HDAC6 modulates the cognitive behavioral function and hippocampal tissue pathological changes of APP/PS1 transgenic mice through HSP90-HSF1 pathway.

The aim of this study was to investigate histone deacetylase 6 (HDAC6) modifies the heat shock protein 90 (HSP90) and heat shock transcription factor 1 (HSF1) affect the levels of pathological markers such as Aß oligomers (Aßo) and Tau phosphorylation (p-Tau) in APP/PS1 double transgenic mice hippocampal tissues or HT22 neurons as well as the changes in cognitive behavioral functions of mice. (1) APP/PS1 transgenic mice (6 months old, 25 ~ 30 g) were randomly assigned to 5 experimental groups, C57BL/6J mice (6 months old, 25 ~ 30 g) were used as 4 control groups, with 8 mice in each group. All mice underwent intracerebroventricular (i.c.v.) cannulation, and the experimental groups were administered with normal saline (APP + NS group), HDAC6 agonist tubastatin A hydrochloride (TSA) (APP + TSA group) or HDAC6 agonist theophylline (Theo) (APP + Theo group), HSP90 inhibitor Ganetespib (Gane) (APP + Gane group), or a combination of pre-injected Gane by TSA (APP + Gane + TSA group); the control group received i.c.v. injections of Gane (Gane group), TSA (TSA group), Theo (Theo group) or NS (NS group), respectively. (2) Mouse hippocampal neurons HT22 were randomly divided into a control group (Control) and an Aß1-42 intervention group (Aß). Within the Aß group, further divisions were made for knockdown HSP90 (Aß + siHSP90 group), overexpression HSP90 (Aß + OE-HSP90 group), knockdown HSF1(Aß + siHSF1 group) and knockdown HSF1 followed by overexpression HSP90 (Aß + siHSF1 + OE-HSP90 group), resulting in a total of 6 groups. Morris water maze test was used to evaluate the cognitive behavior of the mice. Western blot and immunohistochemistry or immunofluorescence were performed to detect the levels of HDAC6, HSP90, HSF1, Aß1-42, Tau protein, and p-Tau in the hippocampal tissue or HT22 cells. qRT-PCR was used to measure the levels of hdac6, hsp90, and hsf1 mRNA in the hippocampus or nerve cells. (1) The levels of HDAC6, Aß1-42 and p-Tau were elevated, while HSP90 and HSF1 were decreased in the hippocampal tissue of APP/PS1 transgenic mice (all P < 0.01). Inhibiting HDAC6 upregulated the expressions of HSP90 and HSF1 in the hippocampal tissue of APP/PS1 mice, while decreasing the levels of Aß1-42 and p-Tau as well as improving the spatial cognitive behavior in mice (P < 0.05 or P < 0.01). The opposite effects were observed upon HDAC6 activation. However, inhibiting HSP90 reduced the expression of HSF1 (P < 0.01) and increased the levels of Aß1-42 and p-Tau (P < 0.05 or P < 0.01) but did not significantly affect the expression of HDAC6 (P > 0.05). No significant changes were observed in the aforementioned indicators in the 4 control groups (P > 0.05). (2) In the Aß1-42 intervention group, HDAC6 and Aß1-42, p-Tau expression levels were elevated, while HSP90 and HSF1 expressions were all decreased, and cell viability was reduced (P < 0.05 or P < 0.01). Overexpression of HSP90 upregulated HSF1 expression, decreased the levels of Aß1-42 and p-Tau, and increased cell viability (P < 0.05 or P < 0.01). Knocking down HSP90 had the opposite effect; and knocking down HSF1 increased the levels of Aß1-42 and p-Tau and decreased cells viability (all P < 0.01), but did not result in significant changes in the expression levels of HSP90 (P > 0.05). Inhibiting HDAC6 can upregulate the expressions of HSP90 and HSF1 but reduce the levels of Aß1-42 and p-Tau in the hippocampus of APP/PS1 mice and improvement of cognitive behavioral function in mice; Overexpression of HSP90 can increase HSF1 but decrease Aß1-42 and p-Tau levels in the hippocampal neurons and increase cell activity. It is suggested that HDAC6 may affect the formation of Aß oligomers and the changes in Tau protein phosphorylation levels in the hippocampus of AD transgenic mouse as well as the alterations in cognitive behavioral functions by regulating the HSP90-HSF1 pathway.

[Age-dependent expression of HSP90 in the hippocampus of APP/PS1 mice].

The present study aims to observe the change in expression of heat shock protein 90 (HSP90) along with amyloid-ß (Aß) and phosphorylated Tau (p-Tau) protein levels in the hippocampus tissue of Alzheimer's disease (AD) transgenic animal model with age. APP/PS1 transgenic mice at age of 6-, 9- and 12-month and C57BL/6J mice of the same age were used. The cognitive abilities of these animals were evaluated using a Morris water maze. Western blot or immunohistochemistry was used to detect the expressions of HSP90 and Aß1-42, as well as the phosphorylation levels of Tau protein in the hippocampus. The hsp90 mRNA levels and the morphology and number of cells in the hippocampus were detected with real-time quantitative polymerase chain reaction (qRT-PCR) and Nissl staining, respectively. The results showed that compared with C57BL/6J mice of the same age, HSP90 and hsp90 mRNA expression were decreased (P < 0.05 or P < 0.01), while Aß1-42 and p-Tau protein levels were increased (P < 0.05 or P < 0.01) in the hippocampal tissue of APP/PS1 transgenic mice. Meanwhile, the decrease in HSP90 and hsp90 mRNA expression (P < 0.05 or P < 0.01), the increase in Aß1-42 and p-Tau levels (P < 0.01 or P < 0.05) in hippocampal tissue and the reduction in behavioral ability showed a progressive development with the advancing of age in the APP/PS1 transgenic mice. In conclusion, in the hippocampal tissue of APP/PS1 mice, the decrease in HSP90 expression and the increase in Aß1-42 and p-Tau levels together with the decline of their cognitive ability are age-dependent.

Prevention effect of total ginsenosides and ginseng extract from Panax ginseng on cyclophosphamide-induced immunosuppression in mice.

Oral decoction is widely applied in traditional Chinese medicines. The polysaccharides of decoction promote the exposure of small molecules and increase their bioavailability. This study mainly compared the component and activities of total ginsenosides (TGS) and ginseng extract (GE) on immunosuppressed mice induced by cyclophosphamide. Thirty-two mice were randomly divided into control, model, TGS, and GE groups. The mice were orally administered for 28 days and then injected with cyclophosphamide on the last four days. The results of component analysis showed the total content of 12 ginsenosides in TGS (67.21%) was higher than GE (2.04%); the total content of 17 amino acids in TGS (1.41%) was lower than GE (5.36%); the total content of 10 monosaccharides was similar in TGS (74.12%) and GE (76.36%). The animal results showed that both TGS and GE protected the hematopoietic function of bone marrow by inhibiting cell apoptosis, and recovering the normal cell cycle of BM; maintained the dynamic balance between the Th1 and Th2 cells; also protected the spleen, thymus, and liver. Meanwhile, TGS and GE protected the intestinal bacteria of immunosuppressed mice by increasing the abundance of lactobacillus and decreasing the abundance of the odoribacter and clostridia_UCG-014. The prevention effect of GE was superior to TGS in some parameters. In conclusion, TGS and GE protected the immune function of immunosuppressed mice induced by cyclophosphamide. Meanwhile, GE showed higher bioavailability and bioactivity compared with TGS, because the synergistic effect of polysaccharides and ginsenosides plays an important role in protecting the immune function.

Ginseng in vascular dysfunction: A review of therapeutic potentials and molecular mechanisms.

Vascular dysfunction can lead to a variety of fatal diseases, including cardiovascular and cerebrovascular diseases, metabolic syndrome, and cancer. Although a large number of studies have reported the therapeutic effects of natural compounds on vascular-related diseases, ginseng is still the focus of research. Ginseng and its active substances have bioactive effects against different diseases with vascular dysfunction. In this review, we summarized the key molecular mechanisms and signaling pathways of ginseng, its different active ingredients or formula in the prevention and treatment of vascular-related diseases, including cardiac-cerebral vascular diseases, hypertension, diabetes complications, and cancer. Moreover, the bidirectional roles of ginseng in promoting or inhibiting angiogenesis have been highlighted. We systematically teased out the relationship between ginseng and vascular dysfunction, which could provide a basis for the clinical application of ginseng in the future.

[PTK2B affects the levels of Aß in blood and brain and behavioral functions via targeting LRP-1 transporter in Aß-induced cognitive dysfunction mice].

The aim of the present study was to explore the correlation between ptk2b/PTK2B (protein tyrosine kinase 2 beta, a ptk2b-encoded protein) and the level of low density lipoprotein receptor-related protein-1 (LRP-1), as well as to uncover the relationship between the changes in beta amyloid protein (Aß) levels in blood and brain and the expression of ptk2b in Aß-induced cognitive dysfunction mice. A total of 64 3-month-old C57BL/6J mice were divided randomly into the experimental group and control group. All mice underwent the intracerebroventricular (i.c.v.) intubation. Mice in the experimental group received the i.c.v. infusion of oligomeric Aß1-42 (0.1 µg/µL, 3.6 µL) to construct the cognitively impaired models, and three days later, those mice were further injected with PF431396 (an inhibitor of PTK2B, 15 µg/mL, Aß + PF group), phorbol-12-myristate-13-acetate (PMA, an agonist of PTK2B, 18.75 µg/mL, Aß + PMA group), RAP (an inhibitor of LRP-1, 0.2 µg/mL, Aß + RAP group) or normal saline (Aß + NS group). For mice in the control group, they underwent the i.c.v. infusion of NS, and 3 days later, they were additionally injected with PF431396 (PF group), PMA (PMA group), RAP (RAP group) or NS (NS group) in the volume of 2 µL. One week later, all mice were subjected to the determination of behavioral function in Morris water maze and the measurement of expression of Aß1-42, LRP-1 and PTK2B in blood and hippocampus using immunohistochemistry (IHC) staining, enzyme-linked immunosorbent assay (ELISA) and Western blot, and the measurement of mRNA expression of ptk2b in hippocampus using qRT-PCR. The results showed that the infusion of Aß induced an increase of Aß1-42 level in hippocampus and a decrease in blood, with the down-regulation of LRP-1 protein expression in hippocampus and up-regulation of mRNA and protein expression of ptk2b in hippocampus. For cognitively impaired mice, intervention of PF431396 caused the down-regulation of protein and mRNA expression of ptk2b in the hippocampus, while LRP-1 in hippocampus was up-regulated with a decrease in the level of Aß1-42 in hippocampus and an increase in the level of Aß1-42 in the blood, as well as significant improvement in cognitive function, while the administration of PMA resulted in the opposite changes. Moreover, the administration of RAP triggered the down-regulation of LRP-1 expression in hippocampus and an increase in the level of Aß1-42 in hippocampus and a decrease in the level of Aß1-42 in blood, with the deterioration of the behavioral functions, while protein and mRNA expression of ptk2b in hippocampus showed no evident changes. These results suggest that, in cognitively impaired mice, PTK2B, possibly via down-regulating LRP-1, increases the Aß1-42 level in brain, but decreases the Aß1-42 level in blood, thereby deteriorating the cognitive and behavioral functions of mice.

[Temporal and spatial changes of α7nAChR and nNOS in cerebral cortex and hippocampus of Aß-induced cognitive dysfunction rats].

The present study was to explore the temporal and spatial distributions and variations of α7 nicotinic acetylcholine receptor (α7nAChR) and neuronal nitric oxide synthetase (nNOS) in cerebral cortex and hippocampus of Aß-induced cognitive dysfunction rats. Sixty Sprague-Dawley (SD) rats were randomly divided into six groups. Three experimental groups were intracerebroventricularly (i.c.v.) injected with condensed-amyloid beta peptides 1-42 (Aß1-42, 2.5 µg/µL, 4 µL) and were observed on day 7 (7 d Aß group), day 14 (14 d Aß group) and day 21 (21 d Aß group), respectively. Three control groups were i.c.v. injected with equivalent volume of normal saline and observed at the same time points as the experimental groups. The learning and memory abilities of rats were tested with Y-maze; the locations and protein expression levels of α7nAChR and nNOS in cerebral cortex and hippocampal CA1, CA3, DG regions were measured by immunohistochemistry and Western blot, respectively. The result showed that, compared with the control groups, the three experimental groups exhibited decreased learning and memory behavioral abilities, and down-regulated expressions of nNOS and α7nAChR in prefrontal cortex and hippocampal regions, especially in superficial layer of prefrontal cortex and hippocampal CA3 region. Comparisons among the three experimental groups showed that the inhibitory effects of Aß on the abilities of learning and memory and the expressions of α7nAChR and nNOS in prefrontal cortex and hippocampus were time dependent. The results suggest that the coincident declines of α7nAChR and nNOS in prefrontal cortex and hippocampus may be the foundations of the cognitive dysfunction.

[The synergetic effects of nitric oxide and nicotinic acetylcholine receptor on learning and memory of rats].

The aim of the present study is to explore the interaction of nitric oxide (NO) and nicotinic acetylcholine receptor (nAChR) on learning and memory of rats. Rats were intracerebroventricularly (i.c.v.) injected with L-arginine (L-Arg, the NO precursor) (L-Arg group) or choline chloride (CC, an agonist of α7nAChR) (CC group), and with combined injection of L-Arg and CC (L-Arg+CC group), and methyllycaconitine (MLA, α7nAChR antagonist) or N(ω)-nitro-L-arginine methylester (L-NAME, nitric oxide synthase inhibitor) i.c.v. injected first and followed by administration of L-Arg combined with CC (MLA+L-Arg+CC group or L-NAME+L-Arg+CC group), respectively, and normal saline was used as control (NS group). The learning and memory ability of rats was tested with Y-maze; the level of NO and the expressions of neuronal nitric oxide synthase (nNOS) or α7nAChR in hippocampus were measured by NO assay kit, immunohistochemistry or Western blot. The results showed that compared with L-Arg group or CC group, the rats' learning and memory behavioral ability in Y-maze was observably enhanced and the level of NO, the optical density of nNOS-like immunoreactivity (LI) or α7nAChR-LI in hippocampus were significantly increased in L-Arg+CC group; Compared with L-Arg+CC group, the ability of learning and memory and the level of NO as well as the expressions of nNOS-LI or α7nAChR-LI were obviously decreased in MLA+L-Arg+CC group or in L-NAME+L-Arg+CC group. In conclusion, i.c.v. administration of L-Arg combined with CC significantly improved the action of the L-Arg or CC on the content of NO and the nNOS or α7nAChR expressions in hippocampus along with the learning and memory behavior of rats; when nNOS or α7nAChR was interrupted in advance, the effects of L-Arg combined with CC were also suppressed. The results suggest that there are probably synergistic effects between NO and nAChR on learning and memory.

Structural Characters and Pharmacological Activity of Protopanaxadiol-Type Saponins and Protopanaxatriol-Type Saponins from Ginseng.

Ginseng has a long history of drug application in China, which can treat various diseases and achieve significant efficacy. Ginsenosides have always been deemed important ingredients for pharmacological activities. Based on the structural characteristics of steroidal saponins, ginsenosides are mainly divided into protopanaxadiol-type saponins (PDS, mainly including Rb1, Rb2, Rd, Rc, Rh2, CK, and PPD) and protopanaxatriol-type saponins (PTS, mainly including Re, R1, Rg1, Rh1, Rf, and PPT). The structure differences between PDS and PTS result in the differences of pharmacological activities. This paper provides an overview of PDS and PTS, mainly focusing on their chemical profile, pharmacokinetics, hydrolytic metabolism, and pharmacological activities including antioxidant, antifatigue, antiaging, immunodulation, antitumor, cardiovascular protection, neuroprotection, and antidiabetes. It is intended to contribute to an in-depth study of the relationship between PDS and PTS.

The impact of oxidative stress-induced mitochondrial dysfunction on diabetic microvascular complications.

Diabetes mellitus (DM) is a metabolic disease characterized by chronic hyperglycaemia, with absolute insulin deficiency or insulin resistance as the main cause, and causes damage to various target organs including the heart, kidney and neurovascular. In terms of the pathological and physiological mechanisms of DM, oxidative stress is one of the main mechanisms leading to DM and is an important link between DM and its complications. Oxidative stress is a pathological phenomenon resulting from an imbalance between the production of free radicals and the scavenging of antioxidant systems. The main site of reactive oxygen species (ROS) production is the mitochondria, which are also the main organelles damaged. In a chronic high glucose environment, impaired electron transport chain within the mitochondria leads to the production of ROS, prompts increased proton leakage and altered mitochondrial membrane potential (MMP), which in turn releases cytochrome c (cyt-c), leading to apoptosis. This subsequently leads to a vicious cycle of impaired clearance by the body's antioxidant system, impaired transcription and protein synthesis of mitochondrial DNA (mtDNA), which is responsible for encoding mitochondrial proteins, and impaired DNA repair systems, contributing to mitochondrial dysfunction. This paper reviews the dysfunction of mitochondria in the environment of high glucose induced oxidative stress in the DM model, and looks forward to providing a new treatment plan for oxidative stress based on mitochondrial dysfunction.

Research Progress and Molecular Mechanisms of Endothelial Cells Inflammation in Vascular-Related Diseases.

Endothelial cells (ECs) are widely distributed inside the vascular network, forming a vital barrier between the bloodstream and the walls of blood vessels. These versatile cells serve myriad functions, including the regulation of vascular tension and the management of hemostasis and thrombosis. Inflammation constitutes a cascade of biological responses incited by biological, chemical, or physical stimuli. While inflammation is inherently a protective mechanism, dysregulated inflammation can precipitate a host of vascular pathologies. ECs play a critical role in the genesis and progression of vascular inflammation, which has been implicated in the etiology of numerous vascular disorders, such as atherosclerosis, cardiovascular diseases, respiratory diseases, diabetes mellitus, and sepsis. Upon activation, ECs secrete potent inflammatory mediators that elicit both innate and adaptive immune reactions, culminating in inflammation. To date, no comprehensive and nuanced account of the research progress concerning ECs and inflammation in vascular-related maladies exists. Consequently, this review endeavors to synthesize the contributions of ECs to inflammatory processes, delineate the molecular signaling pathways involved in regulation, and categorize and consolidate the various models and treatment strategies for vascular-related diseases. It is our aspiration that this review furnishes cogent experimental evidence supporting the established link between endothelial inflammation and vascular-related pathologies, offers a theoretical foundation for clinical investigations, and imparts valuable insights for the development of therapeutic agents targeting these diseases.

Therapeutic application of natural products: NAD+ metabolism as potential target.

BACKGROUND: Nicotinamide adenine dinucleotide (NAD+) metabolism is involved in the entire physiopathological process and is critical to human health. Long-term imbalance in NAD+ homeostasis is associated with various diseases, including non-alcoholic fatty liver disease, diabetes mellitus, cardiovascular diseases, neurodegenerative disorders, aging, and cancer, making it a potential target for effective therapeutic strategies. Currently, several natural products that target NAD+ metabolism have been widely reported to have significant therapeutic effects, but systematic summaries are lacking. PURPOSE: To summarize the latest findings on the prevention and treatment of various diseases through the regulation of NAD+ metabolism by various natural products in vivo and in vitro models, and evaluate the toxicities of the natural products. METHODS: PubMed, Web of Science, and ScienceDirect were searched using the keywords "natural products sources," "toxicology," "NAD+ clinical trials," and "NAD+," and/or paired with "natural products" and "diseases" for studies published within the last decade until January 2023. RESULTS: We found that the natural products mainly include phenols (curcumin, cyclocurcumin, 4-hydroxybenzyl alcohol, salvianolic acid B, pterostilbene, EGCG), flavonoids (pinostrobin, apigenin, acacetin, tilianin, kaempferol, quercetin, isoliquiritigenin, luteolin, silybin, hydroxysafflor yellow A, scutellarin), glycosides (salidroside), quinones (emodin, embelin, ß-LAPachone, shikonin), terpenoids (notoginsenoside R1, ginsenoside F2, ginsenoside Rd, ginsenoside Rb1, ginsenoside Rg3, thymoquinone, genipin), pyrazines (tetramethylpyrazine), alkaloids (evodiamine, berberine), and phenylpropanoids (ferulic acid). These natural products have antioxidant, energy-producing, anti-inflammatory, anti-apoptotic and anti-aging effects, which mainly influence the NAMPT/NAD+/SIRT, AMPK/SIRT1/PGC-1α, Nrf2/HO-1, PKCs/PARPs/NF-κB, and AMPK/Nrf2/mTOR signaling pathways, thereby regulating NAD+ metabolism to prevent and treat various diseases. These natural products have been shown to be safe, tolerable and have fewer adverse effects in various in vivo and in vitro studies and clinical trials. CONCLUSION: We evaluated the toxic effects of natural products and summarized the available clinical trials on NAD+ metabolism, as well as the recent advances in the therapeutic application of natural products targeting NAD+ metabolism, with the aim to provide new insights into the treatment of multiple disorders.

SIRT1-SIRT7 in Diabetic Kidney Disease: Biological Functions and Molecular Mechanisms.

Diabetic kidney disease (DKD) is a severe microvascular complication in patients with diabetes and is one of the main causes of renal failure. The current clinical treatment methods for DKD are not completely effective, and further exploration of the molecular mechanisms underlying the pathology of DKD is necessary to improve and promote the treatment strategy. Sirtuins are class III histone deacetylases, which play an important role in many biological functions, including DNA repair, apoptosis, cell cycle, oxidative stress, mitochondrial function, energy metabolism, lifespan, and aging. In the last decade, research on sirtuins and DKD has gained increasing attention, and it is important to summarize the relationship between DKD and sirtuins to increase the awareness of DKD and improve the cure rates. We have found that miRNAs, lncRNAs, compounds, or drugs that up-regulate the activity and expression of sirtuins play protective roles in renal function. Therefore, in this review, we summarize the biological functions, molecular targets, mechanisms, and signaling pathways of SIRT1-SIRT7 in DKD models. Existing research has shown that sirtuins have the potential as effective targets for the clinical treatment of DKD. This review aims to lay a solid foundation for clinical research and provide a theoretical basis to slow the development of DKD in patients.

[Time dependent expression profiling of PTK2B and its relationship with Aß, Tau and LRP-1 in hippocampus and blood of APPswe/PS1dE9 double-transgenic mouse].

Objective: To uncover the time-dependent expression pattern of ptk2b gene and ptk2b-encoded protein, protein tyrosine kinase 2 beta(PTK2B), in the brain tissues of transgenic animal models of Alzheimer's disease (AD) and its relationship with the levels of Aß1-42, phosphorylation of Tau (p-Tau) and low density lipoprotein receptor-related protein-1(LRP-1) in blood and brain tissues. Methods: In this study, 5-, 10- and 15-month-old APPswe/PS1dE9 double-transgenic mice harboring the genotype of AD confirmed by the gene test were divided into the 5-, 10- and 15-month-old experiment groups, and simultaneously, age-matched C57BL/6J mice were placed into the corresponding control groups, with 8 mice in each group. All mice were subjected to the Morris Water Maze for test of cognitive and behavioral ability. Expression profiles of PTK2B, Aß1-42, p-Tau/Tau and LRP-1 in the hippocampus or blood of mice were quantified by using the immunohistochemistry staining, Western blot or enzyme-linked immunosorbent assay (ELISA), while the mRNA expression of ptk2b in the hippocampus was quantified by using the real-time quantitative polymerase chain reaction (qRT-PCR). Results: Results of experiment groups demonstrated that as mice aged, the expression levels of PTK2B, ptk2b mRNA, Aß1-42 and p-Tau/Tau in the hippocampus were increased, and the expression of LRP-1 was decreased gradually. While in the blood, the level of Aß1-42 was decreased, and the cognitive and behavioral ability was decreased in an age-dependent manner (all P＜ 0.05). However, comparisons among the control groups, only the age-dependent downregulation of LRP-1 were observed in hippocampus(P＜0.05), but other indicators had no significant differences (P＞0.05). Conclusion: In the hippocampus of APP/PS1 double-transgenic mice, the expressions of PTK2B, Aß1-42 and p-Tau/Tau are upregulated, LRP-1 is downregulated, while cognitive and behavioral ability is decreased, and such changes are presented in a time-dependent manner.

Jiedu Tongluo Baoshen formula enhances podocyte autophagy and reduces proteinuria in diabetic kidney disease by inhibiting PI3K/Akt/mTOR signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Traditional Chinese medicine (TCM) has been applied to diabetic kidney disease (DKD). A large number of animal trials each year focus on TCM for DKD, but the evidence for these preclinical studies is not clear. AIM OF THE STUDY: The aim of this study was to study the therapeutic effect of Jiedu Tongluo Baoshen formula (JTBF) on DKD proteinuria and renal protection. At the same time, it is verified that JTBF can reduce podocyte injury by enhancing autophagy function, and then achieve the effect of proteinuria. MATERIALS AND METHODS: We use high performance liquid chromatography to detect and analyze the fingerprint of JTBF to find the chemical composition. Subsequently, we constructed a DKD rat model induced by high-fat diet and streptozocin (HFD + STZ). Urine and blood biochemical automatic analyzer were used to detect 24-h urine protein quantification (24 h-UP) and renal function. The renal pathological changes were observed by H&E and transmission electron microscopy (TEM), and the levels of autophagy-related proteins and mRNA in podocytes were detected by immunohistochemistry, RT-qPCR and Western Blot. The chemical composition of JTBF was screened from traditional Chinese medicine systems pharmacol (TCMSP) and PubChem databases, and the potential targets and associated pathways of JTBF were predicted using kyoto encyclopedia of genes and genomes (KEGG) and protein-protein interaction (PPI) network analysis in network pharmacology, and confirmed in animal experiments and histopathological methods. RESULTS: We discovered 77 active ingredients of JTBF. Through animal experiments, it was found that JTBF reduced 24 h-UP and promoted the expression of podocin, nephrin, and WT-1 in podocytes, thereby reducing podocyte damage. At the same time, JTBF activates the expression of podocyte autophagy-related proteins (beclin-1, LC3 and P62). Subsequently, through network pharmacology predictions, 208 compounds were obtained from JTBF, and phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) was a potential signal pathway. JTBF was obtained in DKD rat kidney tissue to inhibit the expression of PI3K, Akt and mTOR related proteins. CONCLUSIONS: JTBF enhance podocyte autophagy to reduce podocyte damage, thereby effectively treating DKD proteinuria and protecting kidney function.

The critical role of dysregulated autophagy in the progression of diabetic kidney disease.

Diabetic kidney disease (DKD) is one of the major public health problems in society today. It is a renal complication caused by diabetes mellitus with predominantly microangiopathy and is a major cause of end-stage renal disease (ESRD). Autophagy is a metabolic pathway for the intracellular degradation of cytoplasmic products and damaged organelles and plays a vital role in maintaining homeostasis and function of the renal cells. The dysregulation of autophagy in the hyperglycaemic state of diabetes mellitus can lead to the progression of DKD, and the activation or restoration of autophagy through drugs is beneficial to the recovery of renal function. This review summarizes the physiological process of autophagy, illustrates the close link between DKD and autophagy, and discusses the effects of drugs on autophagy and the signaling pathways involved from the perspective of podocytes, renal tubular epithelial cells, and mesangial cells, in the hope that this will be useful for clinical treatment.

Pharmacological properties, molecular mechanisms and therapeutic potential of ginsenoside Rg3 as an antioxidant and anti-inflammatory agent.

Inflammation and oxidative stress lead to various acute or chronic diseases, including pneumonia, liver and kidney injury, cardiovascular and cerebrovascular diseases, metabolic diseases, and cancer. Ginseng is a well-known and widely used ethnic medicine in Asian countries, and ginsenoside Rg3 is a saponin isolated from Panax ginseng C. A. Meyer, Panax notoginseng, or Panax quinquefolius L. This compound has a wide range of pharmacological properties, including antioxidant and anti-inflammatory activities, which have been evaluated in disease models of inflammation and oxidative stress. Rg3 can attenuate lung inflammation, prevent liver and kidney function damage, mitigate neuroinflammation, prevent cerebral and myocardial ischemia-reperfusion injury, and improve hypertension and diabetes symptoms. The multitarget, multipathway mechanisms of action of Rg3 have been gradually deciphered. This review summarizes the existing knowledge on the anti-inflammatory and antioxidant effects and underlying molecular mechanisms of ginsenoside Rg3, suggesting that ginsenoside Rg3 may be a promising candidate drug for the treatment of diseases with inflammatory and oxidative stress conditions.

Frontier progress of the combination of modern medicine and traditional Chinese medicine in the treatment of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC, accounting for 90% of primary liver cancer) was the sixth most common cancer in the world and the third leading cause of cancer death in 2020. The number of new HCC patients in China accounted for nearly half of that in the world. HCC was of occult and complex onset, with poor prognosis. Clinically, at least 15% of patients with HCC had strong side effects of interventional therapy (IT) and have poor sensitivity to chemotherapy and targeted therapy. Traditional Chinese medicine (TCM), as a multi-target adjuvant therapy, had been shown to play an active anti-tumor role in many previous studies. This review systematically summarized the role of TCM combined with clinically commonly used drugs for the treatment of HCC (including mitomycin C, cyclophosphamide, doxorubicin, 5-fluorouracil, sorafenib, etc.) in the past basic research, and summarized the efficacy of TCM combined with surgery, IT and conventional therapy (CT) in clinical research. It was found that TCM, as an adjuvant treatment, played many roles in the treatment of HCC, including enhancing the tumor inhibition, reducing toxic and side effects, improving chemosensitivity and prolonging survival time of patients. This review summarized the advantages of integrated traditional Chinese and modern medicine in the treatment of HCC and provides a theoretical basis for clinical research.

Major ginsenosides from Panax ginseng promote aerobic cellular respiration and SIRT1-mediated mitochondrial biosynthesis in cardiomyocytes and neurons.

Background: Aerobic cellular respiration provides chemical energy, adenosine triphosphate (ATP), to maintain multiple cellular functions. Sirtuin 1 (SIRT1) can deacetylate peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) to promote mitochondrial biosynthesis. Targeting energy metabolism is a potential strategy for the prevention and treatment of various diseases, such as cardiac and neurological disorders. Ginsenosides, one of the major bioactive constituents of Panax ginseng, have been extensively used due to their diverse beneficial effects on healthy subjects and patients with different diseases. However, the underlying molecular mechanisms of total ginsenosides (GS) on energy metabolism remain unclear. Methods: In this study, oxygen consumption rate, ATP production, mitochondrial biosynthesis, glucose metabolism, and SIRT1-PGC-1α pathways in untreated and GS-treated different cells, fly, and mouse models were investigated. Results: GS pretreatment enhanced mitochondrial respiration capacity and ATP production in aerobic respiration-dominated cardiomyocytes and neurons, and promoted tricarboxylic acid metabolism in cardiomyocytes. Moreover, GS clearly enhanced NAD+-dependent SIRT1 activation to increase mitochondrial biosynthesis in cardiomyocytes and neurons, which was completely abrogated by nicotinamide. Importantly, ginsenoside monomers, such as Rg1, Re, Rf, Rb1, Rc, Rh1, Rb2, and Rb3, were found to activate SIRT1 and promote energy metabolism. Conclusion: This study may provide new insights into the extensive application of ginseng for cardiac and neurological protection in healthy subjects and patients.

pH-Triggered controlled drug release from mesoporous silica nanoparticles via intracelluar dissolution of ZnO nanolids.

Acid-decomposable, luminescent ZnO quantum dots (QDs) have been employed to seal the nanopores of mesoporous silica nanoparticles (MSNs) in order to inhibit premature drug (doxorubicin) release. After internalization into HeLa cells, the ZnO QD lids are rapidly dissolved in the acidic intracellular compartments, and as a result, the loaded drug is released into the cytosol from the MSNs. The ZnO QDs behave as a dual-purpose entity that not only acts as a lid but also has a synergistic antitumor effect on cancer cells. We anticipate that these nanoparticles may prove to be a significant step toward the development of a pH-sensitive drug delivery system that minimizes drug toxicity.

Activation of Autophagy Through the NLRP3/mTOR Pathway: A Potential Mechanism for Alleviation of Pneumonia by QingFei Yin.

QingFei Yin (QFY), a Chinese traditional medicine recipe, is known for its excellent therapeutic pharmacological effects for the treatment of bacterial lung infections, although its molecular mechanism of action remains unknown. Here, QFY chemical composition was determined using a High-Performance Liquid Chromatography-Mass (HPLC-MS/MS)-based method then QFY was evaluated for protective pharmacological effects against pneumonia using two models: a Streptococcus pneumoniae-induced in vivo mouse model and an in vitro pneumolysin (PLY)-induced murine lung alveolar-derived MH-S cell line-based model. Notably, QFY exerted prominent anti-pneumonia effects both in vivo and in vitro. To further explore QFY protective effects, 4D label-free proteomics analysis, pathologic evaluation, and immunohistochemical (IHC) analysis were conducted to identify cellular pathways involved in QFY protection. Notably, our results indicated that NF-κB/NLRP3 and autophagy pathways may contribute to pharmacological effects associated with QFY-based protection. Briefly, QFY triggered autophagy via down-regulation of upstream NLRP3/mTOR signaling pathway events, resulting in the amelioration of inflammatory injury. Collectively, our results revealed molecular mechanisms underlying QFY protection against pneumonia as a foundation for the future development of novel treatments to combat this disease and reduce antibiotic abuse.