Is hypovitaminosis D associated with fibromyalgia? A systematic review.

CONTEXT: Recent findings have suggested a high prevalence of vitamin D deficiency or insufficiency in fibromyalgia (FM) patients despite the lack of clinical and pathophysiological evidence. OBJECTIVE: A systematic review was conducted to examine the association between vitamin D status and FM, including the effect of vitamin D supplementation. DATA SOURCE: PubMed, LILACS, Scopus, SciELO, Cochrane, and EMBASE were searched, from January 2000 to July 2018, using the descriptors "Fibromyalgia" and "Vitamin D." STUDY SELECTION: Trials including FM patients in whom vitamin D levels were assessed were eligible for inclusion. DATA EXTRACTION: Data comprised age, gender, country, aims, bias, diagnosis criteria, cutoff point, and status of vitamin D, together with FM symptoms and vitamin D supplementation protocol. RESULTS: A total of 26 articles were selected. Most of the studies were found to present unreliable control groups and small samples. Experimental data on vitamin D supplementation indicated improvement in certain FM symptoms. CONCLUSION: Prevalence of hypovitaminosis D in the FM population and the cause-effect relationship were inconclusive. Nevertheless, vitamin D supplementation may be considered as a co-adjuvant in FM therapy.

Theranostic verteporfin- loaded lipid-polymer liposome for photodynamic applications.

In this study we report a novel theranostic lipid-polymer liposome, obtained from DPPC and the triblock copolymer F127 covalently modified with 5(6)-carboxyfluorescein (CF) for photodynamic applications. Due to the presence of F127, small unilamellar vesicle (SUV) liposomes were synthesized by a simple and fast thin-film hydration method without the need for an extrusion process. The vesicles have around 100 nm, low polydispersity and superb solution stability. The clinically used photosensitizer verteporfin (VP) was entrapped into the vesicles, mostly in monomeric form, with 90% loading efficiency. Stern-Volmer and fluorescence lifetime assays showed heterogeneous distribution of the VP and CF into the vesicles, ensuring the integrity of their individual photophysical properties. The theranostic properties were entirely photoactivatable and can be trigged by a unique wavelength (470 nm). The feasibility of the system was tested against the Glioblastoma multiforme cell line T98G. Cellular uptake by time-resolved fluorescence microscopy showed monomerized VP (monoexponential decay, 6.0 ns) at nucleus level, while CF was detected at the membrane by fluorescence microscopy. The strategy's success was supported by the reduction of 98% in the viability of T98G cells by the photoactivated lipid-polymer liposome with [VP] = 1.0 µmol L-1. Therefore, the novel theranostic liposome is a potential system for use in cancer and ocular disease therapies.

Thermoregulation and vasopressin secretion during polymicrobial sepsis.

OBJECTIVE: We investigated the time course of thermoregulation, nitric oxide (NO) formation and hydroelectrolytic alterations, as well as mean arterial pressure and arginine vasopressin (AVP) secretion, in experimental sepsis induced by cecal ligation and puncture (CLP). METHODS: Male Wistar rats submitted to CLP or a sham operation were divided into 4 groups, as follows: group 1, for survival rate evaluation for 24 h; group 2, for body temperature (Tb) analysis; group 3, for mean arterial pressure registration, and group 4, for blood collection and processing of the neurohypophysis and hypothalamic nuclei 0, 2, 4, 6 and 24 h after surgery. AVP levels and content were measured in plasma, neurohypophysis and the hypothalamic paraventricular and supraoptic nuclei. RESULTS: Animals which underwent CLP showed high mortality, a progressive decrease in mean arterial pressure and an increase in plasma NO. Tb dropped during the first 4 h and showed a progressive increase 6 h after surgery. Plasma AVP levels increased immediately after CLP surgery and again at 6 h, before returning to basal levels at 24 h. This was followed by a depletion of neurohypophyseal AVP content at 4 h that continued until 24 h. AVP content in the supraoptic nucleus was elevated 24 h after CLP surgery, while in the paraventricular nucleus, an increase was observed at 6 h and 24 h. CONCLUSIONS: In the present study, laparotomy and hypotension may have been responsible for the increase in plasma AVP in the initial phase of polymicrobial sepsis, and this may have contributed to the observed hypothermia. Moreover, an apparently impaired replenishment of AVP content in the neurohypophysis, possibly due to increased NO formation, may explain the impaired AVP secretion in the late phase of severe sepsis.

Role of locus coeruleus heme oxygenase-carbon monoxide-cGMP pathway during hypothermic response to restraint.

Central heme oxigenase-carbon monoxide (HO-CO) pathway has been shown to play a pyretic role in the thermoregulatory response to restraint. However, the specific site in the central nervous system where CO may act modulating this response remains unclear. LC is rich not only in sGC but also in heme oxygenase (HO; the enzyme that catalyses the metabolism of heme to CO, along with biliverdin and free iron). Therefore, the possible role of the HO-CO-cGMP pathway in the restraint-induced-hypothermia by LC neurons was investigated. Body temperature dropped about 0.7 degrees C during restraint. ZnDPBG (a HO inhibitor; 5 nmol, intra-LC) prevented the hypothermic response during restraint. Conversely, induction of the HO pathway in the LC with heme-lysinate (7.6 nmol, intra-LC) intensified the hypothermic response to restraint, and this effect was prevented by pretreatment with ODQ (a sGC inhibitor; given intracerebroventricularly, 1.3 nmol). Taken together, these data suggest that CO in the LC produced by the HO pathway and acting via cGMP is implicated in thermal responses to restraint.

Aerobic Exercise Training Attenuates Tumor Growth and Reduces Insulin Secretion in Walker 256 Tumor-Bearing Rats.

Aerobic exercise training can improve insulin sensitivity in many tissues; however, the relationship among exercise, insulin, and cancer cell growth is unclear. We tested the hypothesis that aerobic exercise training begun during adolescence can attenuate Walker 256 tumor growth in adult rats and alter insulin secretion. Thirty-day-old male Wistar rats engaged in treadmill running for 8 weeks, 3 days/week, 44 min/day, at 55-65% VO2max until they were 90 days old (TC, Trained Control). An equivalently aged group was kept inactive during the same period (SC, Sedentary Control). Then, half the animals of the SC and TC groups were reserved as the control condition and the other half were inoculated with Walker 256 cancer cells, yielding two additional groups (Sedentary Walker and Trained Walker). Zero mortalities were observed in tumor-bearing rats. Body weight (BW), food intake, plasma glucose, insulin levels, and peripheral insulin sensitivity were analyzed before and after tumor cell inoculation. We also evaluated tumor growth, metastasis and cachexia. Isolated pancreatic islets secretory activity was analyzed. In addition, we evaluated mechanic sensibility. Our results showed improved physical performance according to the final workload and VO2max and reduced BW in trained rats at the end of the running protocol. Chronic adaptation to the aerobic exercise training decreased tumor weight, cachexia and metastasis and were associated with low glucose and insulin levels and high insulin sensitivity before and after tumor cell inoculation. Aerobic exercise started at young age also reduced pancreatic islet insulin content and insulin secretion in response to a glucose stimulus, without impairing islet morphology in trained rats. Walker 256 tumor-bearing sedentary rats also presented reduced pancreatic islet insulin content, without changing insulin secretion through isolated pancreatic islets. The mechanical sensitivity test indicated that aerobic exercise training did not cause injury or trigger inflammatory processes prior to tumor cell inoculation. Taken together, the current study suggests that aerobic exercise training applied during adolescence may mitigate tumor growth and related disorders in Walker 256 tumor-bearing adult rats. Improved insulin sensibility, lower glucose and insulin levels and/or reduced insulin secretion stimulated by glucose may be implicated in this tumor attenuation.

Exercise therapy normalizes BDNF upregulation and glial hyperactivity in a mouse model of neuropathic pain.

Treatment of neuropathic pain is a clinical challenge likely because of the time-dependent changes in many neurotransmitter systems, growth factors, ionic channels, membrane receptors, transcription factors, and recruitment of different cell types. Conversely, an increasing number of reports have shown the ability of extended and regular physical exercise in alleviating neuropathic pain throughout a wide range of mechanisms. In this study, we investigate the effect of swim exercise on molecules associated with initiation and maintenance of nerve injury-induced neuropathic pain. BALB/c mice were submitted to partial ligation of the sciatic nerve followed by a 5-week aerobic exercise program. Physical training reversed mechanical hypersensitivity, which lasted for an additional 4 weeks after exercise interruption. Swim exercise normalized nerve injury-induced nerve growth factor, and brain-derived neurotrophic factor (BDNF) enhanced expression in the dorsal root ganglion, but had no effect on the glial-derived neurotrophic factor. However, only BDNF remained at low levels after exercise interruption. In addition, exercise training significantly reduced the phosphorylation status of PLCγ-1, but not CREB, in the spinal cord dorsal horn in response to nerve injury. Finally, prolonged swim exercise reversed astrocyte and microglia hyperactivity in the dorsal horn after nerve lesion, which remained normalized after training cessation. Together, these results demonstrate that exercise therapy induces long-lasting analgesia through various mechanisms associated with the onset and advanced stages of neuropathy. Moreover, the data support further studies to clarify whether appropriate exercise intensity, volume, and duration can also cause long-lasting pain relief in patients with neuropathic pain.

Role of the locus coeruleus carbon monoxide pathway in endotoxin fever in rats.

Carbon monoxide (CO) has been identified as a diffusible signaling messenger in the brain, capable of altering body temperature by stimulating soluble guanylate cyclase (sGC). However, its site of action remains unclear. Locus coeruleus (LC) is rich not only in sGC but also in heme oxygenase (HO; the enzyme that catalyses the metabolism of heme to CO, along with biliverdin and free iron). Therefore, the possible role of the HO-CO-cGMP pathway in the lipopolysaccharide (LPS)-induced fever regulation by LC neurones was investigated. Induction of the HO pathway using heme-lysinate (7.6 nmol, intra-LC) attenuated the febrile response, and this effect could be prevented by pretreatment with ODQ (an sGC inhibitor; given intracerebroventricularly, 1.3 nmol). Moreover, ZnDPBG (an HO inhibitor; 5 nmol, intra-LC) augmented the febrile response. Taken together, these data suggest that CO in the LC produced by the HO pathway and acting via cGMP plays an antipyretic role during LPS-fever in rats.