Saponin monomers: Potential candidates for the treatment of type 2 diabetes mellitus and its complications.

Type 2 diabetes mellitus (T2DM), a metabolic disease with persistent hyperglycemia primarily caused by insulin resistance (IR), has become one of the most serious health challenges of the 21st century, with considerable economic and societal implications worldwide. Considering the inevitable side effects of conventional antidiabetic drugs, natural ingredients exhibit promising therapeutic efficacy and can serve as safer and more cost-effective alternatives for the management of T2DM. Saponins are a structurally diverse class of amphiphilic compounds widely distributed in many popular herbal medicinal plants, some animals, and marine organisms. There are many saponin monomers, such as ginsenoside compound K, ginsenoside Rb1, ginsenoside Rg1, astragaloside IV, glycyrrhizin, and diosgenin, showing great efficacy in the treatment of T2DM and its complications in vivo and in vitro. However, although the mechanisms of action of saponin monomers at the animal and cell levels have been gradually elucidated, there is a lack of clinical data, which hinders the development of saponin-based antidiabetic drugs. Herein, the main factors/pathways associated with T2DM and the comprehensive underlying mechanisms and potential applications of these saponin monomers in the management of T2DM and its complications are reviewed and discussed, aiming to provide fundamental data for future high-quality clinical studies and trials.

The Radioprotective Effect of LBP on Neurogenesis and Cognition after Acute Radiation Exposure.

BACKGROUND: Radiation exposure has been linked to the development of brain damage and cognitive impairment, but the protective effect and mechanism of Lycium barbarum pills (LBP) on radiation-induced neurological damage remains to be clarified. METHODS: Behavioral tests and immunohistochemical studies were conducted to evaluate the protective effects of LBP extract (10 g/kg orally daily for 4 weeks) against radiation-induced damage on neurogenesis and cognitive function in Balb/c mice exposed to 5.5 Gy X-ray acute radiation. RESULTS: The results showed that the LBP extract significantly improved body weight loss, locomotor activity and spatial learning and memory. Immunohistochemical tests revealed that the LBP extract prevented the loss of proliferating cells, newly generated neurons and interneurons, especially in the subgranular area of the dentate gyrus. CONCLUSION: The findings suggest that LBP is a potential neuroprotective drug for mitigating radiation-induced neuropsychological disorders.

A review on pharmacokinetics of sinomenine and its anti-inflammatory and immunomodulatory effects.

Autoimmune diseases (ADs), with significant effects on morbidity and mortality, are a broad spectrum of disorders featured by body's immune responses being directed against its own tissues, resulting in chronic inflammation and tissue damage. Sinomenine (SIN) is an alkaloid isolated from the root and stem of Sinomenium acutum which is mainly used to treat pain, inflammation and immune disorders for centuries in China. Its potential anti-inflammatory role for treating immune-related disorders in experimental animal models and in some clinical applications have been reported widely, suggesting an inspiring application prospect of SIN. In this review, the pharmacokinetics, drug delivery systems, pharmacological mechanisms of action underlying the anti-inflammatory and immunomodulatory effects of SIN, and the possibility of SIN as adjuvant to disease-modifying anti-rheumatic drugs (DMARDs) therapy were summarized and evaluated. This paper aims to reveal the potential prospects and limitations of SIN in the treatment of inflammatory and immune diseases, and to provide ideas for compensating its limitations and reducing the side effects, and thus to make SIN better translate to the clinic.

Advances in experimental models of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by persistent articular inflammation and joint damage. RA was first described over 200 years ago; however, its etiology and pathophysiology remain insufficiently understood. The current treatment of RA is mainly empirical or based on the current understanding of etiology with limited efficacy and/or substantial side effects. Thus, the development of safer and more potent therapeutics, validated and optimized in experimental models, is urgently required. To improve the transition from bench to bedside, researchers must carefully select the appropriate experimental models as well as draw the right conclusions. Here, we summarize the establishment, pathological features, potential mechanisms, advantages, and limitations of the currently available RA models. The aim of the review is to help researchers better understand available RA models; discuss future trends in RA model development, which can help highlight new translational and human-based avenues in RA research.

Erratum to "Evaluation of the Mechanism of Modified Lingguizhugan Decoction in the Treatment of Nonalcoholic Fatty Liver Disease".

[This corrects the article DOI: 10.1155/2022/4576679.].

Evaluation of the Mechanism of Modified Lingguizhugan Decoction in the Treatment of Nonalcoholic Fatty Liver Disease.

Nonalcoholic steatohepatitis (NASH) may develop into cirrhosis and liver cancer, which imposes a great burden to individuals and society. Lingguizhugan decoction is a commonly used dampness dispelling medication in traditional Chinese medicine and is often used to treat those with phlegm and retained fluid from various causes and pathogeneses. The objective of this study was to explore the effect and mechanism of modified Lingguizhugan decoction (MLGZG) on lipid metabolism and the inflammatory response to identify a theoretical basis to promote its clinical application in NASH therapy. After treatment with MLGZG for 8 weeks, the weight of high-fat-diet (HFD)-fed NASH rats was significantly higher than that of rats in the normal group, and the weights in each dose group were significantly lower than those in the model group. The treatment groups (low, medium, and high doses) had different degrees of improvement in the changes in hepatocyte tissue structure, steatosis, and inflammatory infiltration. Compared with that in the normal group, the expression of TNF receptor-associated factor-3 (TRAF-3) and nuclear factor κB (NFκB) in the model group significantly increased to varying degrees. Compared with the NASH group, the treatment groups (low, middle, and high doses) showed modified lipid metabolism gene expression and decreased inflammatory factor expression levels. Modified Lingguizhugan decoction can improve the general condition of rats with nonalcoholic fatty liver disease by reducing the expression levels of TRAF3, NF-κB, the Toll-like receptor 4 (TLR-4) pathway, and related proteins, as well as the expression levels of lipid metabolism genes and cytokines.

Neuroprotective Effects of Lycium barbarum Berry on Neurobehavioral Changes and Neuronal Loss in the Hippocampus of Mice Exposed to Acute Ionizing Radiation.

Background: Brain exposure to ionizing radiation during the radiotherapy of brain tumor or metastasis of peripheral cancer cells to the brain has resulted in cognitive dysfunction by reducing neurogenesis in hippocampus. The water extract of Lycium barbarum berry (Lyc), containing water-soluble Lycium barbarum polysaccharides and flavonoids, can protect the neuronal injury by reducing oxidative stress and suppressing neuroinflammation. Reseach Design: To demonstrate the long-term radioprotective effect of Lyc, we evaluated the neurobehavioral alterations and the numbers of NeuN, calbindin (CB), and parvalbumin (PV) immunopositive hippocampal neurons in BALB/c mice after acute 5.5 Gy radiation with/without oral administration of Lyc at the dosage of 10 g/kg daily for 4 weeks. Results: The results showed that Lyc could improve irradiation-induced animal weight loss, depressive behaviors, spatial memory impairment, and hippocampal neuron loss. Immunohistochemistry study demonstrated that the loss of NeuN-immunopositive neuron in the hilus of the dentate gyrus, CB-immunopositive neuron in CA1 strata radiatum, lacunosum moleculare and oriens, and PV-positive neuron in CA1 stratum pyramidum and stratum granulosum of the dentate gyrus after irradiation were significantly improved by Lyc treatment. Conclusion: The neuroprotective effect of Lyc on those hippocampal neurons may benefit the configuration of learning related neuronal networks and then improve radiation induced neurobehavioral changes such as cognitive impairment and depression. It suggests that Lycium barbarum berry may be an alternative food supplement to prevent radiation-induced neuron loss and neuropsychological disorders.

Ionizing Radiation-Induced Brain Cell Aging and the Potential Underlying Molecular Mechanisms.

Population aging is occurring rapidly worldwide, challenging the global economy and healthcare services. Brain aging is a significant contributor to various age-related neurological and neuropsychological disorders, including Alzheimer's disease and Parkinson's disease. Several extrinsic factors, such as exposure to ionizing radiation, can accelerate senescence. Multiple human and animal studies have reported that exposure to ionizing radiation can have varied effects on organ aging and lead to the prolongation or shortening of life span depending on the radiation dose or dose rate. This paper reviews the effects of radiation on the aging of different types of brain cells, including neurons, microglia, astrocytes, and cerebral endothelial cells. Further, the relevant molecular mechanisms are discussed. Overall, this review highlights how radiation-induced senescence in different cell types may lead to brain aging, which could result in the development of various neurological and neuropsychological disorders. Therefore, treatment targeting radiation-induced oxidative stress and neuroinflammation may prevent radiation-induced brain aging and the neurological and neuropsychological disorders it may cause.

Circular RNAs in cell cycle regulation: Mechanisms to clinical significance.

Circular RNAs (circRNAs), a type of non-coding RNA, are single-stranded circularized molecules characterized by high abundance, evolutionary conservation and cell development- and tissue-specific expression. A large body of studies has found that circRNAs exert a wide variety of functions in diverse biological processes, including cell cycle. The cell cycle is controlled by the coordinated activation and deactivation of cell cycle regulators. CircRNAs exert mutifunctional roles by regulating gene expression via various mechanisms. However, the functional relevance of circRNAs and cell cycle regulation largely remains to be elucidated. Herein, we briefly describe the biogenesis and mechanistic models of circRNAs and summarize their functions and mechanisms in the regulation of critical cell cycle modulators, including cyclins, cyclin-dependent kinases and cyclin-dependent kinase inhibitors. Moreover, we highlight the participation of circRNAs in cell cycle-related signalling pathways and the clinical value of circRNAs as promising biomarkers or therapeutic targets in diseases related to cell cycle disorder.

Progress on the study of the anticancer effects of artesunate.

Artesunate (ART) is a derivative of artemisinin that is extracted from the wormwood plant Artemisia annua. ART is an antimalarial drug that has been shown to be safe and effective for clinical use. In addition to its antimalarial properties, ART has been attracting attention over recent years due to its reported inhibitory effects on cancer cell proliferation, invasion and migration. Therefore, ART has a wider range of potential clinical applications than first hypothesized. The aim of the present review was to summarize the latest research progress on the possible anticancer effects of ART, in order to lay a theoretical foundation for the further development of ART as a therapeutic option for cancer.

Guanylate cyclases link serotoninergic signaling to modulate ethanol-induced food intake in C. elegans.

Ethanol affects the nervous system of animals to cause a boost of feeding, sexual, verbal, and locomotor behaviors. To understand the neural mechanisms of these ethanol-induced behaviors, we investigated a neural pathway of ethanol-induced feeding behavior by guanylate cyclases and serotonin signals in C. elegans. We recorded the intracellular calcium signaling of seven sensory neurons in response to ethanol, and only found a significant increase of calcium signaling in BAG among the seven sensor neurons. And both guanylate cyclases GCY-31 and GCY-33 were crucial signaling protein of calcium response in BAG neurons. In addition, serotonin, released from NSM motor neurons, promoted feeding behavior under ethanol stimulation. And the rescue experiment of double mutant indicated the guanylate cyclases and serotonin in the same signaling pathway. So BAG neurons respond to alcohol through the promotion of intracellular calcium signaling, and then the downstream motor neurons NSM release serotonin to regulate the feeding behavior in C. elegans. These findings revealed a neural circuit to understand how the nervous system responds to ethanol and generates corresponding behavior.

A case of gynandromorphy in Ducetia japonica (Thunberg, 1815) (Orthoptera: Tettigoniidae: Phaneropterinae).

In this paper, we described an example of gynandromorphy in a katydid, Ducetia japonica. Its color is brown, while normal individuals are green. Its left maxilla is smaller, and left maxillary palpus is shorter. Left forewing as male is shorter than right one as female. Hindwing is also shorter in left. Cercus, epiproct and subgenital plate are left in male and right in female.

Astroglial connexins in epileptogenesis.

The astroglial network connected through gap junctions assembling from connexins physiologically balances the concentrations of ions and neurotransmitters around neurons. Astrocytic dysfunction has been associated with many neurological disorders including epilepsy. Dissociated gap junctions result in the increased activity of connexin hemichannels which triggers brain pathophysiological changes. Previous studies in patients and animal models of epilepsy indicate that the reduced gap junction coupling from assembled connexin hemichannels in the astrocytes may play an important role in epileptogenesis. This abnormal cell-to-cell communication is now emerging as an important feature of brain pathologies and being considered as a novel therapeutic target for controlling epileptogenesis. In particular, candidate drugs with ability of inhibition of connexin hemichannel activity and enhancement of gap junction formation in astrocytes should be explored to prevent epileptogenesis and control epilepsy.

Radioprotective Effect of Flavonoids on Ionizing Radiation-Induced Brain Damage.

Patients receiving brain radiotherapy may suffer acute or chronic side effects. Ionizing radiation induces the production of intracellular reactive oxygen species and pro-inflammatory cytokines in the central nervous system, leading to brain damage. Complementary Chinese herbal medicine therapy may reduce radiotherapy-induced side effects. Flavonoids are a class of natural products which can be extracted from Chinese herbal medicine and have been shown to have neuroprotective and radioprotective properties. Flavonoids are effective antioxidants and can also inhibit regulatory enzymes or transcription factors important for controlling inflammatory mediators, affect oxidative stress through interaction with DNA and enhance genomic stability. In this paper, radiation-induced brain damage and the relevant molecular mechanism were summarized. The radio-neuro-protective effect of flavonoids, i.e., antioxidant, anti-inflammatory and maintaining genomic stability, were then reviewed. We concluded that flavonoids treatment may be a promising complementary therapy to prevent radiotherapy-induced brain pathophysiological changes and cognitive impairment.

[Emission Characteristics of Light-Duty Gasoline Vehicle Exhaust Based on Acceleration Simulation Mode].

In this study, 127 light-duty gasoline cars and 10 light-duty gasoline trucks with different emission standards were selected to explore the influences of different conditions and vehicle parameters on the emission characteristics of carbon dioxide (CO2), carbon monoxide (CO), nitrogen oxides (NOx), hydrocarbons (HC), and methane (CH4) using a portable emission measurement system based on a chassis dynamometer under acceleration simulation mode. The results showed that the gaseous pollutants of light-duty gasoline vehicles displayed a relatively lower emission rate under the idle condition, which accounted for only 22.9% and 25.8% of the emission rate at the accelerated condition and constant speed condition, respectively. The pollutant emission characteristics were closely related to the working conditions. The emission rates of CO2 and NOx in the accelerated condition were less than those at the constant speed condition, while the emission rates of CO, HC, and CH4 in the accelerated condition were higher than those at the constant speed condition. In the constant low-speed condition, the emission factors of CO2, CO, NOx, HC, and CH4 were 383.20, 2.98, 1.60, 0.14, and 0.03 g·km-1 for light-duty gasoline cars, respectively, and 360.66, 2.64, 1.61, 0.0055, and 0.0027 g·km-1 for light-duty gasoline trucks, respectively. Tighter emission standards have caused significant reductions in emissions. The emission factors of CO, NOx, HC, and CH4 could be decreased by 87.5%, 97.3%, 97.9%, and 86.4%, respectively, from China Ⅰ to China Ⅴ. A non-linear relationship was found between the age, odometer, vehicle weight, and vehicular emissions. In addition, the engine displacement was positively correlated with vehicular emissions.

Inhibiting 6-phosphogluconate dehydrogenase selectively targets breast cancer through AMPK activation

Purpose: 6-phosphogluconate dehydrogenase (6PGD), a key enzyme of the oxidative pentose phosphate pathway, is involved in tumor growth and metabolism. Although high 6PGD activity has been shown to be associated with poor prognosis, its role and therapeutic value in breast cancer remain unknown. Methods: The levels and roles of 6PGD were analyzed in breast cancer cells and their normal counterparts. The underlying mechanisms of 6PGD’s roles are also analyzed. Results: We found that 6PGD is aberrantly activated in breast cancer as shown by its increased transcriptional and translational levels as well as enzyme activity in breast cancer tissues and cell lines compared to normal counterparts. Although similar degree of enzyme activity inhibition was achieved in both breast cancer and normal breast cells, 6PGD inhibition by siRNA-mediated knockdown or pharmacological inhibitor physcion is more effective in inhibiting growth and survival in breast cancer than normal breast cells. Moreover, inhibiting 6PGD significantly sensitizes breast cancer response to chemotherapeutic agents in in vitro cell culture system and in vivo xenograft breast cancer model. We further show that 6PGD inhibition activates AMPK and its downstream substrate ACC1, leading to reduction of ACC1 activity and lipid biosynthesis. AMPK depletion significantly reverses the inhibitory effects of physcion in breast cancer cells, confirming that 6PGD inhibition targets breast cancer cell via AMPK activation. Conclusions: Our work provides experimental evidence on the association of 6PGD with poor prognosis in breast cancer and suggests that 6PGD inhibition may represent a potential therapeutic strategy to augment chemotherapy efficacy in breast cancer

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Inhibiting 6-phosphogluconate dehydrogenase selectively targets breast cancer through AMPK activation.

PURPOSE: 6-phosphogluconate dehydrogenase (6PGD), a key enzyme of the oxidative pentose phosphate pathway, is involved in tumor growth and metabolism. Although high 6PGD activity has been shown to be associated with poor prognosis, its role and therapeutic value in breast cancer remain unknown. METHODS: The levels and roles of 6PGD were analyzed in breast cancer cells and their normal counterparts. The underlying mechanisms of 6PGD's roles are also analyzed. RESULTS: We found that 6PGD is aberrantly activated in breast cancer as shown by its increased transcriptional and translational levels as well as enzyme activity in breast cancer tissues and cell lines compared to normal counterparts. Although similar degree of enzyme activity inhibition was achieved in both breast cancer and normal breast cells, 6PGD inhibition by siRNA-mediated knockdown or pharmacological inhibitor physcion is more effective in inhibiting growth and survival in breast cancer than normal breast cells. Moreover, inhibiting 6PGD significantly sensitizes breast cancer response to chemotherapeutic agents in in vitro cell culture system and in vivo xenograft breast cancer model. We further show that 6PGD inhibition activates AMPK and its downstream substrate ACC1, leading to reduction of ACC1 activity and lipid biosynthesis. AMPK depletion significantly reverses the inhibitory effects of physcion in breast cancer cells, confirming that 6PGD inhibition targets breast cancer cell via AMPK activation. CONCLUSIONS: Our work provides experimental evidence on the association of 6PGD with poor prognosis in breast cancer and suggests that 6PGD inhibition may represent a potential therapeutic strategy to augment chemotherapy efficacy in breast cancer.

Co-expression and significance of Dok2 and Ras p21 protein activator 1 in breast cancer.

Docking protein 2 (Dok2) and Ras p21 protein activator 1 (RASA1) are tumor suppressors which have been identified in numerous solid tumors; however, the association between their expression in breast cancer and patient prognosis remains unclear. A total of 285 consecutive patients diagnosed histopathologically with breast cancer who underwent surgery at Jingzhou Central Hospital were selected for the present study. Dok2 and RASA1 protein were explored using histopathology and western blotting techniques, and the association of patient prognosis with clinicopathological parameters was investigated using univariate and multivariate analyses. Weak expression of Dok2/RASA1 was associated with poorly differentiated breast adenocarcinomas; negatively expressed Dok2 and RASA1 were associated with increased tumor size, a higher proportion of axillary lymph node metastasis and later clinical staging. Additionally, Dok2 and RASA1 expression were associated with disease-free survival of patients with breast cancer. As indicated by Cox's regression analysis, Dok2 and RASA1 expression and the high proportion of axillary lymph node metastasis served as significant independent predictors for the recurrence of breast cancer. The results of the present study suggested that combined Dok2 and RASA1 negative expression may serve as an independent prognostic factor for patients following breast cancer surgery.

Inhibiting prenylation augments chemotherapy efficacy in renal cell carcinoma through dual inhibition on mitochondrial respiration and glycolysis.

Prenylation is a posttranslational lipid modification required for the proper functions of a number of proteins involved in cell regulation. Here, we show that prenylation inhibition is important for renal cell carcinoma (RCC) growth, survival and response to chemotherapy, and its underlying mechanism may be contributed to mitochondrial dysfunction. We first demonstrated that a HMG-CoA reductase inhibitor pitavastatin inhibited mevalonate pathway and thereby prenylation in RCC cells. In addition, pitavastatin is effective in inhibiting growth and inducing apoptosis in a panel of RCC cell lines. Combination of pitavastatin and paclitaxel is significantly more effective than pitavastatin or paclitaxel alone as shown by both in vitro cell culture system and in vivo RCC xenograft model. Importantly, pitavastatin treatment inhibits mitochondrial respiration via suppressing mitochondrial complex I and II enzyme activities. Interestingly, different from mitochondrial inhibitor phenformin that inhibits mitochondrial respiration but activates glycolytic rate in RCC cells, pitavastatin significantly decreases glycolytic rate. The dual inhibitory action of pitavastatin on mitochondrial respiration and glycolysis results in remarkable energy depletion and oxidative stress in RCC cells. In addition, inhibition of prenylation by depleting Isoprenylcysteine carboxylmethyltransferase (Icmt) also mimics the inhibitory effects of pitavastatin in RCC cells. Our work demonstrates the previously unappreciated association between prenylation inhibition and energy metabolism in RCC, which can be therapeutically exploited, likely in tumors that largely rely on energy metabolism.

Matrine Suppresses Proliferation and Invasion of SGC7901 Cells through Inactivation of PI3K/Akt/uPA Pathway.

This study was to examine the inhibitory effect of matrine on the proliferation and metastasis of gastric cancer cells, and to explore the possible mechanisms involved in these processes. MTT was used to evaluate the proliferation ability of SGC7901 cells. A two and three-dimensional cell migration assay were performed to determine the effect of matrine on the migration of SGC7901 cells. Then, the changes of the uPA protein and other possible signal molecules were detected by western blot. We found that the proliferation ability of SGC 7901 cells was suppressed by matrine (p<0.05), and the average cell migration velocity was also significantly inhibited by matrine when compared to the control in a two-dimensional cell migration assay. In addition, SGC7901cells treated with matrine (50µg/ml) migrated less than the control cells in a three-dimensional cell migration assay. At the meantime, the decreased uPA protein expression in SGC7901 cells treated with matrine was observed, and the PI3K/Akt pathway was inhibited. These results suggested that matrine can inhibit the proliferation and metastasis of gastric cancer cells through the PI3K/Akt/uPA pathway, indicating that matrine might be a potential molecular target for treatment of gastric carcinoma.