive microorganisms Gemmatimonas, Pseudolabrys, MND1, and Schizothecium were decreased by 68.79–97.22% (p < 0.01) at high sulfur one; the carbon fixation, nitrogen cycling, phosphorus cycling and resistance genes abundance were significantly lower (p < 0.01) at the latter. Such variations were strongly and closely correlated to the suppression of energy metabolism (M00009, M00011, M00086) and carbon fixation (M00173, M00376) functional module genes abundance in the high sulfur group. Collectively, high sulfur significantly suppressed the abundances of functional microorganisms and functional genes in slightly contaminated soil with Cd and Cr, possibly through inhibition of energy metabolism and carbon fixation of functional microorganisms. This study provided new insights into the environmental behavior of sulfur in slightly contaminated soil with Cd and Cr.

Animal Models of Mitochondrial Diseases Associated with Nuclear Gene Mutations.

Mitochondrial diseases (MDs) associated with nuclear gene mutations are part of a large group of inherited diseases caused by the suppression of energy metabolism. These diseases are of particular interest, because nuclear genes encode not only most of the structural proteins of the oxidative phosphorylation system (OXPHOS), but also all the proteins involved in the OXPHOS protein import from the cytoplasm and their assembly in mitochondria. Defects in any of these proteins can lead to functional impairment of the respiratory chain, including dysfunction of complex I that plays a central role in cellular respiration and oxidative phosphorylation, which is the most common cause of mitopathologies. Mitochondrial diseases are characterized by an early age of onset and a progressive course and affect primarily energy-consuming tissues and organs. The treatment of MDs should be initiated as soon as possible, but the diagnosis of mitopathologies is extremely difficult because of their heterogeneity and overlapping clinical features. The molecular pathogenesis of mitochondrial diseases is investigated using animal models: i.e. animals carrying mutations causing MD symptoms in humans. The use of mutant animal models opens new opportunities in the study of genes encoding mitochondrial proteins, as well as the molecular mechanisms of mitopathology development, which is necessary for improving diagnosis and developing approaches to drug therapy. In this review, we present the most recent information on mitochondrial diseases associated with nuclear gene mutations and animal models developed to investigate them.

Mechanism of inactivation of Aspergillus flavus spores by dielectric barrier discharge plasma

Dielectric barrier discharge plasma (DBDP) displays strong against fungal spores, while its precise mechanism of spore inactivation remains inadequately understood. In this study, we applied morphological, in vivo and in vitro experiments, transcriptomics, and physicochemical detection to unveil the potential molecular pathways underlying the inactivation of Aspergillus flavus spores by DBDP. Our findings suggested that mycelium growth was inhibited as observed by SEM after 30 s treatment at 70 kV, meanwhile spore germination ceased and clustering occurred. It led to the release of cellular contents and subsequent spore demise by disrupting the integrity of spore membrane. Additionally, based on the transcriptomic data, we hypothesized that the induction of spore inactivation by DBDP might be associated with downregulation of genes related to cell membranes, organelles (mitochondria), oxidative phosphorylation, and the tricarboxylic acid cycle. Subsequently, we validated our transcriptomic findings by measuring the levels of relevant enzymes in metabolic pathways, such as superoxide dismutase, acetyl-CoA, total dehydrogenase, and ATP. These physicochemical indicators revealed that DBDP treatment resulted in mitochondrial dysfunction, redox imbalance, and inhibited energy metabolism pathways. These findings were consistent with the transcriptomic results. Hence, we concluded that DBDP accelerated spore rupture and death via ROS-mediated mitochondrial dysfunction, which does not depend on cell membranes.

Biochar relieves the toxic effects of microplastics on the root-rhizosphere soil system by altering root expression profiles and microbial diversity and functions

The accumulation of microplastics in agricultural soil brings unexpected adverse effects on crop growth and soil quality, which is threatening the sustainability of agriculture. Biochar is an emerging soil amendment material of interest as it can remediate soil pollutants. However, the mechanisms underlying biochar alleviated the toxic effects of microplastics in crops and soil were largely unknown. Using a common economic crop, peanut as targeted species, the present study evaluated the plant physiologica and molecular response and rhizosphere microbiome when facing microplastic contamination and biochar amendment. Transcriptome and microbiome analyses were conducted on peanut root and rhizosphere soil treated with CK (no microplastic and no biochar addition), MP (1.5% polystyrene microplastic addition) and MB (1.5% polystyrene microplastic+2% peanut shell biochar addition). The results indicated that microplastics had inhibitory effects on plant root development and rhizosphere bacterial diversity and function. However, biochar application could significantly promote the expressions of key genes associated with antioxidant activities, lignin synthesis, nitrogen transport and energy metabolism to alleviate the reactive oxygen species stress, root structure damage, nutrient transport limitation, and energy metabolism inhibition induced by microplastic contamination on the root. In addition, the peanut rhizosphere microbiome results showed that biochar application could restore the diversity and richness of microbial communities inhibited by microplastic contamination and promote nutrient availability of rhizosphere soil by regulating the abundance of nitrogen cycling-related and organic matter decomposition-related microbial communities. Consequently, the application of biochar could enhance root development by promoting oxidative stress resistance, nitrogen transport and energy metabolism and benefit the rhizosphere microecological environment for root development, thereby improved the plant-soil system health of microplastic-contaminated agroecosystem.

Synergistic Activity and Mechanism of Sanguinarine with Polymyxin B against Gram-Negative Bacterial Infections.

Compounds that potentiate the activity of clinically available antibiotics provide a complementary solution, except for developing novel antibiotics for the rapid emergence of multidrug-resistant Gram-negative bacteria (GNB). We sought to identify compounds potentiating polymyxin B (PMB), a traditional drug that has been revived as the last line for treating life-threatening GNB infections, thus reducing its nephrotoxicity and heterogeneous resistance in clinical use. In this study, we found a natural product, sanguinarine (SA), which potentiated the efficacy of PMB against GNB infections. The synergistic effect of SA with PMB was evaluated using a checkerboard assay and time-kill curves in vivo and the murine peritonitis model induced by Escherichia coli in female CD-1 mice in vivo. SA assisted PMB in accelerating the reduction in bacterial loads both in vitro and in vivo, improving the inflammatory responses and survival rate of infected animals. The subsequent detection of the intracellular ATP levels, membrane potential, and membrane integrity indicated that SA enhanced the bacterial-membrane-breaking capacity of PMB. A metabolomic analysis showed that the inhibition of energy metabolism, interference with nucleic acid biosynthesis, and the blocking of L-Ara4N-related PMB resistance may also contribute to the synergistic effect. This study is the first to reveal the synergistic activity and mechanism of SA with PMB, which highlights further insights into anti-GNB drug development.

Combination of shikonin and gefitinib reverses drug resistance in human non-small cell lung cancer and its mechanism

The occurrence and development of tumors are associated with the cell energy metabolism. Inhibiting energy metabolism of lung cancer cells is an important strategy to overcome drug resistance. Based on the cellular energy metabolism pathway, this study observed the effect of combination of shikonin(SKN) and gefitinib(GFB) on the drug resistance in non-small cell lung cancer and explored the underlying mechanism. The human non-small cell lung cancer line HCC827/GR resistant to gefitinib was used as the cell model in vitro. The CCK-8 assay and flow cytometry were employed to investigate the cell viability and apoptosis, respectively. The high performance liquid chromatography was employed to measure the intracellular accumulation of GFB. A Seahorse XFe96 Analyzer was used to detect the changes of cellular energy metabolism. Western blot was employed to determine the expression of the proteins involved in the drug resistance. The tumor-bearing nude mouse model was used to verify the efficacy of SKN+GFB in overcoming drug resistance in vivo. The results showed that SKN+GFB significantly reduced the IC_(50) of GFB on HCC827/GR cells, with the combination index of 0.628, indicating that the combination of the two drugs had a synergistic effect and promoted cell apoptosis. SKN increased the intracellular accumulation of GFB. SKN+GFB lowered the oxygen consumption rate(OCR) and glycolytic proton efflux rate(GlycoPER) in cell energy metabolism, and down-regulated the overexpression of PKM2, p-EGFR, P-gp, and HIF-1α in drug resistance. The results of reversing drug resistance test in vivo showed that GFB or SKN alone had no significant antitumor effect, while the combination at different doses induced the apoptosis of the tumor tissue and inhibited the expression of PKM2 and P-gp, demonstrating a significant antitumor effect. Moreover, the tumor inhibition rate in the high-dose combination group reached 64.01%. In summary, SKN+GFB may interfere with the energy metabolism to limit the function of HCC827/GR cells, thus reversing the GFB resistance in non-small cell lung cancer.

PPARG and ASS1: Targets of Metabolic Alteration in Venetoclax / Decitabine Resistant Acute Myeloid Leukemia

The combination of venetoclax (VEN), an inhibitor of the anti-apoptotic factor BCL2, with the hypomethylating agent (HMA) decitabine (DEC) is the current frontline standard therapy for elderly patients with acute myeloid leukemia (AML). Despite the success of VEN/HMAs in inducing remission in AML, significant proportion of patients remain refractory to the combination therapy and others relapse after initial response. To elucidate underlying mechanisms of resistance, we performed transcriptomic and DNA methylation analyses on VEN/DEC pre- and post-treatment samples from AML patients participating in a prospective clinical trial of DEC10-VEN (NCT03404193). We have previously reported that AML cells from non-responders demonstrate significant upregulation of mRNA expression of the fatty acid metabolism activator PPARG ( Peroxisome Proliferator-Activated Receptor γ) and ASS1 ( Argininosuccinate Synthase coding rate-limiting enzyme in the arginine biosynthesis) after VEN/DEC treatment, both accompanied by their transcription start site demethylation ( Yamatani et al. ASH 2022). In this study, we performed single cell (sc) ATAC-seq to profile the accessible chromatin changes that are associated with VEN/DEC resistance. BM samples from one patient who achieved complete remission with incomplete count recovery and later relapsed (pre- and post- VEN/DEC treatment) and 2 healthy control bone marrow cells were utilized. A total of 23,803 cells were sequenced, read alignment and initial stages of data processing were performed using Cell Ranger (version 7.0.1; 10x Genomics), then cells were clustered by Uniform Manifold Approximation and Projection (UMAP) and annotated using the Azimuth application, which distinguished leukemia-associated clusters. In the leukemia-associated cell cluster, PPARG motifs in accessible chromatin were significantly enriched compared to other clusters. After VEN/DEC treatment, further increase in the relative abundance of PPARG motifs along with chromatin accessibility of CXCR4 and CDC42EP4 genes, which have RRARG accessible motifs, was observed. Next, the role and mechanism of PPARG in the resistance to VEN/DEC was investigated using four AML cell lines with different sensitivity to DEC. PPARG expression was increased after DEC treatment in the less sensitive cells (HL-60 and MV4-11) but was unchanged in the more sensitive cells (OCI-AML3 and THP-1). To confirm that PPARG upregulation is associated with VEN/DEC resistance, we generated PPARG overexpressing HL-60 and MV4-11 cells using a lentiviral system. In the PPARG-overexpressing (OE) cells, VEN/DEC-induced cell growth inhibition and apoptosis were significantly reduced compared to the mock-transfected cells (PPARG -OE vs mock; cell growth inhibition: HL-60, 30% vs. 54%; MV4-11, 33% vs. 56%; apoptosis induction: HL-60, 14% vs. 38%, MV4-11, 25% vs. 36%; p &amp;lt; 0.05). To determine whether the suppression of energy metabolism by VEN/DEC is inhibited by PPARG overexpression, we performed an extracellular flux assay using PPARG-OE cells and mock HL60 cells. The results showed that VEN/DEC treatment reduced reserve respiratory capacity by 32% in mock cells, while VEN/DEC therapy was associated with an increase of 37% in PPARG-OE cells (p &amp;lt; 0.05). ASS1 is another potential target associated with metabolic alterations in VEN/DEC-resistant AML. We next investigated the effects of arginine deprivation by combining the arginine-degrading enzyme pegylated arginine deiminase (ADI-PEG 20) with VEN/DEC. We used HL-60 cells with low baseline ASS1 expression, which was increased by DEC treatment, and MV4-11 cells with high ASS1 expression, which was not altered by DEC. HL-60 was more sensitive to ADI-PEG 20 than MV4-11 cells (IC 50: HL-60, 20ng/mL; MV4-11, 100ng/ml); however, no further increase of cell growth inhibition by ADI-PEG 20 was observed in the combination with VEN/DEC , which enhances ASS1 expression. In MV4-11, ADI-PEG 20 combination significantly facilitated cell growth inhibition by VEN/DEC (increased VEN/DEC growth inhibition by ADI: HL60, 7%; MV4-11, 57%, p &amp;lt; 0.05). Taken together, this study demonstrated that VEN/DEC treatment facilitates energy metabolism in AML cells through increased expression of PPARG and ASS1, which may in turn translate into therapeutic resistance, and that VEN/DEC /ADI-PEG 20 combination may represent a potential novel therapeutic strategy (Figure 1).

Photocatalytic properties and antibacterial mechanisms of microbial-derived ZnS/CuS nanocomposites

The urgency to combat antibiotic-resistant bacterial infections requires new antibacterial materials and methods. Utilizing Shewanella onesidensis metabolism, biological zinc/copper sulfide (bio-ZnS/CuS) composites with excellent visible-light photocatalysis effects and broad-spectrum antibacterial activity were synthesized. During synthesis, over 95% of heavy metal ions were recovered from wastewater through co-precipitation to form metal sulfides. The biocomposite with Zn/Cu ratio at 1/9 (Zn1S/Cu9S) showed the best photocatalytic performance. Under visible-light catalysis of Zn1S/Cu9S, 98.02 ± 0.13% of methylene blue and 81.74 ± 2.12% of rhodamine B were rapidly removed, while sterilization rates exceeded 99.99% against Escherichia coli and 99.98% against Staphylococcus aureus. The biocomposite showed a nanostructure with sizes between 5 and 20 nm. Characterizations including X-ray photoelectron spectroscopy, UV-Vis absorption spectra, and photoluminescence spectra proved its excellent visible light response capacity (>400 nm) and energy utilization efficiency. Scavenging experiments demonstrated photogenerated holes and hydrogen peroxide as the major reactive oxygen species (ROS) that induce bacterial death. Toxicological studies revealed that ROS attacked bacterial cells by damaging membranes, inhibiting energy metabolism, breaking the antioxidant defense system, and compromising DNA integrity. This research presents innovative solutions for tackling bacterial infections and heavy metal contamination through the advancement of microbial synthetic functional nanomaterials.

An engineered nanoplatform inhibiting energy metabolism and lysosomal activity of tumor cells to multiply cisplatin-based chemotherapy

Although inhibiting the energy metabolism of tumor cells has become an effective measure to enhance chemotherapy, tumor cells can still escape the lethal effect of chemotherapy by entering a dormancy state with low-energy expenditure. Herein, the glutathione (GSH)-responsive nanoplatform (C-A-D NPs) were constructed to inhibit energy metabolism and lysosomal activity of tumor cells, thereby forcing tumor cells to remain vulnerable to cisplatin. In this system, cisplatin prodrug was reduced to cisplatin by GSH, and D-peptide and apoptozole (Az) were released to inhibit the energy metabolism and autophagy-lysosome pathway of tumor cells. The suppressed autophagy-lysosome pathway prevents tumor cells from entering a low-energy dormancy state, resulting in the loss of resistance to the lethal effect of cisplatin with high-energy expenditure and insufficient energy supply. Such engineered nanoplatform effectively enhances the chemotherapeutic effect of cisplatin by inhibiting intracellular energy metabolism and lysosomal activity, showing great clinical prospects.

Clinical manifestations and mechanisms of formation of neurological disorders in patients with vibration disease

The review presents an analysis of literature sources devoted to the study of changes in the nervous system in patients with vibration disease. Vibration-mediated cellular hypoxia, which occurs as a result of spastic changes in blood vessels, phase fluctuations in intravascular pressure, impaired blood and lymph outflow, causes suppression of energy metabolism, contributes to disorders at the level of receptor (glutamate, GABA-ergic, dopamine and cholinergic) and synaptic structures, conductors of pain and temperature sensitivity (demyelinization), analyzing neurons in the parietal region of the brain, regulatory proteins of the nervous tissue (NF-200, GFAP S-100). A low-amplitude, irregular, disorganized and sometimes deformed EEG spectrum with a predominance of the alpha wave and a shift of the alpha rhythm to the left reflects changes in the spontaneous electrical activity of brain structures in patients. With an increase in the experience dose of vibration-noise exposure, the dominant alpha activity changes to slow-wave or polyrhythmic. Mild and moderate diffuse changes in the brain become focal in nature, cortical-subcortical relationships are disrupted at the diencephalic level, creating a pathophysiological basis for sensorineural (sensory-neural) hearing loss, especially in patients with a genetic predisposition mediated by genes encoding proteins of the heat shock system. The psycho-emotional status of patients is characterized by a hypochondriacal focus on the state of health, mental disadaptation, psycho-emotional disorders in the form of anxiety, depressive mood. The analysis of literature sources on the mechanisms of the formation of neurological disorders in patients with vibration disease revealed the lack of data on the state of the multicomponent ghrelin system interacting with GHSR-1A and GHSR-1B receptors, which determines a new vector in further experimental and clinical studies.

In-vitro antibacterial activity and mechanism of Monarda didyma essential oils against Carbapenem-resistant Klebsiella pneumoniae

To fight the global epidemic of drug-resistant bacteria, essential oils have gained increasing attention as a new source of antibiotics. The antimicrobial activity of Monarda didyma essential oils (MDEO) for the Carbapenem-resistant Klebsiella pneumoniae (CRKP) strains were determined by agar disc diffusion assay and broth microdilution assay. To further understand MDEO efficacy, a time-growth curve was performed. The biofilm formation of CRKP were determined by crystalline violet staining method, additionally, changes in intracellular Adenosine triphosphate (ATP), protein, Alkaline phosphatase (AKP) activities, and membrane integrity were investigated to assess the influence of MDEO on cell membrane damage. Finally, the activities of key enzymes in the tricarboxylic acid (TCA) pathways and pentose phosphate (PPP) pathways were examined to determine the effect of MDEO on the respiratory metabolism of CRKP. This study presents the antibacterial mechanism of MDEO against CRKP with a minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of 1.25 mg/ml. To understand MDEO efficacy, a time-kill kinetics approach was performed. The bactericidal effect of MDEO was evident at 2 h compared to the control at its MIC and 2MIC. Surface electron microscopic and ATP assay studies provided evidence for the multi-target action of MDEO against CRKP. MDEO could inhibit CRKP biofilm formation. MDEO could also cause irreversible damage to the CRKP cell membrane, resulting in the leakage of biological macromolecules (protein, ATP) and the reduction of intracellular enzymes (AKP) activities. Finally, MDEO affected the pathways of respiratory metabolism, such as PPP and TCA pathways. MDEO could reduce the activity of key enzymes (Glucose-6-phosphate dehydrogenase, citrate synthase, isocitrate dehydrogenase, and α-ketoglutarate dehydrogenase) in the PPP and TCA pathways to exert its biological effects against CRKP. These results suggest MDEO can exert inhibitory effects on CRKP, and potential mechanisms of action including inhibition of biofilm formation, damage of cell membrane structure and inhibition of energy metabolism.

Antifungal activity of Ligusticum chuanxiong essential oil and its active composition butylidenephthalide against Sclerotium rolfsii.

Peanut stem rot caused by Sclerotium rolfsii is an epidemic disastrous soil-borne disease. Recently, natural products tend to be safe alternative antifungal agents to combat pathogens. This work determined the preliminary antifungal activity of 29 essential oils against S. rolfsii and found that Ligusticum chuanxiong essential oil (LCEO) showed the best antifungal activity, with an EC50 value of 81.79 mg L-1 . Sixteen components (98.78%) were identified in LCEO by gas chromatography-mass spectrometry analysis, the majority by volume comprising five phthalides (93.14%). Among these five phthalides, butylidenephthalide was the most effective compound against S. rolfsii. Butylidenephthalide not only exhibited favorable in vitro antifungal activity against the mycelial growth, sclerotia production and germination of S. rolfsi, but also presented efficient in vivo efficacy in the control of peanut stem rot. Seven days after application in the glasshouse, the protective and curative efficacy of butylidenephthalide at 300 mg L-1 (52.02%, 44.88%) and LCEO at 1000 mg L-1 (49.60%, 44.29%) against S. rolfsii were similar to that of the reference fungicide polyoxin at 300 mg L-1 (54.61%, 48.28%). Butylidenephthalide also significantly decreased the oxalic acid and polygalacturonase content of S. rolfsii, suggesting a decreased infection ability on plants. Results of biochemical actions indicated that butylidenephthalide did not have any effect on the cell membrane integrity and permeability but significantly decreased nutrient contents, disrupted the mitochondrial membrane, inhibited energy metabolism and induced reactive oxygen species (ROS) accumulation of S. rolfsii. Our results could provide an important reference for understanding the application potential and mechanisms of butylidenephthalide in the control of S. rolfsii. © 2023 Society of Chemical Industry.

Yiqi Yangjing recipe stimulates apoptosis while suppressing the energy metabolism via under-expression of PFKFB3 in A549 cells.

Lung cancer is a malignant tumor associated with high morbidity and mortality. Yiqi Yangjing recipe (YYR) is a formula of traditional Chinese medicine (TCM) that is commonly used for the treatment of lung cancer with good clinical efficacy. The specific anti-cancer mechanism of YYR is still unknown. We need to embark on a more in-depth pharmacological study of YYR to determine the complex compound ingredients, which could be promoted in clinical practice to achieve efficacy in prolonging recurrent metastasis of lung cancer. The cytotoxic effects of YYR on A549 cells were evaluated by Cell Counting Kit-8 (CCK-8) assay. The PFKFB3-under-expressed and overexpressed A549 cell lines were constructed via PFK15 treatment and transfection, respectively. The effects of YYR on PFKFB3 messenger RNA (mRNA) and protein expression were detected by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blot. The pro-apoptotic and anti-glycolytic abilities of YYR were measured using flow cytometry assay and hippocampal XF96 extracellular flux analyzer. An in vivo tumorigenicity assay was performed on nude mice to confirm the anti-cancer effects of YYR. YYR has a noticeable cytotoxic activity on A549 cells, with the treatment with both YYR and PFK15 significantly inducing apoptosis. YYR and PFK15 treatment reduced the extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) in A549 cells. Similar to PFK15, YYR can down-regulate PFKFB3 expression, and PFKFB3 overexpression suppressed the apoptosis, which was reversed by YYR. Animal experiments confirmed that YYR was able to inhibit tumor growth, induce tumor cell apoptosis, and down-regulate PFKFB3 in tumor tissues. This study demonstrated that YYR promoted lung cancer cell apoptosis and inhibited energy metabolism by targeting PFKFB3. Furthermore, we believe that YYR may be a suitable supplement or alternative drug for lung cancer treatment.

Antibacterial spectrum of medicinal plants: A review

Medicinal plants exerted their antibacterial effects through many mechanisms included inhibition of cell wall synthesis, inhibition of cell membrane synthesis, disruption of cytoplasmic membrane, inhibition of bacterial proteins synthesis, inhibition of nucleic acid synthesis, inhibition of energy metabolism, as well as inhibition of bacterial virulence factors. The current review highlighted the medicinal plants with antibacterial activity with their spectrum of action.