Anti-Acinetobacter Baumannii single-chain variable fragments provide therapeutic efficacy in an immunocompromised mouse pneumonia model.

BACKGROUND: The emergence of carbapenem-resistant and extensively drug-resistant (XDR) Acinetobacter baumannii as well as inadequate effective antibiotics calls for an urgent effort to find new antibacterial agents. The therapeutic efficacy of two human scFvs, EB211 and EB279, showing growth inhibitory activity against A. baumannii in vitro, was investigated in immunocompromised mice with A. baumannii pneumonia. RESULTS: The data revealed that infected mice treated with EB211, EB279, and a combination of the two scFvs showed better survival, reduced bacterial load in the lungs, and no marked pathological abnormalities in the kidneys, liver, and lungs when compared to the control groups receiving normal saline or an irrelevant scFv. CONCLUSIONS: The results from this study suggest that the scFvs with direct growth inhibitory activity could offer promising results in the treatment of pneumonia caused by XDR A. baumannii.

Intraspecific anatomical variations of the extensor tendons of the carpus and digits with a reexamination of their insertion sites in the domestic dog (Canis lupus familiaris): a cadaveric study.

BACKGROUND: The aim of the current study was to investigate the frequency of variations of the extensor tendons of the carpus and digits in the domestic dog (Canis lupus familiaris) with a reexamination of their insertions as well as the morphometric measurements of the tendons and the brachioradialis muscle. In total, we investigated 68 paired thoracic limbs of the domestic dog (16 females and 18 males) which were fixed in a 10% formalin solution. RESULTS: The extensor carpi radialis (ECR) tendons showed striking variations in both splitting and insertion sites. In 4.4% of dissections, ECR had three tendons. Of these tendons, the extra tendon either attached independently on the fourth metacarpal bone (one right) or joined its counterpart tendon at the distal end (cross-connections) (one bilateral). It is worth mentioning that one of the ECR tendons split into two or three slips which inserted on the first, second, third, or fourth metacarpal bone in 11 (16.2%) of the specimens. In addition, we found a long tendinous slip originating from the ECR tendons to digit II or III in 7.4% of the distal limbs. The most common type of contribution to digit III was a third tendon of the extensor digiti I et II (ED III) joining the extensor digitorum lateralis (EDL III) with a frequency of 17.6%. In other types of variations, the contribution to digit III was incomplete. A part of the abductor pollicis longus (APL) deep to the superficial part of the flexor retinaculum seemed to continue up to the flexor digitorum superficialis (FDS) tendon. CONCLUSIONS: The rare intraspecific variations of the extensor tendons of the manus described in the current research are valuable from both clinical and phylogenetic perspectives. Nonetheless, their functional importance needs more studies.

The anti-inflammatory effects of Akkermansia muciniphila and its derivates in HFD/CCL4-induced murine model of liver injury.

Inflammation plays a critical role in the promotion of hepatocyte damage and liver fibrosis. In recent years the protective role of Akkermansia muciniphila, a next-generation beneficial microbe, has been suggested for metabolic and inflammatory disorders. In this study, we aimed to evaluate the effects of live and pasteurized A. muciniphila and its extra cellular vesicles (EVs) on inflammatory markers involved in liver fibrosis in a mouse model of a high-fat diet (HFD)/carbon tetrachloride (CCl4)-induced liver injury. Firstly, the responses of hepatic stellate cells (HSCs) to live and pasteurized A. muciniphila and its EVs were examined in the quiescent and LPS-activated LX-2 cells. Next, the anti-inflammatory effects of different forms of A. muciniphila were examined in the mouse model of HFD/CCl4-induced liver injury. The gene expression of various inflammatory markers was evaluated in liver, colon, and white adipose tissues. The cytokine secretion in the liver and white adipose tissues was also measured by ELISA. The results showed that administration of live and pasteurized A. muciniphila and its EVs leads to amelioration in HSCs activation. Based on data obtained from the histopathological analysis, an improvement in gut health was observed through enhancing the epithelium and mucosal layer thickness and strengthening the intestinal integrity in all treatments. Moreover, live A. muciniphila and its EVs had inhibitory effects on liver inflammation and hepatocytes damage. In addition, the tissue cytokine production and inflammatory gene expression levels revealed that live A. muciniphila and its EVs had more pronounced anti-inflammatory effects on liver and adipose tissues. Furthermore, EVs had better effects on the modulation of gene expression related to TLRs, PPARs, and immune response in the liver. In conclusion, the present results showed that oral administration of A. muciniphila and its derivatives for four weeks could enhance the intestinal integrity and anti-inflammatory responses of the colon, adipose, and liver tissues and subsequently prevent liver injury in HFD/CCL4 mice.

Binder design for targeting SARS-CoV-2 spike protein: An in silico perspective.

INTRODUCTION: The COVID-19 pandemic is now affecting all people around the world and getting worse. New antiviral medications are desperately needed other than the few approved medications that have shown no promising efficacy so far. METHODS: Here we report three blocking binders for targeting SARS-CoV-2 spike protein to block the interaction between the spike protein on the SARS-CoV-2 and the angiotensin-converting enzyme 2 (ACE2) receptors, responsible for viral homing into the alveolar epithelium type II cells (AECII). RESULTS: The design process is based on the collected natural scaffolds and using Rosetta interface for designing the binders. CONCLUSION: Based on the structural analysis, three binders were selected, and the results showed that they might be promising as new therapeutic targets for blocking COVID-19.

Extracellular vesicles and pasteurized cells derived from Akkermansia muciniphila protect against high-fat induced obesity in mice.

BACKGROUND: Several studies have shown that probiotics have beneficial effects on weight control and metabolic health. In addition to probiotics, recent studies have investigated the effects of paraprobiotics and postbiotics. Therefore, we evaluated the preventive effects of live and pasteurized Akkermansia muciniphila MucT (A. muciniphila) and its extracellular vesicles (EVs) on HFD-induced obesity. RESULTS: The results showed that body weight, metabolic tissues weight, food consumption, and plasma metabolic parameters were increased in the HFD group, whereas A. muciniphila preventive treatments inhibited these HFD. The effects of pasteurized A. muciniphila and its extracellular vesicles were more noticeable than its active form. The HFD led to an increase in the colonic, adipose tissue, and liver inflammations and increased the expression of genes involved in lipid metabolism and homeostasis. Nevertheless, these effects were inhibited in mice that were administered A. muciniphila and its EVs. The assessment of the gut microbiota revealed significant differences in the microbiota composition after feeding with HFD. However, all treatments restored the alterations in some bacterial genera and closely resemble the control group. Also, the correlation analysis indicated that some gut microbiota might be associated with obesity-related indices. CONCLUSIONS: Pasteurized A. muciniphila and its EVs, as paraprobiotic and postbiotic agents, were found to play a key role in the regulation of metabolic functions to prevent obesity, probably by affecting the gut-adipose-liver axis.

Comparative effects of alive and pasteurized Akkermansia muciniphila on normal diet-fed mice.

Recently, Akkermansia muciniphila an anaerobic member of the gut microbiota, has been proposed as a next-generation probiotic. The aim of this study was evaluation of the effect of alive and pasteurized A. muciniphila on health status, intestinal integrity, immune response, lipid metabolism, and gut microbial composition in normal-diet fed mice as well as direct effects of the bacterium on Caco-2 cell line. A total of 30 mice were distributed into three different groups, control, alive, and pasteurized A. muciniphila-treated group. After acclimation, control and treatment groups were administrated with PBS and 109 CFU/200µL of bacterial suspension for 5 weeks, respectively. Besides, Caco-2 separately exposed to alive, pasteurized A. muciniphila and PBS for 24 h. The results showed that administration of A. muciniphila leads to reduction in body, liver, and white adipose weight. Histology data revealed both treatments had no adverse effects in colon, liver, and adipose tissues as well as induced better gut structure. Moreover, biochemical parameters and inflammatory biomarkers in plasma demonstrated that pasteurized A. muciniphila had more pronounce effect. Furthermore, alive A. muciniphia had better effects on the modulation of gene expression related to fatty acid synthesis, energy homeostasis, and immune response in the liver; meanwhile, these effects in the adipose was more in the pasteurized A. muciniphila administration. More importantly, the improvement of gut health by enhancing strengthen intestinal integrity and maintaining immune homeostasis was seen in both treatments; notably, pasteurized A. muciniphila had more effective. Similarly, treatment with the pasteurized form more effectively upregulated tight junction and regulated immune response-related genes in Caco-2 cell line. Both treatments triggered the improvement of microbiota communities, particularly the alive form. Therefore, both forms of A. muciniphila could modulate lipid and immune homeostasis, improved some gut microbiota, and promoted the overall health, while all these effects were dominantly observed in pasteurized form. In conclusion, pasteurized A. muciniphila can be considered as new medical supplement to maintain health state and prevent diseases in normal mice through different mechanisms.

The Protective Effects of Live and Pasteurized Akkermansia muciniphila and Its Extracellular Vesicles against HFD/CCl4-Induced Liver Injury.

Akkermansia muciniphila, as a member of the gut microbiota, has been proposed as a next-generation probiotic. Liver fibrosis is the main determinant of liver dysfunction and mortality in patients with chronic liver disease. In this study, we aimed to determine the beneficial effects of live and pasteurized A. muciniphila and its extracellular vesicles (EVs) on the prevention of liver fibrosis. The response of hepatic stellate cells (HSCs) to live and pasteurized A. muciniphila and its EVs was examined in quiescent, lipopolysaccharide (LPS)-activated LX-2 cells. Liver fibrosis was induced in 8-week-old C57BL/6 mice, using a high-fat diet (HFD) and carbon tetrachloride (CCl4) administration for 4 weeks. The mice were concomitantly treated via oral gavage with three forms of bacteria. The relative expression of different fibrosis and inflammatory markers was assessed in the tissues. Histological markers, serum biochemical parameters, and cytokine production were also analyzed, and their correlations with the relative abundance of targeted fecal bacteria were examined. All A. muciniphila preparations exhibited protective effects against HSC activation; however, EVs showed the greatest activity in HSC regression. Oral gavage with A. muciniphila ameliorated the serum biochemical and inflammatory cytokines and improved liver and colon histopathological damages. The relative expression of fibrosis and inflammatory biomarkers was substantially attenuated in the tissues of all treated mice. The composition of targeted stool bacteria in the live A. muciniphila group was clearly different from that in the fibrosis group. This study indicated that A. muciniphila and its derivatives could successfully protect against HFD/CCl4-induced liver injury. However, further studies are needed to prove the beneficial effects of A. muciniphila on the liver. IMPORTANCE Akkermansia muciniphila, as a member of the gut microbiota, has been proposed as a next-generation probiotic. Liver fibrosis is the main determinant of liver dysfunction and mortality in patients with chronic liver disease. In this study, we aimed to determine the beneficial effects of live and pasteurized A. muciniphila and its extracellular vesicles (EVs) on the prevention of liver fibrosis. The results of the present study indicated that oral administration of live and pasteurized A. muciniphila and its EVs could normalize the fecal targeted bacteria composition, improve the intestinal permeability, modulate inflammatory responses, and subsequently prevent liver injury in HFD/CCl4-administered mice. Following the improvement of intestinal and liver histopathology, HFD/CCl4-induced kidney damage and adipose tissue inflammation were also ameliorated by different A. muciniphila treatments.

The next step of neurogenesis in the context of Alzheimer's disease.

Among different pathological mechanisms, neuronal loss and neurogenesis impairment in the hippocampus play important roles in cognitive decline in Alzheimer's disease (AD). AD is a progressive and complex neurodegenerative diseases, which is very debilitating. The purpose of this paper is to review recent research into neurogenesis and AD and discuss how pharmacological drugs and herbal active components have impacts on neurogenesis and consequently improve cognitive functions. To date, despite huge research, no effective treatment has been approved for AD. Therefore, an avenue for future research and drug discovery is stimulating adult hippocampal neurogenesis (AHN). Evidence suggests that neurogenesis is regulated by the pharmacological treatment that may be recommended as a part of prophylaxis and therapeutic options for AD. However, the underlying mechanisms of regulating neurogenesis in AD are not well understood. To this point, we highlight to achieve an efficient treatment in AD by manipulating neurogenesis, it's necessary to target all steps of neurogenesis.

Histomorphology of the lower respiratory tract in the Indian crested porcupine (Hystrix indica).

The Indian crested porcupine (Hystrix indica) (ICP) is widely distributed in Asia; however, compared with other rodents, little is known about the structures of its respiratory system. The aim of this study was to evaluate the histomorphology of the lower respiratory portion of the ICP to provide a basis for the identification of the normal structure of this organ. The larynx, trachea and lungs of four carcasses of adult Indian crested porcupines (two males and two females) were dissected and fixed in 10% neutral-buffered formalin. The gross anatomy and histology of all specimens were evaluated. A macroscopic evaluation showed unique structures in the ICP respiratory system, including the presence of a chamber-like structure at the origin of the bronchi and a difference in epiglottis shape between males and females. Histologically, the stratified squamous epithelium covered the epiglottis and arytenoid cartilage, and the pseudostratified ciliated columnar epithelium covered the internal part of the thyroid and cricoid cartilages. Histomorphological studies showed a few goblet cells in the tracheal epithelium. In the bronchi and larger bronchioles, pseudostratified ciliated columnar epithelia were observed. Bronchi were surrounded by segments of cartilage. Distal bronchioles had a simple cuboidal/columnar epithelium with club (Clara) cells, lacked cartilaginous tissue in their walls and had a complete smooth muscle layer. These results revealed histomorphological differences between the ICP and other rodents.

Modulation of serotonin signaling/metabolism by Akkermansia muciniphila and its extracellular vesicles through the gut-brain axis in mice.

Several studies have reported that the host-microbe interactions in the gut modulate the host serotonin or 5-hydroxytryptamine (5-HT) system. Here, we evaluated the effects of Akkermansia muciniphila and its extracellular vesicles (EVs) on genes pertaining to the serotonergic system in the colon and hippocampus of mice. Male C57BL/6J mice were administered viable A. muciniphila and its EVs for 4 weeks. The serotonin levels in the colon, hippocampus, and serum of mice, as well as the human colon carcinoma cells (Caco-2), were measured by ELISA assays. Also, the effects of A. muciniphila and its EVs on the expression of serotonin system genes in the colon and hippocampus were examined. A. muciniphila and its EVs may have a biological effect on the induction of serotonin levels in the colon and hippocampus of mice. Also, EVs increased the serotonin level in the Caco-2 cell line. In contrast, both treatments decreased the serotonin level in the serum. Both the bacterium and its EVs had significant effects on the mRNA expression of genes, involved in serotonin signaling/metabolism in the colon and hippocampus of mice. Moreover, A. muciniphila and its EVs affected the mRNA expression of inflammatory cytokines (Il-10 and Tnf-α) in the colon, however, there is no significant difference in inflammatory cell infiltrate in the histopathology of the colon. The presence of A. muciniphila and its EVs in the gut promotes serotonin concentration, they also affect serotonin signaling/metabolism through the gut-brain axis and may be considered in new therapeutic strategies to ameliorate serotonin-related disorders.

The Impact of Estradiol on Neurogenesis and Cognitive Functions in Alzheimer's Disease.

Alzheimer's disease (AD) is described as cognitive and memory impairments with a sex-related epidemiological profile, affecting two times more women than men. There is emerging evidence that alternations in the hippocampal neurogenesis occur at the early stage of AD. Therapies that may effectively slow, stop, or regenerate the dying neurons in AD are being extensively investigated in the last few decades, but none has yet been found to be effective. The regulation of endogenous neurogenesis is one of the main therapeutic targets for AD. Mounting evidence indicates that the neurosteroid estradiol (17ß-estradiol) plays a supporting role in neurogenesis, neuronal activity, and synaptic plasticity of AD. This effect may provide preventive and/or therapeutic approaches for AD. In this article, we discuss the molecular mechanism of potential estradiol modulatory action on endogenous neurogenesis, synaptic plasticity, and cognitive function in AD.

Akkermansia muciniphila-Derived Extracellular Vesicles as a Mucosal Delivery Vector for Amelioration of Obesity in Mice.

Recent evidence suggests that probiotics can restore the mucosal barrier integrity, ameliorate inflammation, and promote homeostasis required for metabolism in obesity by affecting the gut microbiota composition. In this study, we investigated the effect of Akkermansia muciniphila and its extracellular vesicles (EVs) on obesity-related genes in microarray datasets and evaluated the cell line and C57BL/6 mice by conducting RT-PCR and ELISA assays. A. muciniphila-derived EVs caused a more significant loss in body and fat weight of high-fat diet (HFD)-fed mice, compared with the bacterium itself. Moreover, treatment with A. muciniphila and EVs had significant effects on lipid metabolism and expression of inflammatory markers in adipose tissues. Both treatments improved the intestinal barrier integrity, inflammation, energy balance, and blood parameters (i.e., lipid profile and glucose level). Our findings showed that A. muciniphila-derived EVs contain various biomolecules, which can have a positive impact on obesity by affecting the involved genes. Also, our results showed that A. muciniphila and its EVs had a significant relationship with intestinal homeostasis, which highlights their positive role in obesity treatment. In conclusion, A. muciniphila-derived EVs can be used as new therapeutic strategies to ameliorate HFD-induced obesity by affecting various mechanisms.

Some complementary inequalities to Jensen's operator inequality.

In this paper, we study some complementary inequalities to Jensen's inequality for self-adjoint operators, unital positive linear mappings, and real valued twice differentiable functions. New improved complementary inequalities are presented by using an improvement of the Mond-Pecaric method. These results are applied to obtain some inequalities with quasi-arithmetic means.

The histological and histometrical effects of Urtica dioica extract on rat's prostate hyperplasia.

Benign prostatic hyperplasia (BPH) is a common disease in human that gradual overgrowth of the prostate gland leads to impinge on the urethra with impairment in urinary function. Numerous plants improve uncontrolled growth of the prostate gland and improve urinary tract symptoms associated with BPH. In this study, 25 healthy adult male Wistar rats were divided randomly in five groups: G1 (Control group) received ordinary feed without any treatment, G2 received 10 mg kg(-1) testosterone subcutaneously, G3 received 50 mg kg(-1) nettle root extract orally, G4 received 50 mg kg(-1) nettle root extract orally and 10 mg kg(-1) testosterone, G5 received 10 mg kg(-1) almond oil (Almond oil was used as testosterone solvent) subcutaneously. After six weeks, volume and weight of each lobe were measured and samples were taken. The 5 to 6 µm thickness sections were made using paraffin embedding method and stained by hematoxylin and eosin and periodic acid-Schiff. The results showed that prostate volume and ratio of prostate to body weight were increased significantly in the testosterone. Histological and histometrical results showed that dorsal and lateral type 1 and 2 lobes were not changed significantly but the ventral and anterior lobes have changed significantly. Over all, the nettle root could prevent from some of prostatic hyperplasia effects, so that percentage of folded alveoli in ventral lobe reduced insignificantly.