The effect of hetrombopag combined with conventional treatment on immune function and quality of life in patients with severe aplastic anemia.

This study aimed to investigate the effect of hetrombopag combined with conventional treatment on immune function in patients with severe aplastic anemia (SAA). Patients were categorized into the control group (n = 50, receiving conventional treatment only) and experimental group (n = 50, receiving hetrombopag combined with conventional treatment). Before treatment and at weeks 18, 24, and 52 after treatment, the two groups were compared in routine blood test indicators, natural killer (NK) cell activity, and peripheral blood inflammatory factor levels. The overall remission rate and incidence of adverse events were also compared between the two groups. Outpatient or telephone follow-up was performed before treatment and at weeks 18, 24, and 52 after treatment to observe patients' immune function, treatment outcome, quality of life, and adverse events. Hemoglobin (Hb), and platelet count (PLT) (P < 0.05), and a rise in NK cell activity (P < 0.05). Interleukin (IL-10) levels were significantly higher, while IL-6 levels were significantly lower in the experimental group compared to the control group (P < 0.05). After receiving the treatment, all scores of SF-36 domains in both groups were higher than before treatment, particularly with higher scores in the experimental group (P < 0.05). Hetrombopag combined with conventional treatment improved the immune function and hematopoiesis of patients with SAA.

Silencing GDI2 inhibits proliferation, migration and invasion of colorectal cancer through activation of p53 signaling pathway.

Objective: To investigate the effect of silencing GDP dissociation inhibitor 2 (GDI2) on colorectal cancer development and possible mechanisms based on transcriptomic analysis. Methods: The differences in the expression levels of GDI2 in normal colorectal tissues and tumor tissues of colorectal cancer (CRC) patients were detected. The correlation of GDI2 expression levels with survival and clinical characteristics of CRC patients was analyzed. The effects of GDI2 expression levels on the biological functions of CRC cells were examined by CCK-8 assay, plate clone formation assay, wound healing assay, and Transwell assay. The effect of GDI2 on the proliferation and growth of xenograft tumors was investigated by a xenograft tumor model of CRC in nude mice. Based on transcriptomics, we explored the possible mechanisms and associated pathways of the effect of silencing GDI2 on CRC cells. Cellular experiments and Western blot assays were performed to verify the potential mechanisms and related pathway of GDI2 action on CRC. Results: The expression levels of GDI2 in CRC tissues and cells were higher than those in normal tissues and cells. The expression level of GDI2 correlated with clinical characteristics such as lymphatic metastasis, tumor stage, tumor volume, and lymphocyte count. Silencing of GDI2 reduced the proliferative activity and migration and invasion ability of CRC cells, as well as inhibited the proliferation of CRC xenograft tumors. The differentially expressed genes were significantly enriched in biological processes such as cell cycle arrest and the p53 signaling pathway after GDI2 silencing. The percentage of G0/G1 phase cells in CRC cells was increased after silencing GDI2 as verified by flow cytometry. RAB5A was highly associated with the p53 pathway and could interact with TP53 via the ZFYVE20 protein. The mutual binding between GDI2 protein and RAB5A protein was verified by immunoprecipitation assay. Silencing GDI2 while overexpressing RAB5A reversed the reduced proliferation, migration, and invasion ability as well as cell cycle arrest of CRC cells. Meanwhile, the addition of p53 signaling pathway inhibitor Pifithrin-α (PFT-α) also reversed the biological effects of silencing GDI2 on CRC cells. The p-p21 and p-p53 protein expression levels were significantly greater in the sh-GDI2 group than in the sh-NC group. However, the p-p21 and p-p53 protein expression levels were reduced after silencing GDI2 while overexpressing RAB5A. Conclusion: Silencing GDI2 activates the p53 signaling pathway by regulating RAB5A expression levels, which in turn induces cell cycle arrest and ultimately affects the proliferative activity, migration, and invasive ability of CRC cells.

A novel RAV transcription factor from pear interacts with viral RNA-silencing suppressors to inhibit viral infection.

In plants, RNA silencing constitutes a strong defense against viral infection, which viruses counteract with RNA-silencing suppressors (RSSs). Understanding the interactions between viral RSSs and host factors is crucial for elucidating the molecular arms race between viruses and host plants. We report that the helicase motif (Hel) of the replicase encoded by apple stem grooving virus (ASGV)-the main virus affecting pear trees in China-is an RSS that can inhibit both local and systemic RNA silencing, possibly by binding double-stranded (ds) siRNA. The transcription factor related to ABSCISIC ACID INSENSITIVE3/VIVIPAROUS1 from pear (PbRAV1) enters the cytoplasm and binds Hel through its C terminus, thereby attenuating its RSS activity by reducing its binding affinity to 21- and 24-nt ds siRNA, and suppressing ASGV infection. PbRAV1 can also target p24, an RSS encoded by grapevine leafroll-associated virus 2 (GLRaV-2), with similar negative effects on p24's suppressive function and inhibition of GLRaV-2 infection. Moreover, like the positive role of the PbRAV1 homolog from grapevine (VvRAV1) in p24's previously reported RSS activity, ASGV Hel can also hijack VvRAV1 and employ the protein to sequester 21-nt ds siRNA, thereby enhancing its own RSS activity and promoting ASGV infection. Furthermore, PbRAV1 neither interacts with CP, an RSS encoded by grapevine inner necrosis virus, nor has any obvious effect on CP's RSS activity. Our results identify an RSS encoded by ASGV and demonstrate that PbRAV1, representing a novel type of RAV transcription factor, plays a defensive role against viral infection by targeting viral RSSs.

A novel antidepressant homogeneous polysaccharide YLP-1 from Millettia pulchra ameliorates tryptophan metabolism and SCFAs through modulating gut microbiota.

The root of Millettia pulchra (YLS) has been traditionally used as a folk medicine for the treatment of depression and insomnia in the Zhuang nationality of China, and its polysaccharides have potential antidepressant effect. In this study, a novel homogeneous polysaccharide (YLP-1) was purified from the crude polysaccharides of YLS, and it is mainly composed of glucose, arabinose and mannose with molar ratio of 87.25%, 10.77%, and 1.98%, respectively. YLP-1 is a novel α-glucan with the backbone of 1,4-Glcp and branched at C6 of 1,4,6-Glcp to combine 1,4-Manp and 1,5-Araf. The microstructure of YLP-1 displayed a uniform ellipsoidal-like chain morphology and dispersed uniformly in solution. YLP-1 effectively ameliorated depression-like ethological behaviors and restored the decreased catecholamine levels in chronic variable stress (CVS)-induced depression rats. Additionally, it significantly improved the disturbance of gut microbiota induced by CVS stimuli, particularly affecting bacteria that produce short-chain fatty acids (SCFAs), such as bacteria species Lactobacillus spp.. In vitro fermentation study further confirmed that YLP-1 intake could promote SCFAs production by Lactobacillus spp. YLP-1 also mitigated the disruption of tryptophan metabolites in urine and serum. These findings provide evidences for the further development of YLP-1 as a macromolecular antidepressant drug.

The potential treatment of N-acetylcysteine as an antioxidant in the radiation-induced heart disease.

Background: Radiation-induced heart disease (RIHD) is a serious complication of thoracic tumor radiotherapy that substantially affects the quality of life of cancer patients. Oxidative stress plays a pivotal role in the occurrence and progression of RIHD, which prompted our investigation of an innovative approach for treating RIHD using antioxidant therapy. Methods: We used 8-week-old male Sprague-Dawley (SD) rats as experimental animals and H9C2 cells as experimental cells. N-acetylcysteine (NAC) was used as an antioxidant to treat H9C2 cells after X-ray irradiation in this study. In the present study, the extent of cardiomyocyte damage caused by X-ray exposure was determined, alterations in oxidation/antioxidation levels were assessed, and changes in the expression of genes related to mitochondria were examined. The degree of myocardial tissue and cell injury was also determined. Dihydroethidium (DHE) staining, reactive oxygen species (ROS) assays, and glutathione (GSH) and manganese superoxide dismutase (Mn-SOD) assays were used to assess cell oxidation/antioxidation. Flow cytometry was used to determine the mitochondrial membrane potential and mitochondrial permeability transition pore (mPTP) opening. High-throughput transcriptome sequencing and bioinformatics analysis were used to elucidate the expression of mitochondria-related genes in myocardial tissue induced by X-ray exposure. Polymerase chain reaction (PCR) was used to verify the expression of differentially expressed genes. Results: X-ray irradiation damaged myocardial tissue and cells, resulting in an imbalance of oxidative and antioxidant substances and mitochondrial damage. NAC treatment increased cell counting kit-8 (CCK-8) levels (P=0.02) and decreased lactate dehydrogenase (LDH) release (P=0.02) in cardiomyocytes. It also reduced the level of ROS (P=0.002) and increased the levels of GSH (P=0.04) and Mn-SOD (P=0.01). The mitochondrial membrane potential was restored (P<0.001), and mPTP opening was inhibited (P<0.001). Transcriptome sequencing and subsequent validation analyses revealed a decrease in the expression of mitochondria-related genes in myocardial tissue induced by X-ray exposure, but antioxidant therapy did not reverse the related DNA damage. Conclusions: Antioxidants mitigated radiation-induced myocardial damage to a certain degree, but these agents did not reverse the associated DNA damage. These findings provide a new direction for future investigations by our research group, including exploring the treatment of RIHD-related DNA damage.

[Mechanism of tetramethylpyrazine attenuates inflammatory injury in endothelial cells by activating the SIRT1 signaling pathway]. / 川芎嗪通过激活SIRT1ä¿¡å·é€šè·¯å‡è½»å† çš®ç»†èƒžç‚Žç—‡æŸä¼¤çš„æœºåˆ¶ç ”ç©¶.

OBJECTIVES: To study the effects and mechanisms of tetramethylpyrazine (TMP) on tumor necrosis factor-α (TNF-α)-induced inflammatory injury in human coronary artery endothelial cells (HCAEC). METHODS: HCAEC were randomly divided into four groups: the control group (no treatment), the model group (treated with TNF-α, 50 ng/mL for 24 hours), the TMP group (pre-treated with TMP, 80 µg/mL for 12 hours followed by TNF-α treatment for 24 hours), and the SIRT1 inhibitor group (pre-treated with TMP and the specific SIRT1 inhibitor EX527 for 12 hours followed by TNF-α treatment for 24 hours). Cell viability was assessed using the CCK-8 method, lactate dehydrogenase (LDH) activity was measured using an LDH assay kit, reactive oxygen species (ROS) levels were observed using DCFH-DA staining, expression of pyroptosis-related proteins was detected by Western blot, and SIRT1 expression was analyzed using immunofluorescence staining. RESULTS: Compared to the control group, the model group showed decreased cell viability, increased LDH activity, ROS level and expression of pyroptosis-related proteins, and decreased SIRT1 expression (P<0.05). Compared to the model group, the TMP group exhibited increased cell viability, decreased LDH activity, ROS level and expression of pyroptosis-related proteins, and increased SIRT1 expression (P<0.05). In comparison to the TMP group, the SIRT1 inhibitor group showed decreased cell viability, increased LDH activity, ROS level and expression of pyroptosis-related proteins, and decreased SIRT1 expression (P<0.05). CONCLUSIONS: TMP may attenuate TNF-α-induced inflammatory injury in HCAEC, which is associated with the inhibition of pyroptosis and activation of the SIRT1 signaling pathway.

Huang-Lian-Jie-Du Decoction alleviates diabetic encephalopathy by regulating inflammation and pyroptosis via suppression of AGEs/RAGE/NF-κB pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Cognitive dysfunction associated with diabetes, known as diabetic encephalopathy (DE), is a grave neurodegenerative condition triggered by diabetes, and persistent inflammation plays a vital role in its development. The renowned traditional Chinese medicine Huang-Lian-Jie-Du Decoction (HLJDD) is clinically proven to manage diabetes mellitus and Alzheimer's disease and is famous for its heat-clearing and detoxifying effects. However, the underlying mechanisms through which HLJDD affects DE remain to be elucidated. AIM OF THE STUDY: To explore the beneficial effects of HLJDD on improving cognitive dysfunction in DE mice. STUDY DESIGN AND METHODS: A diabetic mouse was established through a high-fat diet and subsequent administration of streptozotocin over five consecutive days. After the animals were confirmed to have diabetes, they were treated with HLJDD. After oral administration of HLJDD or metformin for 14 weeks, behavioral tests were used to assess their cognitive capacity. Biochemical analyses were then performed to detect levels of glucose metabolism, followed by histological analyses to assess pathological damage. Furthermore, AGEs/RAGE/NF-κB axis related proteins were detected by Western blot or immunofluorescence techniques. An advanced UPLC-Q-Orbitrap HRMS/MS analytical technique utilizing a chemical derivatization strategy was employed for comprehensive metabolic profiling of carbonyl compounds in the plasma of DE mice. RESULTS: Pharmacological assessment revealed that HLJDD effectively mitigated cognitive dysfunction, normalized glucose metabolic imbalances, and repaired neuronal damage in DE mice. It reduced neuroinflammation by attenuating carbonyl stress, deactivating astrocytes and microglia, and preserving dopaminergic neurons. Additionally, metabolomics analysis revealed 18 carbonyl compounds with marked disparities between DE and control mice, with 12 metabolites approaching normal levels post-HLJDD intervention. Further investigations showed that HLJDD regulated inflammation and pyroptosis through suppressing AGEs/RAGE/NF-κB pathways. CONCLUSION: Our study indicated that HLJDD could ameliorate carbonyl stress via the regulation of carbonyl compound metabolism profiling, and inhibiting the AGEs/RAGE/NF-κB pathway, thereby alleviating inflammation and pyroptosis to exert beneficial effects on DE.

Vulnerability and driving mechanism of four typical grasslands in China under the coupled impacts of climate change and human activities.

Understanding of how different grasslands types respond to climate change and human activities across different spatial and temporal dimensions is crucial for devising effective strategies to prevent grasslands degradation. In this study, we developed a novel vulnerability assessment model for grasslands that intricately evaluates the combined impact of climate change and human activities. We then applied this model to analyze the vulnerability and driving mechanism of four representative Chinese grasslands to climate change and human activities. Our findings indicate that the vulnerability of the four grasslands would show a pattern of higher in the west and lower in the east under the influence of climate change alone. However, when human activities are factored in, the vulnerability across the four grasslands tends to homogenize, with human activities notably reducing the vulnerability of alpine grasslands in the west and, conversely, increasing the vulnerability of grasslands in the east. Furthermore, our study reveals distinct major environmental drivers of grasslands vulnerability across different regions. The two western alpine grasslands exhibit higher vulnerability to annual mean temperature and isothermality compared to the eastern temperate grasslands, while their vulnerability to precipitation of the coldest quarter is lower than that of the eastern temperate grasslands. These findings are helpful for understanding the multifaceted causes and mechanisms of grasslands degradation, providing a scientific foundation for the sustainable management and conservation of grassland resources.

[Effects of Acid Mine Drainage Leakage on Bacterial Communities in Desert Grassland Soil Profiles].

Acid mine drainage （AMD） is of great concern owing to its safety hazards and environmental risks. However, little is known about the effects of AMD leakage on soil physicochemical properties and bacterial communities in ecologically fragile desert steppe soils, especially in the soil profile. Therefore, an AMD-contaminated profile and clean profile were used as research objects respectively to investigate the effects of AMD on soil physicochemical properties and bacterial community composition, structure, and interactions in soil layers at different depths of desert grassland and, based on this, to analyze the driving factors of bacterial community changes. The results showed that AMD significantly decreased the pH and increased electrical conductivity （EC） and heavy metal content in the upper （0-40 cm） soil layer of the profile. The AMD-contaminated profile bacteria were dominated by Proteobacteria, Firmicutes, and Actinobacterota, whereas clean profile bacteria were dominated by Firmicutes and Bacteroidota, with Thermithiobacillus and Alloprevotella being the biomarkers for the contaminated and clean profiles, respectively. AMD contamination significantly reduced bacterial diversity and significantly altered bacterial community structure in the upper soil layers of the profile. The results of redundancy analysis showed that soil physicochemical properties explained 57.21% of the variation in bacterial community changes, with EC, TP, TN, As, Zn, and Pb being the main drivers of bacterial community changes. Network analyses showed that AMD contamination increased profile complexity, modularity, and intra-community competition, thereby improving bacterial community stability and resilience. In conclusion, the study provided useful information on the effects of AMD pollution on soil physicochemical properties and bacterial communities in desert steppe soils, which may help to improve the understanding of the ecological hazards of AMD pollution on soils in extreme habitats.

[Effects of Long-term Biochar Addition on Denitrification N2O Emissions from Bacteria and Fungi in Paddy Soil].

Denitrification driven by bacteria and fungi is the main source of nitrous oxide （N2O） emissions from paddy soil. It is generally believed that biochar reduces N2O emissions by influencing the bacterial denitrification process, but the relevant mechanism of its impact on fungal denitrification is still unclear. In this study, the long-term straw carbonization returning experimental field in Changshu Agricultural Ecological Experimental Base of the Chinese Academy of Sciences was taken as the object. Through indoor anaerobic culture and molecular biology technology, the relative contributions of bacteria and fungi to denitrifying N2O production in paddy soil and the related microorganism mechanism were studied under different long-term biochar application amounts （blank, 2.25 t·hm-2, and 22.5 t·hm-2, respectively, expressed by BC0, BC1, and BC10）. The results showed that compared with that in BC0, biochar treatment significantly reduced N2O emission rate, denitrification potential, and cumulative N2O emissions, and the contribution of bacterial denitrification was greater than that of fungal denitrification in all three treatments. Among them, the relative contribution rate of bacterial denitrification in BC10 （62.9%） was significantly increased compared to BC0 （50.8%）, whereas the relative contribution rate of fungal denitrification in BC10 （37.1%） was significantly lower than that in BC0 （49.2%）. The application of biochar significantly increased the abundance of bacterial denitrification functional genes （nirK, nirS, and nosZ） but reduced the abundance of fungal nirK genes. The contribution rate of fungal denitrification was significantly positively correlated with the N2O emission rate and negatively correlated with soil pH, TN, SOM, and DOC. Biochar may have inhibited the growth of denitrifying fungi by increasing pH and carbon and nitrogen content, reducing the abundance of related functional genes, thereby weakening the reduction ability of NO to N2O during fungal denitrification process. This significantly reduces the contribution rate of N2O production during the fungal denitrification process and the denitrification N2O emissions from paddy soil. This study helps to broaden our understanding of the denitrification process in paddy soil and provides a theoretical basis for further regulating fungal denitrification N2O emissions.

Exploration of the Mechanisms of Bu-Yang-Huan-Wu Decoction in the Treatment of Diabetic Peripheral Neuropathy by Integrating of Serum Pharmacochemistry and Network Pharmacology.

Diabetic peripheral neuropathy (DPN) is a significant and frequent complication of diabetes. Bu-Yang-Huan-Wu Decoction (BHD) is a classic traditional Chinese herbal prescription that is commonly used in modern clinical practice for the effective treatment of DPN, but the underlying mechanism is not yet clearly defined. The chemical constituents of BHD were characterized by UPLC-Q-Orbitrap HR MS/MS, and a total of 101 chemical components were identified, including 30 components absorbed into blood. An interaction network of "compound-target-disease" interactions was constructed based on the compounds detected absorbed in blood and their corresponding targets of diabetic neuropathy acquired from disease gene databases, and the possible biological targets and potential signalling pathways of BHD were predicted via network pharmacology analysis. Subsequently, methylglyoxal-induced (MGO-induced) Schwann cells (SCs) were used to identify the active ingredients in blood components of BHD and verify the molecular mechanisms of BHD. Through network topological analysis, 30 shared targets strongly implicated in the anti-DPN effects of BHD were identifed. Combined network pharmacology and in vitro cellular analysis, we found that the active ingredient of BHD may treat DPN by modulating the AGEs/RAGE pathway. This study provides valuable evidence for future mechanistic studies and potential therapeutic applications for patients with DPN.

Unveiling the shield: Troglitazone's impact on epilepsy-induced nerve injury through ferroptosis inhibition.

BACKGROUND: Epilepsy is a widespread central nervous system disorder with an estimated 50 million people affected globally. It is characterized by a bimodal incidence peak among infants and the elderly and is influenced by a variety of risk factors, including a significant genetic component. Despite the use of anti-epileptic drugs (AEDs), drug-refractory epilepsy develops in about one-third of patients, highlighting the need for alternative therapeutic approaches. AIMS: The primary aim of this study was to evaluate the neuroprotective effects of troglitazone (TGZ) in epilepsy and to explore the potential mechanisms underlying its action. METHODS: We employed both in vitro and in vivo models to assess TGZ's effects. The in vitro model involved glutamate-induced toxicity in HT22 mouse hippocampal neurons, while the in vivo model used kainic acid (KA) to induce epilepsy in mice. A range of methods, including Hoechst/PI staining, CCK-8 assay, flow cytometry, RT-PCR analysis, Nissl staining, scanning electron microscopy, and RNA sequencing, were utilized to assess various parameters such as cellular damage, viability, lipid-ROS levels, mitochondrial membrane potential, mRNA expression, seizure grade, and mitochondrial morphology. RESULTS: Our results indicate that TGZ, at doses of 5 or 20 mg/kg/day, significantly reduces KA-induced seizures and neuronal damage in mice by inhibiting the process of ferroptosis. Furthermore, TGZ was found to prevent changes in mitochondrial morphology. In the glutamate-induced HT22 cell damage model, 2.5 µM TGZ effectively suppressed neuronal ferroptosis, as shown by a reduction in lipid-ROS accumulation, a decrease in mitochondrial membrane potential, and an increase in PTGS2 expression. The anti-ferroptotic effect of TGZ was confirmed in an erastin-induced HT22 cell damage model as well. Additionally, TGZ reversed the upregulation of Plaur expression in HT22 cells treated with glutamate or erastin. The downregulation of Plaur expression was found to alleviate seizures and reduce neuronal damage in the mouse hippocampus. CONCLUSION: This study demonstrates that troglitazone has significant therapeutic potential in the treatment of epilepsy by reducing epileptic seizures and the associated brain damage through the inhibition of neuronal ferroptosis. The downregulation of Plaur expression plays a crucial role in TGZ's anti-ferroptotic effect, offering a promising avenue for the development of new epilepsy treatments.

Second-Harmonic-Generation Switching via Pressure-Suppressed Dynamical Disorder.

Second-harmonic-generation (SHG) switching is an emerging phenomenon with potential applications in bistable storage and optical switches while also serving as a sensitive probe for inversion-symmetry. Temperature-induced disorder-order phase transition has been proven to be a rational design strategy for achieving SHG bi-state switching; however, pressure-sensitive SHG switching via a disorder-order structural transition mechanism is rarely reported and lacks sensitivity and cyclicity as practical switching materials. Herein, we demonstrate the pressure-induced "dynamical disorder-order" phase transition as an effective strategy for triggering SHG and SHG switching in NH4Cl. The "dynamical disorder-order" phase transition of NH4Cl occurring at as low as 1 GPa is confirmed by comprehensive in situ high-pressure XRD, molecular vibrational spectra, and Brillouin scattering spectra. The pressure-induced SHG is responsive to a wide excitation wavelength region (800-1500 nm), and the "off-on" switching is reversible for up to 50 cycles, setting a record for pressure-driven switching materials. It is worth noting that when pressure is further increased to 14 GPa, NH4Cl exhibits another SHG "on-off" switching, which makes it the first triplet SHG "off-on-off" switching material. Molecular dynamics simulations reveal the key role of N-H···Cl hydrogen bonding in the pressure-induced "dynamic disorder-order" mechanism. Finally, we verified that chemical pressure and physical pressure can jointly regulate the SHG switching behavior of NH4X (X = Cl, Br). The pressure-driven "dynamic disorder-order" transition mechanism sheds light on the rational design of multistable SHG switching materials for photoswitches and information storage.

[3 + 2] Annulation of Vinyl Azides with Aldehydes for the Synthesis of 3-Oxazolines via the [CO + CCN] Strategy.

Despite the widespread utilizable value of 3-oxazolines, mild and efficient access to such a class of unique structures still remains, to date, a challenge. Herein, we present a [3 + 2] annulation strategy, guided by the retrosynthetic principle of [CO + CCN], that utilizes vinyl azides as the CCN module and aldehydes as the CO module. This approach enables the efficient construction of the 3-oxazoline framework with remarkable features, including operational simplicity, environmental friendliness, and high efficiency. Notably, it solely requires the addition of inexpensive and readily available N-hydroxyphthalimide (NHPI) and air oxygen to obtain the desired product. It also provides a new way to generate the hydroxyl radical, which is produced by the homolysis of peroxycarboxylic acid. In addition, control experiments, X-ray crystallographic analysis, high-resolution mass spectrometry (HRMS), and density functional theory (DFT) calculations afford evidence for the key intermediates (hydroxyl radical, carboxyl radical, imine radical, hydroxyl substituted amide derivatives), further confirming the path for realization of 3-oxazolines.

Avicularin Attenuated Lead-Induced Ferroptosis, Neuroinflammation, and Memory Impairment in Mice.

Lead (Pb) is a common environmental neurotoxicant that results in abnormal neurobehavior and impaired memory. Avicularin (AVL), the main dietary flavonoid found in several plants and fruits, exhibits neuroprotective and hepatoprotective properties. In the present study, the effects of AVL on Pb-induced neurotoxicity were evaluated using ICR mice to investigate the molecular mechanisms behind its protective effects. Our study has demonstrated that AVL treatment significantly ameliorated memory impairment induced by lead (Pb). Furthermore, AVL mitigated Pb-triggered neuroinflammation, ferroptosis, and oxidative stress. The inhibition of Pb-induced oxidative stress in the brain by AVL was evidenced by the reduction in malondialdehyde (MDA) levels and the enhancement of glutathione (GSH) and glutathione peroxidase (GPx) activities. Additionally, in the context of lead-induced neurotoxicity, AVL mitigated ferroptosis by increasing the expression of GPX4 and reducing ferrous iron levels (Fe2+). AVL increased the activities of glycogenolysis rate-limiting enzymes HK, PK, and PYG. Additionally, AVL downregulated TNF-α and IL-1ß expression while concurrently enhancing the activations of AMPK, Nrf2, HO-1, NQO1, PSD-95, SNAP-25, CaMKII, and CREB in the brains of mice. The findings from this study suggest that AVL mitigates the memory impairment induced by Pb, which is associated with the AMPK/Nrf2 pathway and ferroptosis.

Preparation of kakkatin derivatives and their anti-tumor activity.

BACKGROUND: Modern pharmacological studies have confirmed that plant-derived compounds from Puerariae flos (PF) has significant biological activities against liver damage, tumors and inflammation. Kakkatin is an isoflavone polyphenolic compound isolated from PF flower. However, the effect of kakkatin and its derivatives on anti-tumor has not been well explored. AIM: To design and synthesize a kakkatin derivative [6-(hept-6-yn-1-yloxy)-3-(4-hydroxyphenyl)-7-methoxy-4H-chromen-4-one (HK)] to explore its anti-tumor biological activity. METHODS: Hept-6-yn-1-yl ethanesulfonate was introduced to replace hydrogen at the hydroxyl position of kakkatin phenol, and the derivative of kakkatin was prepared; the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide was used to detect cell viability, a clone formation assay was adopted to detect cell proliferation, apoptosis, necrosis, and cell cycles were analyzed by Annexin V/propidium iodide staining and flow cytometry. Cell migration and invasion ability were evaluated by cell scratch assay and transwell assay. The potential mechanism of HK on hepatocellular carcinoma (HCC) SMMC-7721 cells was explored through network pharmacology and molecular docking, and finally real-time PCR assays was used to verify the potential targets and evaluate the biological activity of HK. RESULTS: Compared with kakkatin, the modified HK did not significantly increase the inhibitory activity of gastric cancer MGC803 cells, but the inhibitory activity of HCC SMMC-7721 cells was increased by about 30 times, with an IC50 value of 2.5 µM, and the tumor inhibition effect was better than cisplatin, which could significantly inhibit the cloning, invasion and metastasis of HCC SMMC-7721 cells, and induce apoptosis and G2/M cycle arrest. Its mechanism of action is mainly related to the upregulation of PDE3B and NFKB1 target proteins in the cAMP pathway. CONCLUSION: HK have a significant inhibitory effect on HCC SMMC-7721 cells, and the targets of their action may be PDE3B and NFKB1 proteins in the cAMP pathway, making it a good lead drug for the treatment of HCC.

Global, regional, and national burden of HIV-negative tuberculosis, 1990-2021: findings from the Global Burden of Disease Study 2021.

BACKGROUND: Tuberculosis (TB) is a major infectious disease with significant public health implications. Its widespread transmission, prolonged treatment duration, notable side effects, and high mortality rate pose severe challenges. This study examines the epidemiological characteristics of TB globally and across major regions, providing a scientific basis for enhancing TB prevention and control measures worldwide. METHODS: The ecological study used data from the Global Burden of Disease (GBD) Study 2021. It assessed new incidence cases, deaths, disability-adjusted life years (DALYs), and trends in age-standardized incidence rates (ASIRs), mortality rates (ASMRs), and DALY rates for drug-susceptible tuberculosis (DS-TB), multidrug-resistant tuberculosis (MDR-TB), and extensively drug-resistant tuberculosis (XDR-TB) from 1990 to 2021. A Bayesian age-period-cohort model was applied to project ASIR and ASMR. RESULTS: In 2021, the global ASIR for all HIV-negative TB was 103.00 per 100,000 population [95% uncertainty interval (UI): 92.21, 114.91 per 100,000 population], declining by 0.40% (95% UI: - 0.43, - 0.38%) compared to 1990. The global ASMR was 13.96 per 100,000 population (95% UI: 12.61, 15.72 per 100,000 population), with a decline of 0.44% (95% UI: - 0.61, - 0.23%) since 1990. The global age-standardized DALY rate for HIV-negative TB was 580.26 per 100,000 population (95% UI: 522.37, 649.82 per 100,000 population), showing a decrease of 0.65% (95% UI: - 0.69, - 0.57 per 100,000 population) from 1990. The global ASIR of MDR-TB has not decreased since 2015, instead, it has shown a slow upward trend in recent years. The ASIR of XDR-TB has exhibited significant increase in the past 30 years. The projections indicate MDR-TB and XDR-TB are expected to see significant increases in both ASIR and ASMR from 2022 to 2035, highlighting the growing challenge of drug-resistant TB. CONCLUSIONS: This study found that the ASIR of MDR-TB and XDR-TB has shown an upward trend in recent years. To reduce the TB burden, it is essential to enhance health infrastructure and increase funding in low-SDI regions. Developing highly efficient, accurate, and convenient diagnostic reagents, along with more effective therapeutic drugs, and improving public health education and community engagement, are crucial for curbing TB transmission.

Exploring the antimicrobial activity of rare ginsenosides and the progress of their related pharmacological effects.

BACKGROUND: Panax ginseng C. A. Mey is a precious medicinal resource that could be used to treat a variety of diseases. Saponins are the most important bioactive components of, and rare ginsenosides (Rg3, Rh2, Rk1 and Rg5, etc.) refer to the chemical structure changes of primary ginsenosides through dehydration and desugarization reactions, to obtain triterpenoids that are easier to be absorbed by the human body and have higher activity. PURPOSE: At present, the research of P. ginseng. is widely focused on anticancer related aspects, and there are few studies on the antibacterial and skin protection effects of rare ginsenosides. This review summarizes the rare ginsenosides related to bacterial inhibition and skin protection and provides a new direction for P. ginseng research. METHODS: PubMed and Web of Science were searched for English-language studies on P. ginseng published between January 2002 and March 2024. Selected manuscripts were evaluated manually for additional relevant references. This review includes basic scientific articles and related studies such as prospective and retrospective cohort studies. CONCLUSION: This paper summarizes the latest research progress of several rare ginsenosides, discusses the antibacterial effect of rare ginsenosides, and finds that ginsenosides can effectively protect the skin and promote wound healing during use, so as to play an efficient antibacterial effect, and further explore the other medicinal value of ginseng. It is expected that this review will provide a wider understanding and new ideas for further research and development of P. ginseng drugs.