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Osteoarthritis (OA), although extensively researched, still lacks an effective and safe treatment. The only current treatment option available for advanced OA is joint replacement surgery. This surgery may pose the risks of persistent pain, surgical complications and limited implant lifespan. Transforming growth factor (TGF)‑β has a crucial role in multiple cellular processes such as cell proliferation. Any deterioration in TGF‑β signaling pathways can have an immense impact on OA. Owing to the crucial role of TGF‑β in cartilage homeostasis, targeting it could be an alternative therapeutic approach. Additionally, stem cell‑based therapy has recently emerged as an effective treatment strategy that could replace surgery. A number of recent findings suggest that the tissue regeneration effect of stem cells is attributed to the paracrine secretion of anti‑inflammatory and chondroprotective mediators or trophic factors, particularly nanosized extracellular vesicles (i.e., exosomes). Literature searches were performed in the MEDLINE, EMBASE, Cochrane Library and PubMed electronic database for relevant articles published before September 2021. Multiple investigators have confirmed TGF‑β3 as a promising candidate which has the chondrogenic potential to repair articular cartilage degeneration. Combining TGF‑β3 with bone morphogenetic proteins‑6, which has synergistic effect on chondrogenesis, with an efficient platform such as exosomes, which themselves possess a chondroprotective function, offers an innovative and more efficient approach to treat injured cartilage. In addition, multiple findings stating the role of exosomes in chondroprotection has also verified a similar fact showing exosomes may be a more favorable choice than the source itself. In the present review, the importance of TGF‑β family in OA and the possibility of therapeutic treatment using stem cell‑derived exosomes are described.
Learn More >To gather information about prescription of triptans and to evaluate whether vascular comorbidity differs in users and nonusers of triptans over the age of 50 years.
Learn More >Until recently, the majority of preclinical neuroinflammatory studies were performed on males. Because of this, less is known about the female neuroinflammatory response to injury, formation of pain, or response to pain-relieving therapies. A major focus has been on the macrophage and its contribution to the development of neuropathic pain. Under a typical response, the macrophage upregulates expression of cyclooxygenase-2 (COX-2), which in turn leads to the production of proinflammatory prostaglandin E (PGE ), which is linked to neuronal sensitization and pain. Non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to attenuate PGE by the inhibition of COX-2. However, a problem with NSAIDs is that due to the systemic dosage needed to achieve neuropathic pain relief there are risks of off-target toxicity. This study evaluated a COX-2 inhibiting nanotherapeutic in its ability to relieve neuropathic inflammation and pain-like behavior of a chronic constriction injury (CCI) of the right sciatic nerve. We find that under the same injury, both males and females exhibit the same degree of hypersensitivity represented as pain-like behavior. We also find that the nanotherapeutic was able to relieve pain-like behavior in both sexes, but females experienced less relief. This behavioral response was reflected in the number of infiltrating macrophages at the site of injury; where again, both sexes had decreased inflammation but the females had significantly more macrophages present than the males.
Learn More >The immune and nervous systems co-evolved to direct and mount coordinated behaviors, reflexes and immune responses to protect the host. In the neuro-immune paradigm sensory nociceptor neurons, located in multiple peripheral ganglia, have been shown to be sensitive to pattern associated molecular patterns (PAMPs). Upon stimulation, these sensory nociceptors release the neurotransmitter calcitonin gene related peptide (CGRP) which acts as a cytokine to assist with the coordination of the innate immune response. However, it remains unclear which PAMPs are sensed by these sensory c-fiber nerves and what specific substances are released in response to the specific PAMPs. Additionally, how long does this stimulation by PAMPs last? These are critical knowledge gaps in our understanding of how sensory neurons shape the innate immune response. To answer these questions, we cultured immortalized F11 dorsal root ganglion (DRG) neurons and exposed them to lipopolysaccharide (LPS 500 ng/mL, Gram-negative PAMP), lipoteichoic acid (LTA 50 μg/mL, Gram-positive PAMP), tumor necrosis factor alpha (TNFα 500 ng/mL, inflammatory cytokine) and capsaicin (1 μM, known C-fiber agonist, serving as a positive control). The exposures to the stimuli lasted for 0.5, 1, 2, 4 or 8 hours. The experiments were run in triplicate on three separate days where a control condition was run on each day for each time point. We measured the release of CGRP with ELISA, known to be released by DRG neurons in response to LPS. We hypothesized that CGRP would be released early on as neural excitation occurs quickly. All conditions and time points were normalized to the average of respective controls for specific time points on respective days. In contrast to our hypothesis, no condition increased CGRP concentration at 0.5 hours. However, at 1-hour LPS, LTA, TNFα and capsaicin increased CGRP release significantly (p<0.05). At 2 hours, LPS and LTA retained their neural stimulation as CGRP was still increased in comparison to controls (P<0.01). Stimulation subsided at 4 and 8 hours as CGRP concentration returned close to control conditions at respective time points. Our data demonstrate that Gram-positive and Gram-negative PAMPs stimulate the release of a known neurotransmitter from sensory nociceptor cells. Additional experiments with fungal PAMPs will be run as well as identifying the complete secrotome of the neuronal culture in response to a variety of PAMPs. These data coincide with the notion that neurons are stimulated early during infection by PAMPs and inflammation directly, as indicated by TNFα stimulation, in order to quickly assist with the innate immune response.
Learn More >The rapid development of neuromodulation specifically as it pertains to spinal cord stimulation (SCS) has ushered in an era of new and novel waveforms and programming methodologies. Accompanying this evolution has been a significant investment in clinical trials and outcomes-based research solidifying the foundation of SCS while investing in future indications and therapy expansion. Critically evaluating the existing literature to apply these therapies diligently remains vital to the future of neuromodulation.
Learn More >Conceptualizing physical pain and negative affect as potentially interactive, we hypothesized that higher levels of peripheral inflammatory markers would be observed consistently only among individuals with both higher negative affect and pain symptomatology. Participants were generally healthy midlife adults from the Bronx, NY ( = 212, = 46.77; 60.8% Black, 25.5% Hispanic/Latina/o) recruited as part of a larger study. Key measures were: reported pain intensity and pain interference at baseline, recent negative affect averaged from self-reports 5x/day for 7 days, and peripheral inflammatory markers (C-reactive protein [CRP] and a composite cytokine measure based on seven cytokines). Controlling for age, BMI, gender, and education, recent negative affect significantly interacted with both pain variables to explain variance in CRP, with higher CRP levels observed only in individuals with both higher negative affect and either higher pain intensity or pain interference. These findings contribute to an emerging literature suggesting that negative affect, pain, and inflammation are related in important and complex ways.
Learn More >To assess the long-term efficacy and safety of erenumab in the subgroup of patients with chronic migraine (CM) in whom prior preventive treatments had failed (TF) (≥1, ≥2, and ≥3 TF medication categories) and never failed (preventive naïve or prior preventive treatments had not failed), using the data from a 52-week, open-label treatment period (OLTP) of the parent study.
Learn More >Most patients with head and neck squamous cell carcinoma (HNSCC) experience pain and pain is associated with a poor prognosis. Despite the frequency and severity of HNSCC pain, current treatments fail to adequately control pain. Cancer-derived small extracellular vesicles (sEVs, size 30-150 nm) are well-positioned to be a mediator of communication between cancer cells and neurons. We hypothesize that cancer-derived sEVs contribute to cancer pain. Mouse oropharyngeal cells were retrovirally transduced to stably express HPV16 viral oncogenes, E6 and E7, H-Ras and luciferase and therefore called mEERL cells. Implantation of mEERL cells into WT mice induces evoked and spontaneous pain. Administration of the sEV release inhibitor GW4869 attenuates the pain in tumor-bearing mice. Additionally, blocking sEV release specifically in the cancer cells, by deleting Rab27a and Rab27b, two proteins required for exosome release, significantly delayed the development of pain hypersensitivity. To test whether cancer-derived sEVs are sufficient to induce pain, we isolated sEVs from mEERL culture and injected them subcutaneously. Injection of isolated sEVs triggers pain hypersensitivity in both sexes. NSAID ketoprofen has no effect on sEVs-induced pain hypersensitivity. In contrast blocking nociceptor neuron activity with the membrane-impermeant lidocaine derivate QX-314 alleviates sEVs-induced pain hypersensitivity. In primary culture of trigeminal ganglion neurons, addition of cancer-derived sEVs induces expression of the neuronal injury marker activating transcription factor 3 (ATF3) and calcium influx measured by calcium imaging in Trpv1 :GCaMP6 mice. Given that sEVs activate TRPV1+ neurons (mostly nociceptors), we examine the impact of TRP1V1+ neuron ablation on cancer pain. Chemical ablation of TRPV1+ neurons by resiniferatoxin (RTX) treatment prevents the development of evoked and spontaneous pain in tumor-bearing mice. Finally, to further explore the potential mechanism of nociception triggered by sEVs, we used published human RNA-sequencing data to investigate the change in gene expression in human cultured sensory neurons exposed to sEVs. Ingenuity pathways analysis (IPA) identified several pathways linked to the initiation of translation, a pathway known to contribute to nociception and neuroplasticity associated with chronic pain. Pharmacological inhibition of translation by rapamycin (mTOR inhibitor), and narciclasine (AMPK activator), alleviates and prevents pain in tumor-bearing mice respectively. In summary, our study shows that cancer-derived sEVs directly activate TRPV1+ neurons to trigger cancer pain and identify new actionable pharmacological targets.
Learn More >Neuropathic pain is a chronic disorder resulting from damage to the afferent nerve fibers or central pain pathways and is often a complication in pathological conditions such as diabetes, shingles, multiple sclerosis, and stroke. The opioid epidemic has elucidated the need for more efficacious treatments for neuropathic pain. In 2019 alone, nearly 1.6 million people were diagnosed with an opioid use disorder and 48,000 people died from a synthetic opioid overdose. Despite the addictive properties, opioids are still the most frequently prescribed pain medication, even for chronic neuropathic pain. Heterotrimeric G-proteins consisting of the α, β, and γ subunits convey extracellular signals sensed by G-protein coupled receptors (GPCRs) to intracellular effectors. The Gβ5 subunit is a divergent member of the G-protein β subunit family as it does not bind to traditional γ subunits. Instead, Gβ5 complexes with the R7 subfamily of the regulators of G-protein signaling (R7-RGS) containing 4 members: RGS6, 7, 9 and 11. The Gβ5/R7-RGS complex acts as a GTPase accelerating protein (GAP) for G-protein αi/o (Gαi/o) subunits. Previous studies have established the integral role of R7-RGS proteins in pain transmission via their interactions with Gαi/o-coupled receptors including opioid and metabotropic gamma-aminobutyric acid (GABA-B) receptors. Our lab has shown the lack of Gβ5 in sensory ganglia diminishes mechanical, thermal, and chemical nociception. However, the conditional knockout of Gβ5 in Rgs7 expressing neurons reduces only mechanical nociception. This Gβ5/RGS7-dependent mechanical nociception relies on GABA-B receptor signaling as indicated by the rescue of mechanical nociception in Rgs7-Cre; Gnb5 fl/fl mice after treatment with 2-hydroxysaclofen, a GABA-B antagonist. We also established that Rgs9 expressing neurons regulate thermal nociception via a Gβ5-dependent pathway as assayed by the hotplate test in Rgs9-Cre; Gnb5 fl/fl mice. The purpose of this project has been to understand the molecular role of each R7-RGS member in the regulation of pain transmission. First, we confirmed co-localization between the Gnb5 transcript and all four R7-RGS mRNA transcripts in murine dorsal root ganglia (DRG) using the RNAscope HiPlex assay, a novel in situ hybridization technique. We then established the co-localization patterns between each R7-RGS member and various pain related receptors including Mrgprd, Trpa1, and Trpv1. Our RNAscope results support the behavioral tests since Rgs7 transcripts highly co-express with Mrgprd, a mechanical nociceptor, while Rgs9 transcripts most frequently co-express with Trpv1, a thermosensitive receptor. These results suggest that each R7-RGS member might regulate unique types of nociception. We have also shown that Rgs11 transcripts co-localize with Trpv1 and Trpa1 receptor transcripts which indicates Rgs11 might regulate the chemical nociception as tested by capsaicin and mustard oil administration in the eye-wipe test. Next, we aim to study the possible roles of Rgs6 and Rgs11 in regulating chemical nociception using conditional Gβ5 knockout mice mediated by Rgs6-cre and Rgs11-cre, respectively.
Learn More >Low back pain (LBP) is the leading cause of disability in the low- and middle-income countries (LMICs), imposing substantial burden on individuals and health systems. The societal burden of LBP in LMICs challenges the United Nations' Sustainable Development Goals of eliminating poverty and improving health and well-being by pushing the people with the lowest socioeconomic position on the planet to greater poverty and more disability. This aims to (1) summarize the current state of LBP management in LMICs, (2) propose what best care for LBP in LMICs may look like, and (3) provide policy recommendations and a call to action. In this first paper, we summarize the extent of the problem: the prevalence, disability, and costs of LBP in LMICs. .
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