PMID: 

Pain. 2019 Jan ;160(1):117-135. PMID: 30169422

Abstract Title: 

Betulinic acid, derived from the desert lavender Hyptis emoryi, attenuates paclitaxel-, HIV-, and nerve injury-associated peripheral sensory neuropathy via block of N- and T-type calcium channels.

Abstract: 

The Federal Pain Research Strategy recommended development of nonopioid analgesics as a top priority in its strategic plan to address the significant public health crisis and individual burden of chronic pain faced by>100 million Americans. Motivated by this challenge, a natural product extracts library was screened and identified a plant extract that targets activity of voltage-gated calcium channels. This profile is of interest as a potential treatment for neuropathic pain. The active extract derived from the desert lavender plant native to southwestern United States, when subjected to bioassay-guided fractionation, afforded 3 compounds identified as pentacyclic triterpenoids, betulinic acid (BA), oleanolic acid, and ursolic acid. Betulinic acid inhibited depolarization-evoked calcium influx in dorsal root ganglion (DRG) neurons predominantly through targeting low-voltage-gated (Cav3 or T-type) and CaV2.2 (N-type) calcium channels. Voltage-clamp electrophysiology experiments revealed a reduction of Ca, but not Na, currents in sensory neurons after BA exposure. Betulinic acid inhibited spontaneous excitatory postsynaptic currents and depolarization-evoked release of calcitonin gene-related peptide from lumbar spinal cord slices. Notably, BA did not engage human mu, delta, or kappa opioid receptors. Intrathecal administration of BA reversed mechanical allodynia in rat models of chemotherapy-induced peripheral neuropathy and HIV-associated peripheral sensory neuropathy as well as a mouse model of partial sciatic nerve ligation without effects on locomotion. The broad-spectrum biological and medicinal properties reported, including anti-HIV and anticancer activities of BA and its derivatives, position this plant-derived small molecule natural product as a potential nonopioid therapy for management of chronic pain.

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PMID: 

PLoS One. 2014 ;9(9):e108318. Epub 2014 Oct 2. PMID: 25275372

Abstract Title: 

Differential pro-inflammatory responses of astrocytes and microglia involve STAT3 activation in response to 1800 MHz radiofrequency fields.

Abstract: 

Microglia and astrocytes play important role in maintaining the homeostasis of central nervous system (CNS). Several CNS impacts have been postulated to be associated with radiofrequency (RF) electromagnetic fields exposure. Given the important role of inflammation in neural physiopathologic processes, we investigated the pro-inflammatory responses of microglia and astrocytes and the involved mechanism in response to RF fields. Microglial N9 and astroglial C8-D1A cells were exposed to 1800 MHz RF for different time with or without pretreatment with STAT3 inhibitor. Microglia and astrocytes were activated by RF exposure indicated by up-regulated CD11b and glial fibrillary acidic protein (GFAP). However, RF exposure induced differential pro-inflammatory responses in astrocytes and microglia, characterized by different expression and release profiles of IL-1β, TNF-α, IL-6, PGE2, nitric oxide (NO), inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX2). Moreover, the RF exposure activated STAT3 in microglia but not in astrocytes. Furthermore, the STAT3 inhibitor Stattic ameliorated the RF-induced release of pro-inflammatory cytokines in microglia but not in astrocytes. Our results demonstrated that RF exposure differentially induced pro-inflammatory responses in microglia and astrocytes, which involved differential activation of STAT3 in microglia and astrocytes. Our data provide novel insights into the potential mechanisms of the reported CNS impacts associated with mobile phone use and present STAT3 as a promising target to protect humans against increasing RF exposure.

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PMID: 

PLoS One. 2018 ;13(8):e0203042. Epub 2018 Aug 29. PMID: 30157245

Abstract Title: 

Effects of ursolic acid on sub-lesional muscle pathology in a contusion model of spinal cord injury.

Abstract: 

Spinal Cord Injury (SCI) results in severe sub-lesional muscle atrophy and fiber type transformation from slow oxidative to fast glycolytic, both contributing to functional deficits and maladaptive metabolic profiles. Therapeutic countermeasures have had limited success and muscle-related pathology remains a clinical priority. mTOR signaling is known to play a critical role in skeletal muscle growth and metabolism, and signal integration of anabolic and catabolic pathways. Recent studies show that the natural compound ursolic acid (UA) enhances mTOR signaling intermediates, independently inhibiting atrophy and inducing hypertrophy. Here, we examine the effects of UA treatment on sub-lesional muscle mTOR signaling, catabolic genes, and functional deficits following severe SCI in mice. We observe that UA treatment significantly attenuates SCI induced decreases in activated forms of mTOR, and signaling intermediates PI3K, AKT, and S6K, and the upregulation of catabolic genes including FOXO1, MAFbx, MURF-1, and PSMD11. In addition, UA treatment improves SCI induced deficits in body and sub-lesional muscle mass, as well as functional outcomes related to muscle function, motor coordination, and strength. These findings provide evidence that UA treatment may be a potential therapeutic strategy to improve muscle-specific pathological consequences of SCI.

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PMID: 

Chin J Integr Med. 2019 Mar ;25(3):210-215. Epub 2018 Aug 30. PMID: 30159645

Abstract Title: 

Ursolic Acid Prevents Retinoic Acid-Induced Bone Loss in Rats.

Abstract: 

OBJECTIVE: To examine the effects of ursolic acid (UA) on mitigating retinoic acid (RA)-induced osteoporosis in rats.METHODS: Fifty female Sprague-Dawley rats were randomly divided into the control group (n=10) and the osteoporosis group (n=40). The 40 osteoporosis rats were induced by 75 mg/(kg•d) RA once daily for 2 weeks, and then were randomly assigned to vehicle control (model), low-, middle-, and high-dose UA [(UA-L, UA-M, UA-H; 30, 60, 120 mg/(kg•d), respectively] groups (10 rats each). UA were administered once daily to the rats from the 3rd weeks for up to 4 weeks by gavage. Bone turnover markers [serum alkaline phosphatase (ALP), osteocalcin (OCN), urine deoxypyridinoline (DPD)] and other parameters, including serum calcium (S-Ca), serum phosphorus (S-P), urine calcium (U-Ca), urine phosphorus (U-P), and bone mineral density (BMD) of the femur, 4th lumbar vertebra and tibia, bone biomechanical properties and trabecular microarchitecture, were measured.RESULTS: The osteoporosis in rats was successfully induced by RA. Compared with the model group, UA-M and UA-H significantly reversed the RA-induced changes in S-P, U-Ca, U-P, ALP, OCN and urine DPD ratio and markedly enhanced the BMD of right femur, 4th lumbar vertebra and tibia (Plt;0.05 or Plt;0.01). Further, biomechanical test and microcomputed tomography evaluation also showed that UA-H drastically improved biomechanical properties and trabecular microarchitecture (Plt;0.05 or Plt;0.01).CONCLUSION: UA could promote bone formation, increase osteoblastic activity and reduce osteoclastic activity in rats, indicating that UA might be a potential therapeutic of RA-induced acute osteoporosis.

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PMID: 

Electromagn Biol Med. 2013 Mar ;32(1):95-120. Epub 2013 Jan 15. PMID: 23320614

Abstract Title: 

Transient and cumulative memory impairments induced by GSM 1.8 GHz cell phone signal in a mouse model.

Abstract: 

This study was designed to investigate the transient and cumulative impairments in spatial and non-spatial memory of C57Bl/6J mice exposed to GSM 1.8 GHz signal for 90 min daily by a typical cellular (mobile) phone at a specific absorption rate value of 0.11 W/kg. Free-moving male mice 2 months old were irradiated in two experimental protocols, lasting for 66 and for 148 days respectively. Each protocol used three groups of animals (n = 8 each for exposed, sham exposed and controls) in combination with two behavioural paradigms, the object recognition task and the object location task sequentially applied at different time points. One-way analysis of variance revealed statistically significant impairments of both types of memory gradually accumulating, with more pronounced effects on the spatial memory. The impairments persisted even 2 weeks after interruption of the 8 weeks daily exposure, whereas the memory of mice as detected by both tasks showed a full recovery approximately 1 month later. Intermittent every other day exposure for 1 month had no effect on both types of memory. The data suggest that visual information processing mechanisms in hippocampus, perirhinal and entorhinal cortex are gradually malfunctioning upon long-term daily exposure, a phenotype that persists for at least 2 weeks after interruption of radiation, returning to normal memory performance levels 4 weeks later. It is postulated that cellular repair mechanisms are operating to eliminate the memory affecting molecules. The overall contribution of several possible mechanisms to the observed cumulative and transient impairments in spatial andnon-spatial memory is discussed.

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PMID: 

Mol Med Rep. 2018 Nov ;18(5):4675-4681. Epub 2018 Sep 3. PMID: 30221655

Abstract Title: 

Ursolic acid alleviates inflammation and against diabetes‑induced nephropathy through TLR4‑mediated inflammatory pathway.

Abstract: 

Ursolic acid (UA) is a triterpenoid isolated from Chinese herbal medicine. It is extensively distributed in the plant kingdom in at least 63 Chinese herbal medicines of 26 families. UA has multiple bioactivities, including anti‑viral hepatitis, antitumor, anti‑oxidation, anti‑bacterium and anti‑inflammation. The aim of this in vitro study was to examine the effects of UA on diabetes‑induced nephropathy and its possible mechanism. In mice with diabetes‑induced nephropathy, UA increased the body weight, reduced kidney/body weight index, protected kidney cells, alleviated inflammation [tumor necrosis factor (TNF)‑α, interleukin (IL)‑1β, IL‑6 and IL‑18 levels] and kidney cell damage. It was also indicated thatUA suppressed Toll‑like receptor 4 (TLR4), myeloid differentiation factor 88 and nuclear factor‑κB protein expression in mice with diabetes‑induced nephropathy. The inhibition of TLR4 increased the anti‑inflammation of UA on inflammation in rat with diabetes‑induced nephropathy through the TLR4 signaling pathway. In conclusion, UA alleviates inflammation and inhibits diabetes‑induced nephropathy through a TLR4‑mediated inflammatory pathway. The present findings indicated that UA may be a possible therapeutic agent against diabetic nephropathy.

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PMID: 

Int J Radiat Biol. 2013 Sep ;89(9):756-63. Epub 2013 May 13. PMID: 23578013

Abstract Title: 

GSM 900 MHz cellular phone radiation can either stimulate or depress early embryogenesis in Japanese quails depending on the duration of exposure.

Abstract: 

PURPOSE: Our study was designed to assess the effects of low intensity radiation of a GSM (Global System for Mobile communication) 900 MHz cellular phone on early embryogenesis in dependence on the duration of exposure.MATERIALS AND METHODS: Embryos of Japanese Quails were exposed in ovo to GSM 900 MHz cellular phone radiation during initial 38 h of brooding or alternatively during 158 h (120 h before brooding plus initial 38 h of brooding) discontinuously with 48 sec ON (average power density 0.25μW/cm(2), specific absorption rate 3 μW/kg) followed by 12 sec OFF intervals. A number of differentiated somites were assessed microscopically. Possible DNA damage evoked by irradiation was assessed by an alkaline comet assay.RESULTS: Exposure to radiation from a GSM 900 MHz cellular phone led to a significantly altered number of differentiated somites. In embryos irradiated during 38 h the number of differentiated somites increased (p

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PMID: 

Biomed Pharmacother. 2018 Dec ;108:752-756. Epub 2018 Sep 21. PMID: 30248543

Abstract Title: 

Ursolic acid a promising candidate in the therapeutics of breast cancer: Current status and future implications.

Abstract: 

Breast cancer [BC] is the deadliest neoplasm in women globally and the second leading cause of cancer associated deaths. Current treatment methods include chemotherapy, hormonal therapy, radiation therapy and surgery. However, BC has shown resistance to these therapies and are often associated with side effects, multidrug resistance, recurrence are the major issues in BC treatment. Currently, dietary phytocompounds have emerged as beneficial agents for the prevention and treatment of cancer because of their safe and cost effective nature. Ursolic acid [UA] is widely spread in fruits and vegetables having the ability to inhibit BC proliferation, angiogenesis and metastasis, arrest cell cycle, induced apoptosis, scavenge free radicals and regulate several anti-apoptotic and pro-apoptotic proteins. UA has also shown potential anticancer, anti-inflammatory and antioxidant activities in several human BC cells. This review paper encompasses the role of UA against BC and their mechanism of action in vitro and in vivo studies.

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PMID: 

Nutrients. 2018 Nov 9 ;10(11). Epub 2018 Nov 9. PMID: 30423963

Abstract Title: 

Ursolic Acid Attenuates Hepatic Steatosis, Fibrosis, and Insulin Resistance by Modulating the Circadian Rhythm Pathway in Diet-Induced Obese Mice.

Abstract: 

The aim of the current study was to elucidate the effects of long-term supplementation with dietary ursolic acid (UR) on obesity and associated comorbidities by analyzing transcriptional and metabolic responses, focusing on the role of UR in the modulation of the circadian rhythm pathway in particular. C57BL/6J mice were divided into three groups and fed a normal diet, high-fat diet, or high-fat + 0.05% (/) UR diet for 16 weeks. Oligonucleotide microarray profiling revealed that UR is an effective regulator of the liver transcriptome, and canonical pathways associated with the"circadian rhythm"and"extracellular matrix (ECM)⁻receptor interactions"were effectively regulated by UR in the liver. UR altered the expression of various clock and clock-controlled genes (CCGs), which may be linked to the improvement of hepatic steatosis and fibrosis via lipid metabolism control and detoxification enhancement. UR reduced excessive reactive oxygen species production, adipokine/cytokine dysregulation, and ECM accumulation in the liver, which also contributed to improve hepatic lipotoxicity and fibrosis. Moreover, UR improved pancreatic islet dysfunction, and suppressed hepatic gluconeogenesis, thereby reducing obesity-associated insulin resistance. Therapeutic approaches targeting hepatic circadian clock and CCGs using UR may ameliorate the deleterious effects of diet-induced obesity and associated complications such as hepatic fibrosis.

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PMID: 

PLoS One. 2013 ;8(1):e54906. Epub 2013 Jan 23. PMID: 23355902

Abstract Title: 

Cell type-dependent induction of DNA damage by 1800 MHz radiofrequency electromagnetic fields does not result in significant cellular dysfunctions.

Abstract: 

BACKGROUND: Although IARC clarifies radiofrequency electromagnetic fields (RF-EMF) as possible human carcinogen, the debate on its health impact continues due to the inconsistent results. Genotoxic effect has been considered as a golden standard to determine if an environmental factor is a carcinogen, but the currently available data for RF-EMF remain controversial. As an environmental stimulus, the effect of RF-EMF on cellular DNA may be subtle. Therefore, more sensitive method and systematic research strategy are warranted to evaluate its genotoxicity.OBJECTIVES: To determine whether RF-EMF does induce DNA damage and if the effect is cell-type dependent by adopting a more sensitive methodγH2AX foci formation; and to investigate the biological consequences if RF-EMF does increase γH2AX foci formation.METHODS: Six different types of cells were intermittently exposed to GSM 1800 MHz RF-EMF at a specific absorption rate of 3.0 W/kg for 1 h or 24 h, then subjected to immunostaining with anti-γH2AX antibody. The biological consequences in γH2AX-elevated cell type were further explored with comet and TUNEL assays, flow cytometry, and cell growth assay.RESULTS: Exposure to RF-EMF for 24 h significantly inducedγH2AX foci formation in Chinese hamster lung cells and Human skin fibroblasts (HSFs), but not the other cells. However, RF-EMF-elevated γH2AX foci formation in HSF cells did not result in detectable DNA fragmentation, sustainable cell cycle arrest, cell proliferation or viability change. RF-EMF exposure slightly but not significantly increased the cellular ROS level.CONCLUSIONS: RF-EMF induces DNA damage in a cell type-dependent manner, but the elevatedγH2AX foci formation in HSF cells does not result in significant cellular dysfunctions.

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