Microbiological hazard identification in river waters used for recreational activities.

Pathogenic bacteria, viruses, and parasites can cause waterborne disease outbreaks. The study of coastal water quality contributes to identifying potential risks to human health and to improving water management practices. The Río de la Plata River, a wide estuary in South America, is used for recreational activities, as a water source for consumption and as a site for sewage discharges. In the present study, as the first step of a quantitative microbial risk assessment of the coastal water quality of this river, a descriptive study was performed to identify the microbial pathogens prevalent in its waters and in the sewage discharged into the river. Two sites, representing two different potential risk scenarios, were chosen: a heavily polluted beach and an apparently safe beach. Conductivity and fecal contamination indicators including enterococci, Escherichia coli, F + RNA bacteriophages, and human polyomaviruses showed high levels. Regarding enterococci, differences between sites were significant (p-values <0.001). 93.3% and 56.5% of the apparently safe beach exceeded the recreational water limits for E. coli and enterococci. Regarding pathogens, diarrheagenic E. coli, Salmonella, and noroviruses were detected with different frequencies between sites. The parasites Cryptosporidium spp. and Giardia duodenalis were frequently detected in both sites. The results regarding viral, bacterial, and parasitic pathogens, even without correlation with conventional indicators, showed the importance of monitoring a variety of microorganisms to determine water quality more reliably and accurately, and to facilitate further studies of health risk assessment. The taxonomic description of microbial pathogens in river waters allow identifying the microorganisms that infect the population living on its shores but also pathogens not previously reported by the clinical surveillance system.

Calcium and Neural Stem Cell Proliferation.

Intracellular calcium plays a pivotal role in central nervous system (CNS) development by regulating various processes such as cell proliferation, migration, differentiation, and maturation. However, understanding the involvement of calcium (Ca2+) in these processes during CNS development is challenging due to the dynamic nature of this cation and the evolving cell populations during development. While Ca2+ transient patterns have been observed in specific cell processes and molecules responsible for Ca2+ homeostasis have been identified in excitable and non-excitable cells, further research into Ca2+ dynamics and the underlying mechanisms in neural stem cells (NSCs) is required. This review focuses on molecules involved in Ca2+ entrance expressed in NSCs in vivo and in vitro, which are crucial for Ca2+ dynamics and signaling. It also discusses how these molecules might play a key role in balancing cell proliferation for self-renewal or promoting differentiation. These processes are finely regulated in a time-dependent manner throughout brain development, influenced by extrinsic and intrinsic factors that directly or indirectly modulate Ca2+ dynamics. Furthermore, this review addresses the potential implications of understanding Ca2+ dynamics in NSCs for treating neurological disorders. Despite significant progress in this field, unraveling the elements contributing to Ca2+ intracellular dynamics in cell proliferation remains a challenging puzzle that requires further investigation.

Prognostic value of novel serum biomarkers, including C-reactive protein to albumin ratio and fibrinogen to albumin ratio, in COVID-19 disease: A meta-analysis.

With COVID-19 still hovering around and threatening the lives of many at-risk patients, an effective, quick, and inexpensive prognostic method is required. Few studies have shown fibrinogen to albumin ratio (FAR) and C-reactive protein to albumin ratio (CAR) to be promising as prognostic markers for COVID-19 disease. However, their implications remain unclear. This meta-analysis aimed to elucidate the prognostic role of FAR and CAR in COVID-19 disease. A systematic literature search was undertaken using PubMed and Embase till April 2022. Inverse variance standardised mean difference (SMD) was calculated to report the overall effect size using random effect models. The generic inverse variance random-effects method was used to pool the area under the curve (AUC) values. All statistical analyses were performed on Revman and MedCalc Software. A total of 23 studies were included. COVID-19 non-survivors had a higher CAR on admission compared with survivors (SMD = 1.79 [1.04, 2.55]; p < 0.00001; I2  = 97%) and patients with a severe COVID-19 infection had a higher CAR on admission than non-severe patients (SMD = 1.21 [0.54, 1.89]; p = 0.0004; I2  = 97%). Similarly, higher mean FAR values on admission were significantly associated with COVID-19 mortality (SMD = 0.55 [0.32, 0.78]; p < 0.00001; I2  = 82%). However, no significant association was found between mean FAR on admission and COVID-19 severity (SMD = 0.54 [-0.09, 1.18]; p = 0.09; I2  = 91%). The pooled AUC values found that CAR had a good discriminatory-power to predict COVID-19 severity (AUC = 0.81 [0.75, 0.86]; p < 0.00001; I2  = 80%) and mortality (AUC = 0.81 [0.74, 0.87]; p < 0.00001; I2  = 86%). FAR had a fair discriminatory-power to predict COVID-19 severity (AUC = 0.73 [0.64, 0.82]; p < 0.00001; I2  = 89%). Overall, CAR was a good predictor of both severity and mortality associated with COVID-19 infection. Similarly, FAR was a satisfactory predictor of COVID-19 mortality but not severity.

Antinociceptive and antiedema effects produced in rats by Brassica oleracea var. italica sprouts involving sulforaphane.

Natural products are recognized as potential analgesics since many of them are part of modern medicine to relieve pain without serious adverse effects. The aim of this study was to investigate the antinociceptive and anti-inflammatory activities of an aqueous extract of Brassica oleracea var. italica sprouts (AEBS) and one of its main reported bioactive metabolites sulforaphane (SFN). Antinociceptive activity of the AEBS (30, 100, and 300 mg/kg, i.p. or 1000 and 2000 mg/kg, p.o.) and SFN (0.1 mg/kg, i.p.) was evaluated in the plantar test in rats to reinforce its analgesic-like activity at central level using the reference drug tramadol (TR, 50 mg/kg, i.p.). The anti-inflammatory-like response was determined in the carrageenan-induced oedema at the same dosages for comparison with ketorolac (KET, 20 mg/kg, i.p.) or indomethacin (INDO, 20 mg/kg, p.o.). A histological analysis of the swollen paw was included to complement the anti-inflammatory response. Additionally, acute toxicity observed in clinical analgesics as the most common adverse effects, such as sedation and/or gastric damage, was also explored. As a result, central and peripheral action of the AEBS was confirmed using enteral and parenteral administration, in which significant reduction of the nociceptive and inflammatory responses resembled the effects of TR, KET, or INDO, respectively, involving the presence of SFN. No adverse or toxic effects were observed in the presence of the AEBS or SFN. In conclusion, this study supports that Brassica oleracea var. italica sprouts are a potential source of antinociceptive natural products such as SFN for therapy of pain alone and associated to an inflammation condition.

A systematic review of acute telogen effluvium, a harrowing post-COVID-19 manifestation.

This systematic review focuses on the clinical features, physical examination findings, outcomes, and underlying pathology of acute telogen effluvium (TE), a type of diffuse hair loss, occurring in coronavirus disease 2019 (COVID-19) recovered patients. MEDLINE/PubMed and Embase databases were queried till October 2021 to identify studies reporting acute TE occurring after COVID-19 recovery. Data were obtained from 19 studies, which included 465 patients who were diagnosed with acute TE. The median age of these patients was 44 years and 67.5% were females. The most common trichoscopic findings were decreased hair density, the presence of empty follicles, or short regrowing hair. The mean duration from COVID-19 symptom onset to the appearance of acute TE was 74 days, which is earlier than classic acute TE. Most patients recovered from hair loss, while a few patients had persistent hair fall. Our results highlight the need to consider the possibility of post-COVID-19 acute TE in patients presenting with hair fall, with a history of COVID-19 infection, in the context of COVID-19 pandemic. Despite being a self-limiting condition, hair loss post-COVID-19 is a stressful manifestation. Identifying COVID-19 infection as a potential cause of acute TE will help the clinicians counsel the patients, relieving them from undue stress.

RUNX1 and CBFß-SMMHC transactivate target genes together in abnormal myeloid progenitors for leukemia development.

Inversion of chromosome 16 is a consistent finding in patients with acute myeloid leukemia subtype M4 with eosinophilia, which generates a CBFB-MYH11 fusion gene. It is generally considered that CBFß-SMMHC, the fusion protein encoded by CBFB-MYH11, is a dominant negative repressor of RUNX1. However, recent findings challenge the RUNX1-repression model for CBFß-SMMHC-mediated leukemogenesis. To definitively address the role of Runx1 in CBFB-MYH11-induced leukemia, we crossed conditional Runx1 knockout mice (Runx1f/f) with conditional Cbfb-MYH11 knockin mice (Cbfb+/56M). On Mx1-Cre activation in hematopoietic cells induced by poly (I:C) injection, all Mx1-CreCbfb+/56M mice developed leukemia in 5 months, whereas no leukemia developed in Runx1f/fMx1-CreCbfb+/56M mice, and this effect was cell autonomous. Importantly, the abnormal myeloid progenitors (AMPs), a leukemia-initiating cell population induced by Cbfb-MYH11 in the bone marrow, decreased and disappeared in Runx1f/fMx1-CreCbfb+/56M mice. RNA-seq analysis of AMP cells showed that genes associated with proliferation, differentiation blockage, and leukemia initiation were differentially expressed between Mx1-CreCbfb+/56M and Runx1f/fMx1-CreCbfb+/56M mice. In addition, with the chromatin immunocleavage sequencing assay, we observed a significant enrichment of RUNX1/CBFß-SMMHC target genes in Runx1f/fMx1-CreCbfb+/56M cells, especially among downregulated genes, suggesting that RUNX1 and CBFß-SMMHC mainly function together as activators of gene expression through direct target gene binding. These data indicate that Runx1 is indispensable for Cbfb-MYH11-induced leukemogenesis by working together with CBFß-SMMHC to regulate critical genes associated with the generation of a functional AMP population.

Prolactin from Pluripotency to Central Nervous System Development.

Prolactin (PRL) is a versatile hormone that exerts more than 300 functions in vertebrates, mainly associated with physiological effects in adult animals. Although the process that regulates early development is poorly understood, evidence suggests a role of PRL in the early embryonic development regarding pluripotency and nervous system development. Thus, PRL could be a crucial regulator in oocyte preimplantation and maturation as well as during diapause, a reversible state of blastocyst development arrest that shares metabolic, transcriptomic, and proteomic similarities with pluripotent stem cells in the naïve state. Thus, we analyzed the role of the hormone during those processes, which involve the regulation of its receptor and several signaling cascades (Jak/Mapk, Jak/Stat, and PI3k/Akt), resulting in either a plethora of physiological actions or their dysregulation, a factor in developmental disorders. Finally, we propose models to improve the knowledge on PRL function during early development.

Pluripotency markers in tissue and cultivated cells in vitro of different regions of human amniotic epithelium.

Studies have described the presence of pluripotent markers in vivo and in vitro in human amnion. However, the amnion can be divided into reflected, placental and umbilical regions that are anatomically and functionally heterogeneous. Here, we evaluated the expression of pluripotency markers in tissue and cultivated cells in vitro of different regions of human amnion. To this end, we determined the presence of the core pluripotency factors OCT-4, NANOG and SOX-2 by immunofluorescence and RT-PCR and also performed transcriptome analysis of the different regions of amnion tissue. We identified the mRNA and protein of the pluripotency factors in the different regions of human amnion tissue. However, the OCT-4 and NANOG immunolocalization was cytoplasmic, whereas SOX-2 immunolocalization was nuclear regardless of the region analyzed. Moreover, we found three subpopulations of cells in the in vitro cultures of reflected and placental amnion: cells with immunostaining only in the nucleus, only in the cytoplasm, or in both compartments. Yet no statistically significant differences were found between the reflected and placental amnion. These results suggest a homogeneous distribution of the pluripotency transcription factors of the different regions of human amnion to isolate stem cells that can be used in regenerative medicine.

Associations between dietary patterns and metabolic syndrome in adolescents.

OBJECTIVE: Evaluate association of dietary patterns with metabolic syndrome (MetS) and metabolic markers. MATERIALS AND METHODS: 654 adolescents from Guadalajara, Jalisco, participated in a cross-sectional study. Diet was evaluated using a food frequency questionnaire; 24 food groups were integrated, and dietary patterns were derived using cluster analysis. MetS was defined according to International Diabetes Federation (IDF), Cook and colleagues, Ford and colleagues, and de Ferranti and colleagues criteria. RESULTS: Dietary patterns identified were: "DP1", "DP2", and "DP3". Among males, "DP3" was associated with MetS (Cook and collaborators) (OR, 12.14; 95%CI, 1.66-89.05), hypertriglyceridemia (OR, 3.89; 95%CI, 1.01-15.07), and insulin resistance (OR, 6.66; 95%CI, 1.12-39.70). "DP2" was associated with abdominal obesity (OR, 5.11; 95%CI, 1.57-16.66). CONCLUSIONS: "DP3" entertained a greater risk of MetS, hypertriglyceridemia, and insulin resistance, while "DP2" possessed a greater risk of abdominal obesity among adolescent males.

OBJETIVO: Evaluar la asociación de patrones dietarios (PD) con síndrome metabólico (SM) y marcadores metabólicos. MATERIAL Y MÉTODOS: Estudio transversal con 654 adolescentes. Dieta evaluada con el cuestionario "frecuencia de consumos de alimentos"; se identificaron 24 grupos de alimentos, para obtener PD mediante análisis de conglomerados. SM se definió según los criterios: Federación de Diabetes Internacional (IDF), Cook y colaboradores, Ford y colaboradores y Ferranti y colaboradores. RESULTADOS: Se identificaron tres PD: "PD1", "PD2" y "PD3". En hombres, "PD3" se asoció con SM (Cook y colaboradores) (RM, 12.14; IC95%, 1.66-89.05), hipertrigliceridemia (RM, 3.89; IC95%, 1.01-15.07) y resistencia a insulina (RM, 6.66; IC95%, 1.12-39.70). El patrón "PD2" se asoció con obesidad abdominal (RM, 5.11; IC95%, 1.57- 16.66). CONCLUSIONES: El patrón "PD3" aumenta el riesgo de SM, hipertrigliceridemia y resistencia a insulina y el "PD2" el riesgo de obesidad abdominal en adolescentes hombres.

Secretion of heat shock -60, -70 kD protein, IL-1ß and TNFα levels in serum of a term normal pregnancy and patients with pre-eclampsia development.

The extracellular heat shock proteins (eHsp) family act as molecular chaperones regulating folding, transporting protein and are associated with immune modulation in different physiological and pathological processes. They have been localized in different gestational tissues and their concentration in amniotic fluid and serum has been determined. In the present study, we proposed to determine the concentration of eHsp-60, -70, IL-1ß and TNFα in the serum of pregnant patients with 34 weeks of gestation with and without clinical evidences of preeclampsia (PE). Our results indicate significant increase of these markers in patients with PE with respect to healthy pregnant patients without active labor. Finally, the concentration of eHsp-60 and -70 correlated positively with the hepatic dysfunction markers uric acid, lactate dehydrogenase (LDH), glutamic oxaloacetic transaminase (GOT) glutamic pyruvic transaminase (GPT), and inflammatory IL-1ß and TNFα response. In conclusion, our results demonstrate a strong associated between Hsp and marker of hepatic dysfunction.

Microbiological comparison of blood culture and amplification of 16S rDNA methods in combination with DGGE for detection of neonatal sepsis in blood samples.

It is estimated that 15% of all newborns admitted to the neonatal intensive care unit (NICU) for suspected sepsis receive multiple broad-spectrum antibiotics without pathogen identification. The gold standard for bacterial sepsis detection is blood culture, but the sensitivity of this method is very low. Recently, amplification and analysis of the 16S ribosomal DNA (rDNA) bacterial gene in combination with denaturing gradient gel electrophoresis (DGGE) has proven to be a useful approach for identifying bacteria that are difficult to isolate by standard culture methods. The main goal of this study was to compare two methods used to identify bacteria associated with neonatal sepsis: blood culture and broad range 16S rDNA-DGGE. Twenty-two blood samples were obtained from newborns with (n = 15) or without (n = 7) signs and symptoms of sepsis. Blood samples were screened to identify pathogenic bacteria with two different methods: (1) bacteriological culture and (2) amplification of the variable V3 region of 16S rDNA-DGGE. Blood culture analysis was positive in 40%, whereas 16S rDNA-DGGE was positive in 87% of neonatal sepsis cases. All 16S rDNA-DGGE positive samples were associated with some other signs of neonatal sepsis. CONCLUSION: Our study shows that the molecular approach with 16S rDNA-DGGE identifies twofold more pathogenic bacteria than bacteriological culture, including complex bacterial communities associated with the development of bacterial sepsis in neonates. What is Known: • Neonatal sepsis affects 2.3% of birth in the NICU with a high mortality risk. • Evidence supports the use of molecular methods as an alternative to blood culture for identification of bacterial associated neonatal sepsis. What is New: • The DGGE gel is a good methodological approach for the identification of bacterial in neonatal blood samples. • This study describes the pattern of electrophoretic mobility obtained by DGGE gels and allows to determine the type of bacteria associated in the development of neonatal sepsis.

Biochar, compost and biochar-compost blend as options to recover nutrients and sequester carbon.

This work assessed the potential environmental impact of recycling organic materials in agriculture via pyrolysis (biochar) and composting (compost), as well its combination (biochar-compost blend) versus business-as-usual represented by mineral fertiliser. Life cycle assessment methodology was applied using data sourced from experiments (FP7 project Fertiplus) in three countries (Spain, Italy and Belgium), and considering three environmental impact categories, (i) global warming; (ii) acidification and (iii) eutrophication. The novelty of this analysis is the inclusion of the biochar-compost blend with a focus on multiple European countries, and the inclusion of the acidification and eutrophication impact categories. Biochar, compost and biochar-compost blend all resulted in lower environmental impacts than mineral fertiliser from a systems perspective. Regional differences were found between biochar, compost and biochar-compost blend. The biochar-compost blend offered benefits related to available nutrients and sequestered C. It also produced yields of similar magnitude to mineral fertiliser, which makes its acceptance by farmers more likely whilst reducing environmental impacts. However, careful consideration of feedstock is required.

Analysis of cytokine gene polymorphisms in Mestizo and native populations from Mexico.

OBJECTIVES: To determine whether the well-known genetic structure of the Mexican population observed with other multiallelic markers can be detected by analyzing functional polymorphisms of cytokine and other inflammatory-response-related genes. METHODS: A total of 834 Mestizo individuals from five Mexican cities and 92 Lacandonians - an Amerindian group from southeastern Mexico - were genotyped for 14 polymorphisms in the CRP, IL10, IL6, TGFB1, TNFA, LTA, ICAM1 IFNG, and IL1RN genes. Allele and haplotype frequencies were used for genetic structure analysis using F-statistics pairwise distances and multidimensional scaling plot. Ancestry analysis was performed, as well. RESULTS: Significant interpopulational differences at the allele and haplotype frequency level were observed, mainly between Northern (Guadalajara, Monterrey, and Culiacan) and Southern (Tierra Blanca and Puebla) Mexican populations. Also, low but significant substructure was detected between some populations from these two broad regions. Interestingly, both Lacandonian populations were highly differentiated from each other and with respect to Mestizos. Consistent with previous data, Amerindian ancestry in the Southern Mexican groups was higher compared to Northern ones. CONCLUSIONS: The Mexican population exhibits regional differences in functional polymorphisms of inflammatory-response genes, as observed for other genetic markers. This information constitutes a reference for epidemiological studies that include these genetic markers to assess the susceptibility of the Mexican population to several immune-response-related diseases, such as diabetes, obesity, and renal disease, which have been shown to be common in the Mexican population but with prevalence differences within this country.

Capturing the ephemeral human pluripotent state.

During human development, pluripotency is present only in early stages of development. This ephemeral cell potential can be captured in vitro by obtaining pluripotent stem cells (PSC) with self-renewal properties, the human embryonic stem cells (hESC). However, diverse studies suggest the existence of a plethora of human PSC (hPSC) that can be derived from both embryonic and somatic sources, depending on defined culture conditions, their spatial origin, and the genetic engineering used for reprogramming. This review will focus on hPSC, covering the conventional primed hESC, naïve-like hPSC that resemble the ground-state of development, region-selective PSC, and human induced PSC (hiPSC). We will analyze differences and similarities in their differentiation potential as well as in the molecular circuitry of pluripotency. Finally, we describe the need for human feeder cells to derive and maintain hPSC, because they could emulate the interaction of in vivo pluripotent cells with extraembryonic structures that support development. Developmental Dynamics 245:762-773, 2016. © 2016 Wiley Periodicals, Inc.

Antihyperalgesic Activity of Rhodiola rosea in a Diabetic Rat Model.

Preclinical Research Rhodiola rosea L. (Crassulaceae) is used for enhancing physical and mental performance. Recent studies demonstrated that R. rosea had anti-inflammatory activity in animal models, for example, carrageenan- and nystatin-induced edema in rats, possibly by inhibiting phospholipase A2 and cyclooxygenases-1 and -2. In addition, R. rosea had antinociceptive activity in thermal and chemical pain tests as well as mechanical hyperalgesia. The purpose of the present study was to assess the antihyperalgesic effect of an ethanol extract of Rhodiola rosea (R. rosea) in a diabetic rat model. Rats were administered a single dose of streptozotocin (STZ; 50 mg/kg, i.p.) and hyperalgesia was evaluated four weeks later. Formalin-evoked (0.5%) flinching was increased in diabetic rats compared with nondiabetic controls Systemic (1-100 mg/kg, i.p.) and local (0.1-10 mg/paw into the dorsal surface of the right hind paw) administration of R. rosea ethanol extract dose-dependently reduced formalin-induced hyperalgesia in diabetic rats. The antihyperalgesic effect of R. rosea was compared with gabapentin. These results suggest that R. rosea ethanol extract may have potential as a treatment for diabetic hyperalgesia.

[Human amniotic epithelium (HAE) as a possible source of stem cells (SC)]. / Las células del epitelio amniótico humano (CEAh) como posible fuente de células troncales (CT).

There have been major recent advances in the field of developmental biology due to the investigation on stem cells (SC). Stem cells are characterized by their capacity of auto-renewal and differentiation to different cellular phenotypes. Based on the developmental stage, they can be classified into two different types: embryonic SCs and adult SCs. It has been widely reported that several problems need to be resolved before their possible clinical applications. As a result, fetal membranes have been suggested as an alternative source of SCs. In the human amniotic epithelium, the presence of markers of pluripotent SC´s has been reported, and its capacity as a feeder layer for expansion of different SC types. Also, fetal membranes are a discarded product after delivery, and thus there are not any ethical issues related to its use. In conclusion, the human amniotic epithelium can be a strong candidate for regenerative medicine.

MicroRNAs in central nervous system development.

During early and late embryo neurodevelopment, a large number of molecules work together in a spatial and temporal manner to ensure the adequate formation of an organism. Diverse signals participate in embryo patterning and organization synchronized by time and space. Among the molecules that are expressed in a temporal and spatial manner, and that are considered essential in several developmental processes, are the microRNAs (miRNAs). In this review, we highlight some important aspects of the biogenesis and function of miRNAs as well as their participation in ectoderm commitment and their role in central nervous system (CNS) development. Instead of giving an extensive list of miRNAs involved in these processes, we only mention those miRNAs that are the most studied during the development of the CNS as well as the most likely mRNA targets for each miRNA and its protein functions.

Antinociceptive activity of Ligusticum porteri preparations and compounds.

CONTEXT: The roots and rhizomes of Ligusticum porteri Coulter & Rose (Apiaceae) are widely used in Mexican folk medicine for several purposes, including painful complaints. OBJECTIVE: The main goal of this work was to demonstrate the analgesic action in mice of some preparations and major compounds from L. porteri. MATERIALS AND METHODS: The extracts, aqueous (AE) and organic (OE), the essential oil (EO) and major compounds (10-316 mg/kg) from L. porteri were evaluated as potential antinociceptive agents using the acetic acid-induced writhing and hot plate tests in ICR mice. RESULTS: All preparations tested exhibited significant antinociceptive effect in the two animal pain models selected. AE and EO were more effective in the writhing test while OE had a better effect in the hot-plate model. On the other hand, Z-ligustilide (1) provoked an increment in the latency period to the thermal stimuli in the hot-plate test at a dose of 31.6 mg/kg, and a decrease in the number of abdominal writhes at 10 mg/kg. Z-3-butylidenephthalide (2) induced a dose-dependent antinociceptive action in the hot-plate assay; this compound was also effective for controlling the pain provoked by chemical irritation at the doses of 10 and 31.6 mg/kg. Finally, diligustilide (3) inhibited the number of writhing responses at all doses tested but was inactive in the hot-plate model. CONCLUSION: The present investigation provides in vivo evidence supporting the use of L. porteri to treat painful conditions in folk medicine.

Clavulanic Acid and its Potential Therapeutic Effects on the Central Nervous System.

Clavulanic acid (CLAV) is a non-antibiotic ß-lactam that has been used since the late 1970s as a ß-lactamase inhibitor in combination with amoxicillin, another ß-lactam with antibiotic activity. Its long-observed adverse reaction profile allows it to say that CLAV is a well-tolerated drug with mainly mild adverse reactions. Interestingly, in 2005, it was discovered that ß-lactams enhance the astrocytic expression of GLT-1, a glutamate transporter essential for maintaining synaptic glutamate homeostasis involved in several pathologies of the central nervous system (CNS). This finding, along with a favorable pharmacokinetic profile, prompted the appearance of several studies that intended to evaluate the effect of CLAV in preclinical disease models. Studies have revealed that CLAV can increase GLT-1 expression in the nucleus accumbens (NAcc), medial prefrontal cortex (PFC), and spinal cord of rodents, to affect glutamate and dopaminergic neurotransmission, and exert an anti-inflammatory effect by modulating the levels of the cytokines TNF-α and interleukin 10 (IL-10). CLAV has been tested with positive results in preclinical models of epilepsy, addiction, stroke, neuropathic and inflammatory pain, dementia, Parkinson's disease, and sexual and anxiety behavior. These properties make CLAV a potential therapeutic drug if repurposed. Therefore, this review aims to gather information on CLAV's effect on preclinical neurological disease models and to give some perspectives on its potential therapeutic use in some diseases of the CNS.

Antinociceptive effect of LMH-2, a new sigma-1 receptor antagonist analog of haloperidol, on the neuropathic pain of diabetic mice.

This study evaluates the antiallodynic and antihyperalgesic effects of LMH-2, a new haloperidol (HAL) analog that acts as sigma-1 receptor (σ1 R) antagonist, in diabetic mice using a model of neuropathic pain induced by chronic hyperglycemia. Additionally, we compared its effects with those of HAL. Hyperglycemia was induced in mice by nicotinamide-streptozotocin administration (NA-STZ, 50-130 mg/kg). Four weeks later, mechanical allodynia was assessed using the up-down method, and hyperalgesia was evoked with formalin 0.5%. We evaluated antiallodynic and antihyperalgesic effects of LMH-2 (5.6-56.2 mg/kg), HAL (0.018-0.18 mg/kg) and gabapentin (GBP, 5.6-56.2 mg/kg). The results showed that LMH-2 had a more significant antiallodynic effect compared to HAL and GBP (90.4±8.7 vs 75.1±3.1 and 41.9±2.3%, respectively; P<0.05), as well as an antihyperalgesic effect (96.3±1.2 vs 86.9±7.41 and 86.9±4.8%, respectively; P<0.05). Moreover, the antiallodynic and antihyperalgesic effect of both LMH-2 and HAL were completely abolished by PRE-084 (σ1 R agonist); and partially by pramipexole (a D2-like receptor agonist). Finally, the effect of all treatments on the rotarod test, barra, open field and exploratory behaviors showed that LMH-2 did not alter the animals' balance or the exploratory behavior, unlike as HAL or GBP. The molecular docking included indicate that LMH-2 has lower affinity to the D2R than HAL. These results provide evidence that LMH-2 exerts its antinociceptive effects as a σ1 R antagonist without the adverse effects induced by HAL or GBP. Consequently, LMH-2 can be considered a good and safe strategy for treating neuropathic pain caused by hyperglycemia in patients with diabetes.