Antimicrobial Resistance and New Antimicrobial Agents, A Review of the Literature.

Antibiotic resistance has progressively diminished the effectiveness of conventional antibiotics, necessitating the cessation of clinical treatment. Consequently, novel antibacterial agents are urgently needed. We review studies on antimicrobial agents published during 2002-2023. Most of these studies were published within the last 10 years. By analyzing recent articles on antibiotic resistance and the development of new antibacterial drugs, we showed that although drug resistance is inevitable, the issue is being addressed gradually via the discovery and clinical application of antimicrobial peptides, nanomaterial drugs, and bacteriophage therapy. In light of the emergence of antimicrobial resistance, the development of new antimicrobial agents will require innovation in a field that has relied on traditional methods of discovery and development.

Common pathogenic bacteria-induced reprogramming of the host proteinogenic amino acids metabolism.

Apart from cancer, metabolic reprogramming is also prevalent in other diseases, such as bacterial infections. Bacterial infections can affect a variety of cells, tissues, organs, and bodies, leading to a series of clinical diseases. Common Pathogenic bacteria include Helicobacter pylori, Salmonella enterica, Mycobacterium tuberculosis, Staphylococcus aureus, and so on. Amino acids are important and essential nutrients in bacterial physiology and support not only their proliferation but also their evasion of host immune defenses. Many pathogenic bacteria or opportunistic pathogens infect the host and lead to significant changes in metabolites, especially the proteinogenic amino acids, to inhibit the host's immune mechanism to achieve its immune evasion and pathogenicity. Here, we review the regulation of host metabolism, while host cells are infected by some common pathogenic bacteria, and discuss how amino acids of metabolic reprogramming affect bacterial infections, revealing the potential adjunctive application of amino acids alongside antibiotics.

Gastric adenocarcinoma of the fundic gland type: A review of the literature.

Background and Aim: Gastric adenocarcinoma of the fundic gland type (GA-FG) is a newly described tumor entity but lacking consensus. This review summarizes the key features and controversies regarding this uncommon neoplasm. Methods: We reviewed studies on GA-FG published in English from 2007 to 2021. Results: We found that 327 cases (340 lesions) have been reported. GA-FG lesions originate from deep layers of the gastric mucosa, with the following characteristics on conventional white-light endoscopy examination. These lesions, macroscopically identified as submucosal tumor-like 0-IIa, tend to have a whitish discoloration without inflammation, atrophy, or intestinal metaplasia in the background mucosa. Tumors located in the upper third of the stomach are usually solitary, with an average size <10 mm. Contrastingly, magnifying endoscopy with narrow-band imaging mostly shows the absence of any demarcation line, with a regular microvascular pattern and regular microsurface pattern. GA-FGs are covered with normal foveolar epithelium, forming a so-called endless glands pattern in the deeper region, which are mainly composed of chief cells or parietal cells. Most tumors exhibit submucosal invasion, but lymphovascular invasion and nodal metastasis are rare. Regarding the treatment of GA-FG, endoscopic submucosal dissection (ESD) and endoscopic mucosal resection (EMR) are effective treatment methods. Conclusions: GA-FG is a rare tumor that typically follows a benign course. This neoplasm has distinct endoscopic and pathological features and could be treated by ESD or EMR.

Combination of constraint-induced movement therapy with fasudil amplifies neurogenesis after focal cerebral ischemia/reperfusion in rats.

PURPOSE: Spontaneous axonal plasticity and functional restoration after stroke may be limited by Nogo-A, a myelin-associated inhibitor, via activation of the Rho/Rho-associated protein kinase (ROCK) pathway. Constraint-induced movement therapy (CIMT) is a rehabilitation technique based on neuroplasticity and neural recombination. We recently reported that CIMT promoted neurogenesis after cerebral ischemia/reperfusion in part by inhibiting the Nogo-A-RhoA-ROCK pathway. Here, we examine the hypothesis that CIMT combined with the ROCK inhibitor fasudil further amplifies neurogenesis during stroke recovery. METHODS: Four groups of rats were randomized as follows: Cerebral ischemia-reperfusion (IR), Fasudil, CIMT and CIMT + Fasudil. Seven days after stroke, CIMT and/or intraperitoneal infusion of fasudil were initiated and continued for 3 weeks. The behavioral outcomes and immunohistochemical markers of neurogenesis were quantified. RESULTS: Compared with other groups, the combination of CIMT with fasudil after IR significantly improved motor and memory function recovery. In addition, BrdU, BrdU/doublecortin and BrdU/GFAP all increased significantly in the brain tissue of the combined treatment group compared to the CIMT or Fasudil group. CONCLUSION: These results suggest that the effects of CIMT on neurogenesis are amplified by fasudil during the recovery phase after stroke.

Posterior reversible encephalopathy syndrome induced by intracranial hypotension in a postpartum patient.

Objective: A number of hormonal, physiologic, immunologic, and hemodynamic changes can cause a series of central nervous system-related problems in pregnant and postpartum women. Posterior reversible encephalopathy syndrome (PRES) is commonly seen in these conditions. However, PRES during pregnancy and the postpartum period are not always due to pregnancy.Methods: We describe a patient who presented with headache followed by an epileptic seizure after cesarean section and whose computed tomography (CT) showed bilateral low-density lesions in the frontal lobe. To explore the pathogenesis, we further examined the patient with brain magnetic resonance imaging (MRI) and lumbar puncture.Results: Brain MRI revealed vasogenic edema in the frontal lobe and temporal-occipital regions of both hemispheres. MRI of the brain with contrast showed diffuse enhancement of the supratentorial dura mater and decreased of bilateral lateral ventricles. There was no abnormality in brain magnetic resonance angiography and magnetic resonance venography. Bloody cerebrospinal fluid flowed very slowly during lumbar puncture.Conclusion: These findings suggest that, although rare, intracranial hypotension in postpartum patients may be a cause of PRES.

Constraint-induced movement therapy enhances angiogenesis and neurogenesis after cerebral ischemia/reperfusion.

Constraint-induced movement therapy after cerebral ischemia stimulates axonal growth by decreasing expression levels of Nogo-A, RhoA, and Rho-associated kinase (ROCK) in the ischemic boundary zone. However, it remains unclear if there are any associations between the Nogo-A/RhoA/ROCK pathway and angiogenesis in adult rat brains in pathological processes such as ischemic stroke. In addition, it has not yet been reported whether constraint-induced movement therapy can promote angiogenesis in stroke in adult rats by overcoming Nogo-A/RhoA/ROCK signaling. Here, a stroke model was established by middle cerebral artery occlusion and reperfusion. Seven days after stroke, the following treatments were initiated and continued for 3 weeks: forced limb use in constraint-induced movement therapy rats (constraint-induced movement therapy group), intraperitoneal infusion of fasudil (a ROCK inhibitor) in fasudil rats (fasudil group), or lateral ventricular injection of NEP1-40 (a specific antagonist of the Nogo-66 receptor) in NEP1-40 rats (NEP1-40 group). Immunohistochemistry and western blot assay results showed that, at 2 weeks after middle cerebral artery occlusion, expression levels of RhoA and ROCK were lower in the ischemic boundary zone in rats treated with NEP1-40 compared with rats treated with ischemia/reperfusion or constraint-induced movement therapy alone. However, at 4 weeks after middle cerebral artery occlusion, expression levels of RhoA and ROCK in the ischemic boundary zone were markedly decreased in the NEP1-40 and constraint-induced movement therapy groups, but there was no difference between these two groups. Compared with the ischemia/reperfusion group, modified neurological severity scores and foot fault scores were lower and time taken to locate the platform was shorter in the constraint-induced movement therapy and fasudil groups at 4 weeks after middle cerebral artery occlusion, especially in the constraint-induced movement therapy group. Immunofluorescent staining demonstrated that fasudil promoted an immune response of nerve-regeneration-related markers (BrdU in combination with CD31 (platelet endothelial cell adhesion molecule), Nestin, doublecortin, NeuN, and glial fibrillary acidic protein) in the subventricular zone and ischemic boundary zone ipsilateral to the infarct. After 3 weeks of constraint-induced movement therapy, the number of regenerated nerve cells was noticeably increased, and was accompanied by an increased immune response of tight junctions (claudin-5), a pericyte marker (α-smooth muscle actin), and vascular endothelial growth factor receptor 2. Taken together, the results demonstrate that, compared with fasudil, constraint-induced movement therapy led to stronger angiogenesis and nerve regeneration ability and better nerve functional recovery at 4 weeks after cerebral ischemia/reperfusion. In addition, constraint-induced movement therapy has the same degree of inhibition of RhoA and ROCK as NEP1-40. Therefore, constraint-induced movement therapy promotes angiogenesis and neurogenesis after cerebral ischemia/reperfusion injury, at least in part by overcoming the Nogo-A/RhoA/ROCK signaling pathway. All protocols were approved by the Institutional Animal Care and Use Committee of China Medical University, China on December 9, 2015 (approval No. 2015PS326K).

Early microalbuminuria as a clinical marker for acute cerebral small vessel infarction.

BACKGROUND: Previous studies have shown the potential interactions between cerebrovascular diseases and microalbuminuria. However, the relationship between urine microalbumin and acute lacunar infarction caused by cerebral small vessel disease (CSVD) remains unknown. METHODS: The clinical data of 148 patients with acute lacunar infarction admitted to the Department of Neurology, Shengjing Hospital of China Medical University between April 2016 and April 2017 were analyzed. They were divided into either a CSVD group (n = 70) or a cerebral large vessel disease (CLVD) group (n = 78) according to their carotid artery B-mode ultrasonography and head magnetic resonance angiography (MRA) findings. The concentration of urinary microalbumin in both groups was determined. Statistic analysis was conducted using SAS 9.1 software (North Carolina state university, USA). A Logistic regression analysis was used to determine the independent risk factors for acute lacunar infarction caused by CSVD. RESULTS: The concentration of urine microalbumin in the CSVD group (23 ± 12 mg/L) was significantly lower than that in the CLVD group (29 ± 15 mg/L) (p < 0. 01). However, there was an increasing trend for the proportion of patients with urine microalbumin concentration 10- < 30 mg/L (34.3%) in the CSVD group compared with the CLVD group (19.2%). Logistic regression analysis showed that microalbuminuria (10- < 30 mg/L) was independently associated with acute lacunar infarction caused by CSVD (OR = 3.582; 95% CI 1.347～6.274; p < 0.01). CONCLUSIONS: These findings demonstrate that in patients with acute lacunar infarction, slightly increased microalbuminuria seems to be a potential clinical marker for CSVD. The presence of microalbuminuria early may help to differentiate CSVD from stroke subtypes.

Left-right asymmetry influenced the infarct volume and neurological dysfunction following focal middle cerebral artery occlusion in rats.

OBJECTIVE: To investigate the differential effects of left versus right cerebral hemisphere on the infarct volume and behavioral function following focal cerebral ischemia in rats. METHODS AND MATERIALS: Middle cerebral artery occlusion (MCAO) was induced in the right-handed rats by filament insertion for 1.5 hr, and then reperfusion was established according to Zea-Longa method. A total of 36 male Sprague Dawley rats were randomly divided into a left MCAO group or a right MCAO group. The modified neurological severity scores (mNSS), tapered beam-walking test, and Morris water maze experiment were all carried out to evaluate the sensorimotor and cognitive outcomes at the 1d, 3d, and 7d after MCAO, respectively. Infarct volume of the brains was measured by triphenyltetrazolium chloride (TTC) staining. RESULTS: The sensorimotor function was more worse in the left MCAO group than that in the right MCAO group at the 1d, 3d, and 7d after MCAO (p < 0.05). While the cognitive function was much better in the left MCAO group than that in the right MCAO group at the 1d and 3d after MCAO (p < 0.05). But no significant difference was achieved in cognitive function between the two groups at 7d after MCAO (p > 0.05). There was no significant difference in total infarct volume between the two groups at the 1d, 3d, and 7d after MCAO, respectively (p > 0.05). CONCLUSION: The infarct volume is not affected significantly by the left or right MCAO model in the early days. The lesions in the left hemisphere produce more severe sensorimotor impairments, while more severe cognitive impairments are produced by the right hemispherical lesions. These findings suggest that it is structural and functional asymmetry between the two hemispheres other than infarct volume that affects the outcomes of rat MCAO.

Methionine enkephalin regulates microglia polarization and function.

Methionine enkephalin (MENK), an opioid peptide, is known to function as a regulator in the immune system. As microglia are considered the most important immune cells in the central nervous system (CNS), we aimed to assess the function of MENK on microglia polarization and tumoricidal responses. Initially, we chose the most optimal condition of 10-12M for 48h; however, MENK had no function on the viability and apoptosis of microglia under this treatment. However, MENK treatment markedly increased levels of M1-associated genes, such as CD86, CD40, IL-12, and TNF-α, but had no effect on M2 markers, including CD163, IL-10, and TGF-ß. Moreover, microglia in the MENK-treated group showed high phagocytosis capacity, which coincided with characteristics of M1 microglia. MENK stimulation also induced up-regulation of reactive oxygen species (ROS) expression, which contributed to maintaining homeostasis. We also detected NO production by measuring the end product nitrite, and found that MENK treatment increased expression of nitrite and inducible NO synthase (iNOS), but did not influence arginase-1 (Arg1) expression. Furthermore, treatment of microglia with MENK led to a significant increase in cytotoxicity against glioblastoma cells, indicating that MENK possessed anti-tumor ability. Overall, MENK treatment could induce microglia to an M1 phenotype, modulating Th1 responses in the immune system. Additionally, microglia treated with MENK had tumoricidal activity, which provides new insight into anti-tumor immunity.

Repulsive guidance molecule a blockade exerts the immunoregulatory function in DCs stimulated with ABP and LPS.

Repulsive guidance molecule a (RGMa) is an axonal guidance molecule that has recently found to exert function in immune system. This study evaluated the function of RGMa in modulation of dendritic cells (DCs) function stimulated with Achyranthes bidentata polysaccharide (ABP) and lipopolysaccharide (LPS) using a RGMa-neutralizing antibody. Compared with the Control-IgG/ABP and Control-IgG/LPS groups, DCs in the Anti-RGMa/ABP and Anti-RGMa/LPS groups 1) showed small, round cells with a few cell processes and organelles, and many pinocytotic vesicles; 2) had decreased MHC II, CD86, CD80, and CD40 expression; 3) displayed the decreased IL-12p70, IL-1ß and TNF-α levels and increased IL-10 secretion; 4) had a high percentage of FITC-dextran uptake; and 5) displayed a reduced ability to drive T cell proliferation and reinforced T cell polarization toward a Th2 cytokine pattern. We conclude that DCs treated with RGMa-neutralizing antibodies present with tolerogenic and immunoregulatory characteristics, which provides new insights into further understanding of the function of RGMa.

Correlation analysis between the expression of P21WAF1/CIP1, P16 proteins and human glioma.

AIM: Glioma is the most common neoplasm of the brain. Unfortunately, surgical cure of it is practically impossible and clinical course is primarily determined by the biological behaviour of the tumour cells. The purpose of this study was to investigate the correlation between the expression levels of P21WAF1/CIP1, P16 proteins and the grading of glioma. METHODS: T98G human glioma cell line, normal human astrocyte (HA) cell line, tumour tissue samples from 70 patients suffering from glioma and normal brain tissues from 20 cases with brain contusion were investigated. The expression levels of P21WAF1/CIP1 and P16 proteins were detected using SABC immunohistochemical staining and semi-quantitive reverse transcriptase polymerase chain reaction (RT-PCR) assay. Then, the correlation of the two markers' expression with glioma grading of patients was analysed. RESULTS: The expression levels of P21WAF1/CIP1 and P16 proteins in the T98G cell line were much lower than that in the HA cell line. Their positive expression rates in glioma tissues were 55.71% and 42.86% respectively, and a significant increase was observed in normal brain tissues (p = 0.012, 0.008). Combined with the result of semi-quantitive RT-PCR, we could demonstrate that the expression intensity of P21WAF1/CIP1 and P16 decreased with the glioma grade increase. Co-expression of them was also found in glioma and normal brain tissues. Furthermore, there was a negative correlation between the two markers' expression and glioma grading of patients (rs = -0.68, -0.56). CONCLUSIONS: The positive expression rate and co-expression rate of P21WAF1/CIP1 and P16 proteins could reflect the malignant grade of glioma to some extent, and they can be considered as a sensitive index for glioma grading.