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OBJECTIVES: This study aimed to explore the correlation between Fibroblast Growth Factor-23 (FGF23) levels and Cerebral Infarction (CI), and to determine whether there is a significant relationship between FGF23 and the occurrence and severity of CI. METHODS: The study categorized Cerebral Infarction (CI) patients into severe and mild stenosis groups based on vertebrobasilar artery stenosis, using Digital Subtraction Angiography (DSA) and Magnetic Resonance Imaging (MRI). The study compared the levels of Fibroblast Growth Factor-23 (FGF23) in the serum of CI patients and healthy controls using a t-test and evaluated the diagnostic effectiveness of serum FGF23 using a Receiver Operating Characteristic (ROC) curve. Additionally, the study analyzed the correlation between FGF23 levels and CI severity after treatment using the National Institute of Health Stroke Scale score. RESULTS: The study found a significant increase in serum Fibroblast Growth Factor-23 (FGF23) levels in patients with Cerebral Infarction (CI) compared to healthy volunteers, (p < 0.001). A higher serum FGF23 level was observed in the severe stenosis group than in the mild stenosis group (p < 0.001). Furthermore, the study showed that a high FGF23 level at admission was significantly related to more severe symptoms of CI as indicated by the National Institute of Health Stroke Scale (NIHSS) score on the 7th day after treatment (p < 0.001). CONCLUSIONS: This study discovered a correlation between Fibroblast Growth Factor-23 (FGF23) levels, vertebrobasilar artery stenosis, and short-term prognosis in patients who had recently experienced acute Cerebral Infarction (CI).

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MAIN CONCLUSION: We generated transplastomic tobacco lines that stably express a human Basic Fibroblast Growth Factor (hFGFb) in their chloroplasts stroma and purified a biologically active recombinant hFGFb. MAIN: The use of plants as biofactories presents as an attractive technology with the potential to efficiently produce high-value human recombinant proteins in a cost-effective manner. Plastid genome transformation stands out for its possibility to accumulate recombinant proteins at elevated levels. Of particular interest are recombinant growth factors, given their applications in animal cell culture and regenerative medicine. In this study, we produced recombinant human Fibroblast Growth Factor (rhFGFb), a crucial protein required for animal cell culture, in tobacco chloroplasts. We successfully generated two independent transplastomic lines that are homoplasmic and accumulate rhFGFb in their leaves. Furthermore, the produced rhFGFb demonstrated its biological activity by inducing proliferation in HEK293T cell lines. These results collectively underscore plastid genome transformation as a promising plant-based bioreactor for rhFGFb production.

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RESUMEN La acondroplasia severa con retraso del desarrollo y acantosis nigricans (SADDAN) es una rara y letal displasia esquelética. Presentamos el primer caso detectado en Perú, en un infante de 13 meses con características fenotípicas de macrocefalia relativa, tórax estrecho, extremidades micromélicas y piel en acordeón; asimismo, un marcado retraso del desarrollo psicomotor en todos los hitos (prueba peruana) y acantosis nigricans. El paciente tuvo mala evolución clínica caracterizada por crisis convulsivas recurrentes, dificultad respiratoria progresiva, y falleció por insuficiencia respiratoria concomitante a neumonía. Esta entidad requiere del acceso a exámenes específicos como el panel de displasias esqueléticas, la cual no es parte de la oferta en la mayoría de los hospitales del Perú. Se requiere una mayor atención las enfermedades raras, a fin de proveer diagnósticos e información oportuna a los involucrados.

ABSTRACT Severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN) is a rare and lethal skeletal dysplasia. We present the first case detected in Peru, in a 13-month-old infant with phenotypic characteristics of relative macrocephaly, narrow thorax, micromelic extremities and accordion skin; likewise, a marked delay in psychomotor development in all milestones (Peruvian test), and acanthosis nigricans. The patient had a poor clinical evolution characterized by recurrent seizures, progressive respiratory difficulty, dying from respiratory failure concomitant to pneumonia. This entity requires access to specific exams such as the skeletal dysplasia panel, which is not part of the offering in most hospitals in Peru. Greater attention is required for rare diseases, to provide timely diagnoses and information to those involved.

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BACKGROUND: Spinal ventral root avulsion results in massive motoneuron degeneration with poor prognosis and high costs. In this study, we compared different isoforms of basic fibroblast growth factor 2 (FGF2), overexpressed in stably transfected Human embryonic stem cells (hESCs), following motor root avulsion and repair with a heterologous fibrin biopolymer (HFB). METHODS: In the present work, hESCs bioengineered to overexpress 18, 23, and 31 kD isoforms of FGF2, were used in combination with reimplantation of the avulsed roots using HFB. Statistical analysis was conducted using GraphPad Prism software with one-way or two-way ANOVA, followed by Tukey's or Dunnett's multiple comparison tests. Significance was set at *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001. RESULTS: For the first set of experiments, rats underwent avulsion of the ventral roots with local administration of HFB and engraftment of hESCs expressing the above-mentioned FGF2 isoforms. Analysis of motoneuron survival, glial reaction, and synaptic coverage, two weeks after the lesion, indicated that therapy with hESCs overexpressing 31 kD FGF2 was the most effective. Consequently, the second set of experiments was performed with that isoform, so that ventral root avulsion was followed by direct spinal cord reimplantation. Motoneuron survival, glial reaction, synaptic coverage, and gene expression were analyzed 2 weeks post-lesion; while the functional recovery was evaluated by the walking track test and von Frey test for 12 weeks. We showed that engraftment of hESCs led to significant neuroprotection, coupled with immunomodulation, attenuation of astrogliosis, and preservation of inputs to the rescued motoneurons. Behaviorally, the 31 kD FGF2 - hESC therapy enhanced both motor and sensory recovery. CONCLUSION: Transgenic hESCs were an effective delivery platform for neurotrophic factors, rescuing axotomized motoneurons and modulating glial response after proximal spinal cord root injury, while the 31 kD isoform of FGF2 showed superior regenerative properties over other isoforms in addition to the significant functional recovery.

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Since their discovery in 2000, there has been a continuous expansion of studies investigating the physiology, biochemistry, and pharmacology of endocrine fibroblast growth factors (FGFs). FGF19, FGF21, and FGF23 comprise a subfamily with attributes that distinguish them from typical FGFs, as they can act as hormones and are, therefore, referred to as endocrine FGFs. As they participate in a broad cross-organ endocrine signaling axis, endocrine FGFs are crucial lipidic, glycemic, and energetic metabolism regulators during energy availability fluctuations. They function as powerful metabolic signals in physiological responses induced by metabolic diseases, like type 2 diabetes and obesity. Pharmacologically, FGF19 and FGF21 cause body weight loss and ameliorate glucose homeostasis and energy expenditure in rodents and humans. In contrast, FGF23 expression in mice and humans has been linked with insulin resistance and obesity. Here, we discuss emerging concepts in endocrine FGF signaling in the brain and critically assess their putative role as therapeutic targets for treating metabolic disorders.

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SUMMARY OBJECTIVE: The objective of this study was to determine serum fibroblast growth factor-23 levels in preeclampsia, eclampsia, gestational hypertension, and the presence of fetal growth restriction subgroups. METHODS: A total of 55 pregnant women with planned cesarean section were included in this cross-sectional study. They were divided into two groups, namely, control (25) and gestational hypertensive disease (30). The gestational hypertensive disease group was evaluated by dividing it into three subgroups (preeclampsia, eclampsia, and gestational hypertension) according to the clinical and laboratory findings of the disease and two subgroups (presence of fetal growth restriction and absence of fetal growth restriction) according to the birth weight percentile. Demographic parameters, obstetric history, physical examination findings, and laboratory values were evaluated. RESULTS: Demographic parameters and obstetric history were similar between the two groups, while gestational week of delivery was lower in the gestational hypertensive disease group (p=0.002). Laboratory parameters and serum fibroblast growth factor-23 (pg/mL) values were similar between the two groups. In the subgroup analysis for gestational hypertension, preeclampsia, and eclampsia, there was no statistically significant difference in serum fibroblast growth factor-23 levels between gestational hypertension, preeclampsia, eclampsia, and control groups. In the subgroup analysis based on the presence of fetal growth restriction, serum fibroblast growth factor-23 levels were similar to the control group in the gestational hypertensive disease absence of fetal growth restriction, while serum fibroblast growth factor-23 levels and serum calcium levels were statistically significantly lower in the gestational hypertensive disease with the presence of fetal growth restriction (p=0.044 and p<0.001, respectively). Conclusion: Serum fibroblast growth factor-23 levels are similar between pregnancies complicated with gestational hypertensive disease and normotensive pregnancies. However, serum fibroblast growth factor-23 levels were found to be lower in pregnancies complicated with gestational hypertensive disease with the presence of fetal growth restriction.

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ABSTRACT Purpose: To assess the effects of the preoperative application of artificial tears combined with recombinant bovine basic fibroblast growth factor on the ocular surface function and inflammatory factor levels after operation in cataract patients complicated with dry eyes. Methods: A total of 118 cataract patients (118 eyes) complicated with dry eyes treated from February 2019 to February2020 were assigned to control and observation groups (n=59 eyes/group) using a random number table. One week before the operation, the control group was administered 0.1% sodium hyaluronate eye drops (artificial tears), based on which the observation group received Beifushu eye drops (recombinant bovine basic fibroblast growth factor), both 6 times daily for 1 week. A comparison was made between the scores of clinical symptoms and the indices of ocular surface function, inflammatory factors in tears, and oxidative stress indices before and after the operation. The ocular surface function was evaluated by an ocular surface disease index questionnaire, tear film breakup-time assay, Schirmer's I test, and corneal fluorescein stain test. The inflammatory factors in tears were measured. Results: No significant differences were noted in the general data and clinical symptom score, ocular surface disease index, tear film breakup-time, Schirmer's I test score, fluorescein stain score, interleukin-6, tumor necrosis factor-alpha, malondialdehyde, superoxide dismutase, lipid peroxide, and total antioxidant capacity before treatment between the 2 groups (p>0.05). After treatment, the clinical symptom score, ocular surface disease index, fluorescein stain score, tumor necrosis factor-alpha, interleukin-6, malondial-dehyde and lipid peroxide declined significantly, and tear film breakup-time, Schirmer's I test score, superoxide dismutase, and total antioxidant capacity increased in both the groups. The improvements in the clinical symptom score as well as in the indices of ocular surface function, inflammatory factors, and oxidative stress were more prominent in the observation group than in the control group (p<0.05). Conclusions: Artificial tears combined with recombinant bovine basic fibroblast growth factor before operation. significantly improved the ocular surface function, reduced inflammatory factors in tears, and alleviated dry eye symptoms after operation in cataract patients.

RESUMO Objetivo: Avaliar os efeitos da aplicação pré-operatória de lágrimas artificiais combinadas com o fator de crescimento de fibroblastos básicos bovinos recombinantes na função da superfície ocular e níveis de fator inflamatório após cirurgia em pacientes com catarata complicada com olhos secos. Métodos: Um total de 118 pacientes com catarata complicada com olhos secos (118 olhos), tratados entre fevereiro de 2019 e fevereiro de 2020, foram divididos em grupos de controle e de observação (n=59, 59 olhos) usando uma tabela de números aleatórios. Uma semana antes da cirurgia, o grupo controle recebeu colírio de hialuronato de sódio a 0,1% (lágrimas artificiais), enquanto o grupo de observação recebeu colírio Beifushu (fator de crescimento de fibroblastos básicos bovinos recombinantes), ambos, seis vezes ao dia, por uma semana. Antes do tratamento e um mês após a cirurgia, os escores de sintomas clínicos, índices de função da superfície ocular, níveis de fatores inflamatórios nas lágrimas e índices de estresse oxidativo foram comparados. A função da superfície ocular foi avaliada pelo questionário do índice de doença da superfície ocular, ensaio de tempo de ruptura do filme lacrimal, teste I de Schirmer e teste de coloração por fluoresceína da córnea. Os níveis de fatores inflamatórios nas lágrimas foram medidos. Resultados: Não houve diferenças significativas nos dados gerais e no escore de sintomas clínicos, índice de doença da superfície ocular, tempo de ruptura do filme lacrimal, escore do teste I de Schirmer, pontuação do teste de coloração por fluoresceína da córnea, interleucina-6, fator de necrose tumoral alfa, malondialdeído, superóxido dismutase, peróxido lipídico e capacidade antioxidante total antes do tratamento entre os dois grupos (p>0,05). Após o tratamento, o escore de sintomas clínicos, índice de doença da superfície ocular, escore do teste de coloração por fluoresceína da córnea, fator de necrose tumoral alfa, interleucina-6, malondialdeído e peróxido lipídico diminuíram significativamente, e o tempo de ruptura do filme lacrimal, escore do teste I de Schirmer, superóxido dismutase e a capacidade antioxidante total aumentou em ambos os grupos. As melhorias no escore de sintomas clínicos, bem como os índices de função da superfície ocular, fatores inflamatórios e estresse oxidativo foram mais proeminentes no grupo de observação do que no grupo controle (p<0,05). Conclusões: Lágrimas artificiais combinadas com fator de crescimento de fibroblastos básicos recombinantes antes da cirurgia melhoram notavelmente a função da superfície ocular, diminuem os níveis de fatores inflamatórios nas lágrimas e aliviam os sintomas de olho seco após a cirurgia em pacientes com catarata complicada com olhos secos.

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ABSTRACT Objective: To observe the therapeutic effect of gentiopicroside, as the main component of Gentianaceae, on wounds in pressure injury (PI) model rats and explore its mechanism. Method: Male Sprague Dawley rats were randomly divided into control group, model group and gentiopicroside groups (50, 100 and 200 mg·kg-1·d-1 for 9 consecutive days). The mice's skeletal muscle fibroblast line NOR-10 cells were collected after being treated with gentiopicroside (0.2~5.0 M) and basic fibroblast growth factor receptor 1 (bFGFR1) inhibitor (5.0 M SU5402) for 7 days. Results: Compared to the model group, the gentiopicroside groups showed significantly increased wound healing rates, reduced inflammatory cells in the wound tissues, and significantly increased expression levels of proliferating cell nuclear antigen (PCNA) and bFGFR1, accompanied by increased proliferation of new myofibroblasts. Gentiopicroside upregulated the mRNA expression of bFGFR1 and PCNA in NOR-10 cells in a dose-dependent manner; however, SU5402 reversed the effect of gentiopicroside. Conclusion: Gentiopicroside may promote myofibroblast proliferation by upregulating the expression of bFGFR1 and PCNA and ultimately accelerating the healing of PI wounds.

RESUMO Objetivo: Observar o efeito terapêutico do gentiopicrosídeo como principal componente das Gentianáceas em feridas de lesão por pressão (LP) em modelos de ratos e explorar seu mecanismo. Métodos: Ratos Sprague Dawley machos foram divididos aleatoriamente em grupo controle, grupo modelo e grupos gentiopicrosídeo (50, 100 e 200 mg·kg-1·d-1 por 9 dias consecutivos). As células NOR-10 da linha de fibroblastos do músculo esquelético de camundongos foram coletadas após serem tratadas com gentiopicrosídeo (0,2~5,0 μM) e inibidor do receptor 1 do fator de crescimento fibroblástico básico (bFGFR1) (5.0 μM SU5402) por 7 dias. Resultados: Em comparação com o grupo modelo, os grupos gentiopicrosídeo apresentaram taxas de cicatrização de feridas significativamente maiores, menos células inflamatórias nos tecidos da ferida e níveis de expressão de antígeno nuclear de proliferação celular (PCNA) e bFGFR1 significativamente maiores, acompanhados por aumento da proliferação de novos miofibroblastos. O gentiopicrosídeo regulou positivamente a expressão de mRNA de bFGFR1 e PCNA em células NOR-10 de maneira dependente da dose, enquanto o SU5402 reverteu o efeito do gentiopicrosídeo. Conclusão: O gentiopicrosídeo pode promover a proliferação de miofibroblastos, suprarregulando a expressão de bFGFR1 e PCNA e, em última análise, acelerando a cicatrização de feridas de LP.

RESUMEN Objetivo: Observar el efecto terapéutico del gentiopicrósido como componente principal de la Gentianaceae en heridas por lesión por presión (LP) en modelos de ratas y explorar su mecanismo. Método: Se dividieron aleatoriamente ratas macho Sprague Dawley en grupo control, grupo modelo y grupos gentiopicrósido (50, 100 y 200 mg·kg-1·d-1 durante 9 días consecutivos). Se recogieron células NOR-10 de la línea de fibroblastos de músculo esquelético de ratón después de ser tratadas con gentiopicrósido (0.2~5.0 μM) y un inhibidor del receptor 1 del factor de crecimiento de fibroblastos básico (bFGFR1) (5.0 μM SU5402) durante 7 días. Resultados: En comparación con el grupo modelo, los grupos de gentiopicrósido mostraron tasas de curación de heridas significativamente más altas, menos células inflamatorias en los tejidos de la herida y niveles de expresión significativamente mayores del antígeno nuclear de proliferación celular (PCNA) y bFGFR1, acompañados de una mayor proliferación de nuevos miofibroblastos. El gentiopicrósido podría regular positivamente la expresión de ARNm de bFGFR1 y PCNA en células NOR-10 de manera dependiente de la dosis, sin embargo, SU5402 revirtió el efecto del gentiopicrósido. Conclusión: El gentiopicrósido puede promover la proliferación de miofibroblastos al aumentar la expresión de bFGFR1 y PCNA y, en última instancia, acelerar la cicatrización de las heridas de LP.

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Vertical sleeve gastrectomy (VSG) restores glucose homeostasis in obese mice and humans. In addition, the increased fibroblast growth factor (FGF)15/19 circulating level postsurgery has been implicated in this effect. However, the impact of FGF15/19 on pancreatic islets remains unclear. Using a diet-induced obese mice model, we demonstrate that VSG attenuates insulin hypersecretion in isolated pancreatic islets, likely due to morphological alterations in the endocrine pancreas such as reduction in islet, ß-cell, and α-cell mass. In addition, VSG relieves gene expression of endoplasmic reticulum (ER) stress and inflammation markers in islets from obese mice. Incubation of INS-1E ß-cells with serum from obese mice induced dysfunction and cell death, whereas these conditions were not induced with serum from obese mice submitted to VSG, implicating the involvement of a humoral factor. Indeed, VSG increased FGF15 circulating levels in obese mice, as well as the expression of FGF receptor 1 (Fgfr1) and its coreceptor ß-klotho (Klb), both in pancreatic islets from VSG mice and in INS-1E cells treated with the serum from these mice. Moreover, exposing INS-1E cells to an FGFR inhibitor abolished the effects of VSG serum on insulin secretion and cell death. Also, recombinant FGF19 prevents INS-1E cells from dysfunction and death induced by serum from obese mice. These findings indicate that the amelioration of glucose-insulin homeostasis promoted by VSG is mediated, at least in part, by FGF15/19. Therefore, approaches promoting FGF15/19 release or action may restore pancreatic islet function in obesity.NEW & NOTEWORTHY Vertical sleeve gastrectomy (VSG) decreases insulin secretion, endoplasmic reticulum (ER) stress, and inflammation in pancreatic islets from obese mice. In addition, VSG increased fibroblast growth factor (FGF)15 circulating levels in obese mice, as well as the expression of FGF receptor 1 (Fgfr1) and its coreceptor ß-klotho (Klb), both in pancreatic islets from VSG mice and in INS-1E ß-cells treated with the serum from these mice. Serum from operated mice protects INS-1E cells from dysfunction and apoptosis, which was mediated by FGF15/19.

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RESUMEN La displasia tanatofórica tipo 1 es una forma de displasia esquelética letal, se caracteriza por desproporciones del esqueleto axial-apendicular además de talla baja, macrocefalia, prominencia frontal, tórax estrecho, arqueamiento femoral y micromelia. Dichas características fenotípicas son el resultado de variantes patogénicas en el gen del receptor 3 del factor de crecimiento de fibroblastos (FGFR-3), localizada en el cromosoma 4p16.3 Para su estudio la ecografía obstétrica, el examen físico y los hallazgos radiográficos son importantes. Sin embargo, se debe confirmar el diagnóstico mediante estudio genético a fin de descubrir variantes o asociaciones nuevas, así como dar a conocer su casuística real en una determinada región.

ABSTRACT Thanatophoric dysplasia type 1 is a form of lethal skeletal dysplasia, characterized by disproportions of the axial-appendicular skeleton in addition to short stature, macrocephaly, frontal prominence, narrow chest, femoral bowing, and micromelia. These phenotypic characteristics are the result of pathogenic variants in the fibroblast growth factor receptor 3 gene (FGFR-3), located on chromosome 4p16.3. For its study, obstetric ultrasound, physical examination, and radiographic findings are important. However, the diagnosis must be confirmed by genetic study in order to discover new variants or associations, as well as to make known its real casuistry in a given region.

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Disadvantages of using murine monoclonal antibodies (mAb) in human therapy, such as immunogenicity response, led to the development of technologies to transform murine antibodies into human antibodies. The murine anti-FGF2 3F12E7 mAb was proposed as a promising agent to treat metastatic melanoma tumors; once it blocks the FGF2, responsible for playing a role in tumor growth, angiogenesis, and metastasis. Considering the therapeutic potential of anti-FGF2 3F12E7 mAb and its limited use in humans due to its origin, we used this antibody as the template for a guided selection humanization technique to obtain human anti-FGF2 mAbs. Three Fab libraries (murine, hybrid, and human) were constructed for humanization. The libraries were phage-displayed, and the panning was performed against recombinant human FGF2 (rFGF2). The selected human variable light and heavy chains were cloned into AbVec vectors for full-length IgG expression into HEK293-F cells. Surface plasmon resonance analyses showed binding to rFGF2 of seven mAbs out of 20 expressed. Assays performed with these mAbs resulted in two that showed proliferation reduction and cell migration attenuation of HUVEC and SK-Mel-28 melanoma cells. In-silico analyses predicted that these two human anti-FGF2 mAbs interact with FGF2 at a similar patch of residues than the chimeric anti-FGF2 antibody, comprehending a region within the heparin-binding domains of FGF2, essential for its function. These results are comparable to those achieved by the murine anti-FGF2 3F12E7 mAb and showed success in the humanization process and selection of two human mAbs with the potential to inhibit undesirable FGF2 roles.

The guided selection humanization process enabled the production of 20 human mAbs anti-FGF2;Seven human anti-FGF2 mAbs showed binding to the rFGF2 antigen in the SPR binding assay;Two human anti-FGF2 mAbs inhibited the proliferation and migration of HUVEC and SK-Mel-28 cells and were predicted to contact the FGF2 at a similar patch of residues than the original mAb.

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RESUMEN Introducción: La displasia tanatofórica tipo 1 es una forma de displasia esquelética letal, se caracteriza por desproporciones del esqueleto axial-apendicular además de talla baja, macrocefalia, prominencia frontal, tórax estrecho, arqueamiento femoral y micromelia. Reporte de caso: Neonato varón de 38 semanas, nacido de cesárea electiva debido a malformaciones esqueléticas y polihidramnios. La evolución clínica mostró deterioro progresivo en el tiempo y pese a los diferentes dispositivos se soporte oxigenatorio y ventilatorio. Conclusiones: Para su estudio la ecografía obstétrica, el examen físico y los hallazgos radiográficos son importantes. Sin embargo, se debe confirmar el diagnóstico mediante estudio genético a fin de descubrir variantes o asociaciones nuevas, así como dar a conocer su casuística real en una determinada región.

ABSTRACT Introduction: Thanatophoric dysplasia type 1 is a form of lethal skeletal dysplasia, it is characterized by disproportions of the axial-appendicular skeleton in addition to short stature, macrocephaly, frontal prominence, narrow thorax, femoral bowing and micromelia. Case report: 38-week-old male neonate, born by elective cesarean section due to skeletal malformations and polyhydramnios. The clinical evolution showed progressive deterioration over time and despite the different oxygenatory and ventilatory support devices. Conclusions: For its study, obstetric ultrasound, physical examination and radiographic findings are important. However, the diagnosis must be confirmed through a genetic study in order to discover new variants or associations, as well as to make known their real case mix in a certain region.

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Fibroblast growth factor 21 (FGF21) is a hormone involved in the regulation of lipid, glucose, and energy metabolism. Although it is released mainly from the liver, in recent years it has been shown that it is a "myokine", synthesized in skeletal muscles after exercise and stress conditions through an Akt-dependent pathway and secreted for mediating autocrine and endocrine roles. To date, the molecular mechanism for the pathophysiological regulation of FGF21 production in skeletal muscle is not totally understood. We have previously demonstrated that muscle membrane depolarization controls gene expression through extracellular ATP (eATP) signaling, by a mechanism defined as "Excitation-Transcription coupling". eATP signaling regulates the expression and secretion of interleukin 6, a well-defined myokine, and activates the Akt/mTOR signaling pathway. This work aimed to study the effect of electrical stimulation in the regulation of both production and secretion of skeletal muscle FGF21, through eATP signaling and PI3K/Akt pathway. Our results show that electrical stimulation increases both mRNA and protein (intracellular and secreted) levels of FGF21, dependent on an extracellular ATP signaling mechanism in skeletal muscle. Using pharmacological inhibitors, we demonstrated that FGF21 production and secretion from muscle requires the activation of the P2YR/PI3K/Akt/mTOR signaling pathway. These results confirm skeletal muscle as a source of FGF21 in physiological conditions and unveil a new molecular mechanism for regulating FGF21 production in this tissue. Our results will allow to identify new molecular targets to understand the regulation of FGF21 both in physiological and pathological conditions, such as exercise, aging, insulin resistance, and Duchenne muscular dystrophy, all characterized by an alteration in both FGF21 levels and ATP signaling components. These data reinforce that eATP signaling is a relevant mechanism for myokine expression in skeletal muscle.

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Brown adipose tissue (BAT) remains active in adults, oxidizing fatty acids or glucose and releasing energy in the form of heat. Brown adipocytes and enhanced thermogenesis are targets for treating obesity and its comorbidities. BAT shows high synthesis activity and secretes several signaling molecules. The brown adipokines, or batokines, take action in an autocrine, paracrine, and endocrine manner. Batokines have a role in the homeostasis of the cardiovascular system, central nervous system, white adipose tissue, liver, and skeletal muscle and exert beneficial effects on BAT. The systemic function of batokines gives BAT an endocrine organ profile. Besides, the batokines Fibroblast Growth Factor-21, Vascular Endothelial Growth Factor A, Bone Morphogenetic Protein 8, Neuregulin 4, Myostatin, and Interleukin-6 emerge as targets to treat obesity and its comorbidities, deserving attention. This review outlines the role of six emerging batokines on BAT and their cross-talk with other organs, focusing on their physiological significance and diet-induced changes.

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ABSTRACT Objective: Lymphangioleiomyomatosis (LAM) is a rare, destructive disease of the lungs with a limited number of determinants of disease activity, which are a critical need for clinical trials. FGF23 has been implicated in several chronic pulmonary diseases. We aimed to determine the association between serum FGF23 levels and pulmonary function in a cohort of patients with LAM. Methods: This was a descriptive single-center study in which subjects with LAM and controls with unreported lung disease were recruited. Serum FGF23 levels were measured in all subjects. Clinical data, including pulmonary function testing, were retrospectively obtained from electronic medical records of LAM subjects. Associations between FGF23 levels and clinical features of LAM were explored via nonparametric hypothesis testing. Results: The sample comprised 37 subjects with LAM and 16 controls. FGF23 levels were higher in the LAM group than in the control group. In the LAM group, FGF23 levels above the optimal cutoff point distinguished 33% of the subjects who had nondiagnostic VEGF-D levels. Lower FGF23 levels were associated with impaired DLCO (p = 0.04), particularly for those with isolated diffusion impairment with no other spirometric abnormalities (p = 0.04). Conclusions: Our results suggest that FGF23 is associated with pulmonary diffusion abnormalities in LAM patients and elicit novel mechanisms of LAM pathogenesis. FGF23 alone or in combination with other molecules needs to be validated as a biomarker of LAM activity in future clinical research.

RESUMO Objetivo: A linfangioleiomiomatose (LAM) é uma doença rara e destrutiva dos pulmões com um número limitado de determinantes da atividade da doença, que são uma necessidade crítica para ensaios clínicos. O FGF23 já foi implicado em várias doenças pulmonares crônicas. O nosso objetivo foi determinar a associação entre os níveis séricos de FGF23 e a função pulmonar em uma coorte de pacientes com LAM. Métodos: Estudo descritivo unicêntrico no qual foram recrutados indivíduos com LAM e controles com doenças pulmonares não declaradas. Os níveis séricos de FGF23 foram medidos em todos os indivíduos. Os dados clínicos, incluindo testes de função pulmonar, foram obtidos retrospectivamente a partir dos prontuários eletrônicos dos indivíduos com LAM. As associações entre os níveis de FGF23 e as características clínicas da LAM foram exploradas por meio do teste de hipóteses não paramétrico. Resultados: A amostra incluiu 37 indivíduos com LAM e 16 controles. Os níveis de FGF23 foram mais altos no grupo LAM do que no grupo controle. No grupo LAM, níveis de FGF23 acima do ponto de corte ideal distinguiram 33% dos indivíduos com níveis não diagnósticos de VEGF-D. Níveis mais baixos de FGF23 estavam associados à DLCO comprometida (p = 0,04), particularmente naqueles com comprometimento isolado da difusão e sem outras alterações espirométricas (p = 0,04). Conclusões: Nossos resultados sugerem que o FGF23 está associado a alterações na difusão pulmonar em pacientes com LAM e potencialmente indicam novos mecanismos de patogênese da LAM. O FGF23 isoladamente ou em combinação com outras moléculas precisa ser validado como um biomarcador da atividade da LAM em futuras pesquisas clínicas.

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Aloe Vera, a perennial Liliaceae plant, has medical, cosmetic, and wound-healing properties. Aloe vera has antioxidant, anti-cancer, anti-diabetic, and regenerative effects. Glucommannan increases collagen synthesis and aids healing after ginivectomy treatment. Natural mouthwashes may offer gingival wound healing efficacy with reduced side-effects when compared to Chlorhexidine. Objective: the objective of this clinical study was to compare the effects on wound healing of a one-week Aloe vera mouthwash with chlorhexidine mouthwash before gingivectomy surgical therapy. Material and Methods:a total of 45 individuals experiencing inflammatory gingival enlargement were included in the study. They underwent professional mechanical plaque removal and were then randomly divided into three groups. In group I, comprising 15 patients, participants were advised to utilize 100% Aloe vera juice as a mouthwash twice daily. Group II, also consisting of 15 patients, was instructed to use Chlorhexidine (0.2%) mouthwash twice daily. The Control group, which consisted of 15 patients, was recommended to use a placebo mouth rinse in addition to mechanical plaque removal. During the second visit, which occurred one week after the initial visit, the enlarged gingival tissue was surgically removed through scalpel gingivectomy. Immunohistochemical (IHC) analysis was performed on the excised tissue to measure the l evels of fibroblast growth factor-2. Results: when compared to the control group, Aloe vera showed significant differences regarding the expression of fibroblast growth factor-2(FGF-2), and highly significant differences in angiogenesis. At the same time, there were substantial differences in angiogenesis w ith no significant differences in the expression of FGF2 between Chlorhexidine and control groups. Conclusion: aloe vera has exhibited potential wound-healing effects as i t s ignificantly affected the IHC expression of FGF2 and angiogenesis when used as an adjunct to plaque control before gingivectomy surgical therapy (AU)

Aloe Vera, uma planta perene de Liliaceae, tem propriedades médicas, cosméticas e cicatrizantes. Aloe vera tem efeitos antioxidantes, anticancerígenos, antidiabéticos e regenerativos. O glucomanano aumenta a síntese de colágeno e auxilia na cicatrização a pós o tratamento de gengivectomia. Enxaguatórios bucais naturais podem oferecer efi cácia na reparação de feridas gengivais com efeitos colaterais reduzidos quando comparados à clorexidina. Objetivo:O objetivo deste estudo clínico foi comparar os efeitos na cicatrização de feridas de uma semana de enxaguatório bucal de Aloe vera com clorexidina antes da terapia cirúrgica de gengivectomia. Material e Métodos: um total de 45 indivíduos com aumento gengival inflamatório foram incluídos no estudo. Eles foram submetidos à remoção mecânica profissional da placa e foramdivididos aleatoriamente em três grupos. No grupo I, composto por 15 pacientes, os participantes foram orientados a utilizar 100% de suco de Aloe vera como enxaguante bucal duas vezes ao dia. O grupo II, também composto por 15 pacientes, foi instruído a usar enxaguante bucal com clorexidina (0,2%) duas vezes ao dia. O grupo controle, composto por 15 pacientes, foi recomendado o uso de enxaguatório bucal placebo além da remoção mecânica da placa. Durante a segunda visita, que ocorreu uma semana após a visita inicial, o tecido gengival aumentado foi removido cirurgicamente por meio de gengivectomia com bisturi. A análise imuno-histoquímica (IHC) foi realizada no tecido excisado para medir os níveis do fator de crescimento de fibroblastos-2 (FGF-2). Resultados: quando comparado ao grupo controle, o Aloe vera apresentou diferenças significativas em relação àexpressão do FGF-2, e diferenças altamente significativas na angiogênese. Ao mesmo tempo, houve diferenças substanciais na angiogênese, sem diferenças significativas na expressão de FGF-2 entre a clorexidina e os grupos controle. Conclusão: Aloe vera exibiu potenciais efeitos de cicatrização de feridas, pois afetou significativamente a expressão IHC de FGF-2 e a angiogênese quando usada como adjuvante no controle de placa antes da terapia cirúrgica de gengivectomia (AU)

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Disadvantages of using murine monoclonal antibodies (mAb) in human therapy, such as immunogenicity response, led to the development of technologies to transform murine antibodies into human antibodies. The murine anti-FGF2 3F12E7 mAb was proposed as a promising agent to treat metastatic melanoma tumors; once it blocks the FGF2, responsible for playing a role in tumor growth, angiogenesis, and metastasis. Considering the therapeutic potential of anti-FGF2 3F12E7 mAb and its limited use in humans due to its origin, we used this antibody as the template for a guided selection humanization technique to obtain human anti-FGF2 mAbs. Three Fab libraries (murine, hybrid, and human) were constructed for humanization. The libraries were phage-displayed, and the panning was performed against recombinant human FGF2 (rFGF2). The selected human variable light and heavy chains were cloned into AbVec vectors for full-length IgG expression into HEK293-F cells. Surface plasmon resonance analyses showed binding to rFGF2 of seven mAbs out of 20 expressed. Assays performed with these mAbs resulted in two that showed proliferation reduction and cell migration attenuation of HUVEC and SK-Mel-28 melanoma cells. In-silico analyses predicted that these two human anti-FGF2 mAbs interact with FGF2 at a similar patch of residues than the chimeric anti-FGF2 antibody, comprehending a region within the heparin-binding domains of FGF2, essential for its function. These results are comparable to those achieved by the murine anti-FGF2 3F12E7 mAb and showed success in the humanization process and selection of two human mAbs with the potential to inhibit undesirable FGF2 roles.

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ABSTRACT Objective: The aim of this study was to assess the effect of hyperthyroidism and its treatment on body weight and composition, insulin resistance, and mediators of appetite and energy homeostasis, namely ghrelin, leptin, adiponectin, and fibroblast growth factor 21 (FGF21). Subjects and methods: Thirty-five adult patients (27 female and 8 male, aged 39.63 ± 9.70 years) with overt hyperthyroidism were evaluated for leptin, ghrelin, adiponectin, and FGF21 levels; insulin resistance; and body composition using DEXA both at baseline and a minimum of two months following normalization of serum thyroxin on carbimazole treatment. Comparison of means between the baseline and post treatment values was performed by the paired t test for normally distributed parameters and by the Wilcoxon signed-rank test for non-normally distributed data. Results: Hyperthyroidism correction resulted in an increase in weight from 51.15 ± 8.50 kg to 55.74 ± 8.74 kg (P < 0.001), paradoxically accompanied by a decrease in insulin resistance as measured by HOMA-IR from 1.35 (1.02-1.72) to 0.73 (0.52-0.93) ( P < 0.001). Correction of hyperthyroidism was also associated with a decrease in FGF21 from 58 (55-64) to 52 (47-58) pg/mL ( P < 0.001) and in leptin levels from 17 (7-36) to 11 (4.6-28) ng/mL ( P = 0.03). Conclusion: Despite lower body weight, thyrotoxicosis is associated with insulin resistance. High levels of thermogenic hormones, leptin, and FGF21 were observed in thyrotoxicosis and may be partly responsible for the excessive heat production typical of this condition.

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Objetive: To determine the expression of Fibroblast Growth Factor (FGF)-2 and Bone Morphogenetic Protein (BMP)-2 after application of scaffold hydroxyapatite from Rajungan crab shell (Portunus pelagicus) in the tooth extraction socket of Cavia cobaya. Material and Methods: This study used a post-test only control group design with 28 Cavia cobaya separated into two groups, control and treatment group. The left mandibular incisor was extracted, and socket preservation was conducted. A hydroxyapatite graft derived from crab shells was mixed with gelatin and eventually turned into a scaffold, which was afterward put into the extraction socket. After 7 days and 14 days, each group was terminated and examined using immunohistochemical staining to observe the expression of FGF-2 and BMP-2. One-Way Anova and Tukey HSD were used to examine the research data. Results: FGF-2 and BMP-2 expressions were observed higher in the group that received hydroxyapatite scaffold at the post-extraction socket than those in the group that did not receive hydroxyapatite scaffold. Conclusion: The application of a hydroxyapatite scaffold from Rajungan crab shell (Portunus pelagicus) to the tooth extraction socket can increase FGF-2 and BMP-2 expression.

Objetivo: Determinar la expresión del factor de crecimiento de fibroblastos (FGF)-2 y la proteína morfogenética ósea (BMP)-2 después de la aplicación de hidroxiapatita de andamio de caparazón de cangrejo Rajungan (Portunus pelagicus) en el alvéolo de extracción dental de Cavia cobaya. Material y Métodos: Este estudio utilizó un diseño de grupo de control solo posterior a la prueba con 28 Cavia cobaya separados en dos grupos, grupo de control y grupo de tratamiento. Se extrajo el incisivo mandibular izquierdo y se realizó la preservación del alvéolo. Un injerto de hidroxiapatita derivado de caparazones de cangrejo se mezcló con gelatina y se convirtió en un andamio, que luego se colocó en el alvéolo de extracción. Después de 7 días y 14 días, se terminó cada grupo y se examinó mediante tinción inmunohistoquímica para observar la expresión de FGF-2 y BMP-2. Se utilizaron One-Way Anova y Tukey HSD para examinar los datos de la investigación. Resultados: Las expresiones de FGF-2 y BMP-2 se observaron más altas en el grupo que recibió la estructura de hidroxiapatita en el alvéolo posterior a la extracción que en el grupo que no recibió la estructura de hidroxiapatita. Conclusión: La aplicación de un andamio de hidroxiapatita de caparazón de cangrejo Rajungan (Portunus pelagicus) al alvéolo de extracción dental puede aumentar la expresión de FGF-2 y BMP-2.

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In the developing retina, precise coordination of cell proliferation, differentiation, and survival is essential for proper retinal maturation and function. We have previously reported evidence that interleukin-4 (IL-4) plays critical roles in neuronal differentiation and survival during retinal development. However, little is known about the role of IL-4 on retinal cell proliferation. In the current study, we investigated if IL-4 regulates cell proliferation induced by epidermal growth factor (EGF) and by fibroblast growth factor 2 (FGF2) in primary retinal cell cultures obtained from newborn rats. First, we show that EGF and FGF2 act as mitogens for glial cells, increasing proliferation of these cells in the retina. EGF- and FGF2-induced mitogenesis requires activation of distinct cell-intrinsic signals. In retinal cells exposed to FGF2, IL-4 downregulates p53 levels (a protein whose activation induces cell-cycle arrest) and increases mitogenic responsiveness to FGF2 through activation of protein kinase A (PKA) pathway. Conversely, in retinal cells exposed to EGF, IL-4 downregulates cyclin D1 levels (a protein required for cell-cycle progression), upregulates p53 levels, and decreases mitogenic responsiveness to EGF. The inhibitory effect induced by IL-4 on retinal cells exposed to EGF requires activation of Janus kinase 3 (JAK3), but not activation of PKA. Based on previous and current findings, we propose that IL-4 serves as a node of signal divergence, modulating multiple cell-intrinsic signals (e.g., cyclin D1, p53, JAK3, and PKA) and mitogenic responsiveness to cell-extrinsic signals (e.g., FGF2 and EGF) to control cell proliferation, differentiation, and survival during retinal development.

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