Upregulation of delta opioid receptor by meningeal interleukin-10 prevents relapsing pain.

Chronic pain often includes periods of transient amelioration and even remission that alternate with severe relapsing pain. While most research on chronic pain has focused on pain development and maintenance, there is a critical unmet need to better understand the mechanisms that underlie pain remission and relapse. We found that interleukin (IL)-10, a pain resolving cytokine, is produced by resident macrophages in the spinal meninges during remission from pain and signaled to IL-10 receptor-expressing sensory neurons.

Mast cell-derived chymases are essential for the resolution of inflammatory pain in mice.

Unlabelled: Immune cells play a critical role in the transition from acute to chronic pain. However, the role of mast cells in pain remains under-investigated. Here, we demonstrated that the resolution of inflammatory pain is markedly delayed in mast-cell-deficient mice.

Massage-like stroking produces analgesia in mice.

Chronic pain treatment remains a major challenge and pharmacological interventions are associated with important side effects. Manual medicine treatments such as massage, acupuncture, manipulation of the fascial system (MFS), and osteopathic manipulative treatments produce pain relief in humans, but the underlying mechanism is poorly understood limiting leverage and optimization of manual medicine techniques as safe pain therapy. To decipher the physiological mechanisms of manipulative medicine treatments, we have established a preclinical model.

Interleukin-10 signaling in somatosensory neurons controls CCL2 release and inflammatory response.

Appropriate regulation of the inflammatory response is essential for survival. Interleukin-10 (IL-10), a well-known anti-inflammatory cytokine, plays a major role in controlling inflammation. In addition to immune cells, we previously demonstrated that the IL-10 receptor (IL-10R1) is expressed in dorsal root ganglion sensory neurons.

Interleukin-10-producing monocytes contribute to sex differences in pain resolution in mice and humans.

Pain is closely associated with the immune system, which exhibits sexual dimorphism. For these reasons, neuro-immune interactions are suggested to drive sex differences in pain pathophysiology. However, our understanding of peripheral neuro-immune interactions on sex differences in pain resolution remains limited.

HPV+ head and neck cancer-derived small extracellular vesicles communicate with TRPV1+ neurons to mediate cancer pain.

Severe pain is often experienced by patients with head and neck cancer and is associated with a poor prognosis. Despite its frequency and severity, current treatments fail to adequately control cancer-associated pain because of our lack of mechanistic understanding. Although recent works have shed some light of the biology underlying pain in HPV-negative oral cancers, the mechanisms mediating pain in HPV+ cancers remain unknown.

Tonic Meningeal Interleukin-10 Upregulates Delta Opioid Receptor to Prevent Relapse to Pain.

Chronic pain often alternates between transient remission and relapse of severe pain. While most research on chronic pain has focused on mechanisms maintaining pain, there is a critical unmet need to understand what prevents pain from re-emerging in those who recover from acute pain. We found that interleukin (IL)-10, a pain resolving cytokine, is persistently produced by resident macrophages in the spinal meninges during remission from pain.

Istradefylline protects from cisplatin-induced nephrotoxicity and peripheral neuropathy while preserving cisplatin antitumor effects.

Cisplatin is a potent chemotherapeutic drug that is widely used in the treatment of various solid cancers. However, its clinical effectiveness is strongly limited by frequent severe adverse effects, in particular nephrotoxicity and chemotherapy-induced peripheral neuropathy. Thus, there is an urgent medical need to identify novel strategies that limit cisplatin-induced toxicity.

Follistatin supplementation induces changes in CDX2 CpG methylation and improves in vitro development of bovine SCNT preimplantation embryos.

Caudal Type Homeobox 2 (CDX2) is a key regulator of trophectoderm formation and maintenance in preimplantation embryos. We previously demonstrated that supplementation of exogenous follistatin, during in vitro culture of bovine IVF embryos, upregulates CDX2 expression, possibly, via alteration of the methylation status of CDX2 gene. Here, we further investigated the effects of exogenous follistatin supplementation on developmental competence and CDX2 methylation in bovine somatic cell nuclear transfer (SCNT) embryos.

Can FDA-Approved Immunomodulatory Drugs be Repurposed/Repositioned to Alleviate Chronic Pain?

Pain is among the most widespread chronic health condition confronting society today and our inability to manage chronic pain contributes to the opioid abuse epidemic in America. The immune system is known to contribute to acute and chronic pain, but only limited therapeutic treatments such as non-steroid anti-inflammatory drugs have resulted from this knowledge. The last decade has shed light on neuro-immune interactions mediating the development, maintenance, and resolution of chronic pain.

A Novel Syngeneic Immunocompetent Mouse Model of Head and Neck Cancer Pain Independent of Interleukin-1 Signaling.

Background: Pain is one of the first presenting symptoms in patients with head and neck cancer, who often develop chronic and debilitating pain as the disease progresses. Pain is also an important prognostic marker for survival. Unfortunately, patients rarely receive effective pain treatment due to our limited knowledge of the mechanisms underlying head and neck cancer pain (HNCP).

Follistatin treatment modifies DNA methylation of the CDX2 gene in bovine preimplantation embryos.

CDX2 plays a crucial role in the formation and maintenance of the trophectoderm epithelium in preimplantation embryos. Follistatin supplementation during the first 72 hr of in vitro culture triggers a significant increase in blastocyst rates, CDX2 expression, and trophectoderm cell numbers. However, the underlying epigenetic mechanisms by which follistatin upregulates CDX2 expression are not known.

Role of bone morphogenetic protein signaling in bovine early embryonic development and stage specific embryotropic actions of follistatin†.

Characterization of the molecular factors regulating early embryonic development and their functional mechanisms is critical for understanding the causes of early pregnancy loss in monotocous species (cattle, human). We previously characterized a stage specific functional role of follistatin, a TGF-beta superfamily binding protein, in promoting early embryonic development in cattle. The mechanism by which follistatin mediates this embryotropic effect is not precisely known as follistatin actions in cattle embryos are independent of its classically known activin inhibition activity.

Transgenerational Effects of Periconception Heavy Metal Administration on Adipose Weight and Glucose Homeostasis in Mice at Maturity.

We previously demonstrated that periconception maternal administration (2 mg/kg body weight each) of cadmium chloride (CdCl2) plus methylmercury (II) chloride (CH3HgCl) impaired glucose homeostasis and increased body weights and abdominal adipose tissue weight of male offspring in the F1 generation. However, transgenerational effects of this exposure have not been studied. Therefore, the effects of periconception Cd+Hg administration on indices of chronic diseases at adulthood in F2-F4 generations were examined.

Follistatin supplementation during in vitro embryo culture improves developmental competence of bovine embryos produced using sex-sorted semen.

Using sex-sorted semen to produce offspring of desired sex is associated with reduced developmental competence in vitro and lower fertility rates in vivo. The objectives of the present study were to investigate the effects of exogenous follistatin supplementation on the developmental competence of bovine embryos produced with sex-sorted semen and possible link between TGF-β regulated pathways and embryotrophic actions of follistatin. Effects of follistatin on expression of cell lineage markers (CDX2 and Nanog) and downstream targets of SMAD signaling (CTGF, ID1, ID2 and ID3) and AKT phosphorylation were investigated.

Functional role of AKT signaling in bovine early embryonic development: potential link to embryotrophic actions of follistatin.

Background: TGF-β signaling pathways regulate several crucial processes in female reproduction. AKT is a non-SMAD signaling pathway regulated by TGF-β ligands essential for oocyte maturation and early embryonic development in the mouse, but its regulatory role in bovine early embryonic development is not well established. Previously, we demonstrated a stimulatory role for follistatin (a binding protein for specific members of TGF-β superfamily) in early bovine embryonic development.

Characterization of H3.3 and HIRA expression and function in bovine early embryos.

Histone variant H3.3 is encoded by two distinct genes, H3F3A and H3F3B, that are closely associated with actively transcribed genes. H3.

Pre- and Peri-/Post-Compaction Follistatin Treatment Increases In Vitro Production of Cattle Embryos.

Our previous studies demonstrated that maternal (oocyte derived) follistatin (FST) expression is positively associated with bovine oocyte competence and exogenous follistatin treatment during the pre-compaction period of development (d 1-3 post insemination) is stimulatory to bovine early embryogenesis in vitro [blastocyst rates and cell numbers/allocation to trophectoderm (TE)]. In the present study, bovine embryos were treated with exogenous follistatin during d 1-3, d 4-7 and d 1-7 post insemination to test the hypothesis that embryotropic effects of exogenous follistatin are specific to the pre-compaction period (d 1-3) of early embryogenesis. Follistatin treatment during d 4-7 (peri-/post-compaction period) of embryo culture increased proportion of embryos reaching blastocyst and expanded blastocyst stage and total cell numbers compared to controls, but blastocyst rates and total cell numbers were lower than observed following d 1-3 (pre-compaction) follistatin treatment.

Effects of Periconception Cadmium and Mercury Co-Administration to Mice on Indices of Chronic Diseases in Male Offspring at Maturity.

Background: Long-term exposure to the heavy metals cadmium (Cd) and mercury (Hg) is known to increase the risk of chronic diseases. However, to our knowledge, exposure to Cd and Hg beginning at the periconception period has not been studied to date.

Objective: We examined the effect of Cd and Hg that were co-administered during early development on indices of chronic diseases in adult male mice.

CHD1 Regulates Deposition of Histone Variant H3.3 During Bovine Early Embryonic Development.

The CHD family of proteins is characterized by the presence of chromodomains and SNF2-related helicase/ATPase domains, which alter gene expression by modification of chromatin structure. Chd1-null embryos arrest at the peri-implantation stage in mice. However, the functional role of CHD1 during preimplantation development remains unclear, given maternal-derived CHD1 may mask the essential role of CHD1 during this stage in traditional knockout models.

Evidence supporting a role for SMAD2/3 in bovine early embryonic development: potential implications for embryotropic actions of follistatin.

The TGF-beta-SMAD signaling pathway is involved in regulation of various aspects of female reproduction. However, the intrinsic functional role of SMADs in early embryogenesis remains poorly understood. Previously, we demonstrated that treatment with follistatin, an activin (TGF-beta superfamily ligand)-binding protein, is beneficial for bovine early embryogenesis and specific embryotropic actions of follistatin are dependent on SMAD4.

Effect of Vitamin D on basal and Luteinizing Hormone (LH) induced testosterone production and mitochondrial dehydrogenase activity in cultured Leydig cells from immature and mature rams.

The objectives of this study were to investigate the potential effects of 1α,25-(OH)2VD3 (biologically active form of Vitamin D) on basal and LH-induced testosterone production and mitochondrial dehydrogenase activity in Leydig cells from immature and mature rams cultured in vitro. Leydig cells were isolated from testes of immature and mature rams, treated without (control) or with increasing concentrations of LH (1, 10, 100ng/ml) and/or 1α,25-(OH)2VD3 (1, 10, 100nM). After 24h, concentrations of testosterone in culture media were measured.

Expression of TGFβ superfamily components and other markers of oocyte quality in oocytes selected by brilliant cresyl blue staining: relevance to early embryonic development.

Brilliant cresyl blue (BCB) is a super-vital stain that has been used to select competent oocytes in different species. One objective of the present study was to assess the relationship between BCB staining, which correlates with an oocyte's developmental potential, and the transcript abundance for select TGFβ-superfamily components, SMAD2/3 and SMAD1/5 phosphorylation levels, and oocyte (JY1) and cumulus-cell (CTSB, CTSK, CTSS, and CTSZ) transcript markers in bovine oocytes and/or adjacent cumulus cells. The capacity of exogenous follistatin or JY1 supplementation or cathepsin inhibitor treatment to enhance development of embryos derived from low-quality oocytes, based on BCB staining, was also determined.

Requirement of the transcription factor USF1 in bovine oocyte and early embryonic development.

Upstream stimulating factor 1 (USF1) is a basic helix-loop-helix transcription factor that specifically binds to E-box DNA motifs, known cis-elements of key oocyte expressed genes essential for oocyte and early embryonic development. However, the functional and regulatory role of USF1 in bovine oocyte and embryo development is not understood. In this study, we demonstrated that USF1 mRNA is maternal in origin and expressed in a stage specific manner during the course of oocyte maturation and preimplantation embryonic development.

Evidence supporting a functional requirement of SMAD4 for bovine preimplantation embryonic development: a potential link to embryotrophic actions of follistatin.

Transforming growth factor beta (TGFbeta) superfamily signaling controls various aspects of female fertility. However, the functional roles of the TGFbeta-superfamily cognate signal transduction pathway components (e.g.