Mitochondrial quality control in the brain: The physiological and pathological roles.

The human brain has high energetic expenses and consumes over 20% of total oxygen metabolism. Abnormal brain energy homeostasis leads to various brain diseases. Among multiple factors that contribute to these diseases, mitochondrial dysfunction is one of the most common causes. Maintenance of mitochondrial integrity and functionality is of pivotal importance to brain energy generation. Mitochondrial quality control (MQC), employing the coordination of multiple mechanisms, is evolved to overcome many mitochondrial defects. Thus, not surprisingly, aberrant mitochondrial quality control results in a wide range of brain disorders. Targeting MQC to preserve and restore mitochondrial function has emerged as a promising therapeutic strategy for the prevention and treatment of brain diseases. Here, we set out to summarize the current understanding of mitochondrial quality control in brain homeostasis. We also evaluate potential pharmaceutically and clinically relevant targets in MQC-associated brain disorders.

Galactose in the Post-Weaning Diet Programs Improved Circulating Adiponectin Concentrations and Skeletal Muscle Insulin Signaling.

Short-term post-weaning nutrition can result in long-lasting effects in later life. Partial replacement of glucose by galactose in the post-weaning diet showed direct effects on liver inflammation. Here, we examined this program on body weight, body composition, and insulin sensitivity at the adult age. Three-week-old female C57BL/6JRccHsd mice were fed a diet with glucose plus galactose (GAL; 16 energy% (en%) each) or a control diet with glucose (GLU; 32 en%) for three weeks, and afterward, both groups were given the same high-fat diet (HFD). After five weeks on a HFD, an oral glucose tolerance test was performed. After nine weeks on a HFD, energy metabolism was assessed by indirect calorimetry, and fasted mice were sacrificed fifteen minutes after a glucose bolus, followed by serum and tissue analyses. Body weight and body composition were not different between the post-weaning dietary groups, during the post-weaning period, or the HFD period. Glucose tolerance and energy metabolism in adulthood were not affected by the post-weaning diet. Serum adiponectin concentrations were significantly higher (p = 0.02) in GAL mice while insulin, leptin, and insulin-like growth factor 1 concentrations were not affected. Expression of Adipoq mRNA was significantly higher in gonadal white adipose tissue (gWAT; p = 0.03), while its receptors in the liver and skeletal muscles remained unaffected. Irs2 expression was significantly lower in skeletal muscles (p = 0.01), but not in gWAT or Irs1 expression (in both tissues). Gene expressions of inflammatory markers in gWAT and the liver were also not affected. Conclusively, galactose in the post-weaning diet significantly improved circulating adiponectin concentrations and reduced skeletal muscle Irs2 expression in adulthood without alterations in fat mass, glucose tolerance, and inflammation.

Biophysical Insight into the SARS-CoV2 Spike-ACE2 Interaction and Its Modulation by Hepcidin through a Multifaceted Computational Approach.

At the center of the SARS-CoV2 infection, the spike protein and its interaction with the human receptor ACE2 play a central role in the molecular machinery of SARS-CoV2 infection of human cells. Vaccine therapies are a valuable barrier to the worst effects of the virus and to its diffusion, but the need of purposed drugs is emerging as a core target of the fight against COVID19. In this respect, the repurposing of drugs has already led to discovery of drugs thought to reduce the effects of the cytokine storm, but still a drug targeting the spike protein, in the infection stage, is missing. In this work, we present a multifaceted computational approach strongly grounded on a biophysical modeling of biological systems, so to disclose the interaction of the SARS-CoV2 spike protein with ACE2 with a special focus to an allosteric regulation of the spike-ACE2 interaction. Our approach includes the following methodologies: Protein Contact Networks and Network Clustering, Targeted Molecular Dynamics, Elastic Network Modeling, Perturbation Response Scanning, and a computational analysis of energy flow and SEPAS as a protein-softness and monomer-based affinity predictor. We applied this approach to free (closed and open) states of spike protein and spike-ACE2 complexes. Eventually, we analyzed the interactions of free and bound forms of spike with hepcidin (HPC), the major hormone in iron regulation, recently addressed as a central player in the COVID19 pathogenesis, with a special emphasis to the most severe outcomes. Our results demonstrate that, compared with closed and open states, the spike protein in the ACE2-bound state shows higher allosteric potential. The correspondence between hinge sites and the Allosteric Modulation Region (AMR) in the S-ACE complex suggests a molecular basis for hepcidin involvement in COVID19 pathogenesis. We verify the importance of AMR in different states of spike and then study its interactions with HPC and the consequence of the HPC-AMR interaction on spike dynamics and its affinity for ACE2. We propose two complementary mechanisms for HPC effects on spike of SARS-CoV-2; (a) HPC acts as a competitive inhibitor when spike is in a preinfection state (open and with no ACE2), (b) the HPC-AMR interaction pushes the spike structure into the safer closed state. These findings need clear molecular in vivo verification beside clinical observations.

Application of Multiparametric Intraoperative Ultrasound in Glioma Surgery.

Gliomas are the most invasive and fatal primary malignancy of the central nervous system that have poor prognosis, with maximal safe resection representing the gold standard for surgical treatment. To achieve gross total resection (GTR), neurosurgery relies heavily on generating continuous, real-time, intraoperative glioma descriptions based on image guidance. Given the limitations of currently available equipment, developing a real-time image-guided resection technique that provides reliable functional and anatomical information during intraoperative settings is imperative. Nowadays, the application of intraoperative ultrasound (IOUS) has been shown to improve resection rates and maximize brain function preservation. IOUS, which presents an attractive option due to its low cost, minimal operational flow interruptions, and lack of radiation exposure, is able to provide real-time localization and accurate tumor size and shape descriptions while helping distinguish residual tumors and addressing brain shift. Moreover, the application of new advancements in ultrasound technology, such as contrast-enhanced ultrasound, three-dimensional ultrasound, navigable ultrasound, ultrasound elastography, and functional ultrasound, could help to achieve GTR during glioma surgery. The current review describes current advancements in ultrasound technology and evaluates the role and limitation of IOUS in glioma surgery.

Role of Exosomes in the Progression, Diagnosis, and Treatment of Gliomas.

Gliomas are the most common primary malignant brain tumors associated with a low survival rate. Even after surgery, radiotherapy, and chemotherapy, gliomas still have a poor prognosis. Extracellular vesicles are a heterogeneous group of cell-derived membranous structures. Exosomes are a type of extracellular vesicles, their size ranges from 30 nm to 100 nm. Recent studies have proved that glioma cells could release numerous exosomes; therefore, exosomes have gained increasing attention in glioma-related research. Recent studies have confirmed the importance of extracellular vesicles, particularly exosomes, in the development of brain tumors, including gliomas. Exosomes mediate intercellular communication in the tumor microenvironment by transporting biomolecules (proteins, lipids, deoxyribonucleic acid, and ribonucleic acid); thereby playing a prominent role in tumor proliferation, differentiation, metastasis, and resistance to chemotherapy or radiation. Given their nanoscale size, exosomes can traverse the blood-brain barrier and promote tumor progression by modifying the tumor microenvironment. Based on their structural and functional characteristics, exosomes are demonstrating their value not only as diagnostic and prognostic markers, but also as tools in therapies specifically targeting glioma cells. Therefore, exosomes are a promising therapeutic target for the diagnosis, prognosis, and treatment of malignant gliomas. More research will be needed before exosomes can be used in clinical applications. Here, we describe the exosomes, their morphology, and their roles in the diagnosis and progression of gliomas. In addition, we discuss the potential of exosomes as a therapeutic target/drug delivery system for patients with gliomas.

Overexpression of microRNA-129-5p in glioblastoma inhibits cell proliferation, migration, and colony-forming ability by targeting ZFP36L1.

Glioblastoma multiforme (GBM) is a highly invasive cancer with a high recurrence rate. The prognosis of GBM patients remains poor, even after standard surgical resection combined with chemoradiotherapy. Thus, there is an urgent need for new therapeutic targets in GBM. In recent years, microRNAs have received considerable attention due to their important role in tumor development and progression. In this study, we investigated the role of miR-129-5p and miR-129-5p/ZFP36L1 axis in GBM tumorigenesis. Analysis of GSE103228 microarray data from the GEO database showed that miR-129-5p was significantly downregulated in GBM vs. normal brain tissues. Quantitative reverse transcription PCR analysis of miR-129-5p expression in seven GBM cell lines (LN229, A172, U87, T98G, U251, H4, and LN118) vs. normal human astrocytes (NHA) showed miR-129-5p was significantly downregulated in GBM cells. Overexpression of miR-129-5p in LN229 and A172 cells significantly suppressed cell proliferation, migration, invasion, and colony-forming ability. Target Scan analysis identified ZFP36L1 as the target of miR-129-5p. UALCAN dataset analysis found that ZFP36L1 was significantly upregulated in GBM vs. normal brain tissues, and high ZFP36L1 expression was positively associated with poor survival of GBM patients. Western blot analysis demonstrated that ZFP36L1 was significantly upregulated in seven GBM cell lines vs. NHA. Overexpression of miR-129-5p in LN229 and A172 cells significantly inhibited ZFP36L1 mRNA and protein expression, while overexpression of ZFP36L1 in LN229 and A172 cells reversed miR-129-5p-mediated inhibition on GBM tumorigenesis. Our results revealed an important role of miR-129-5p in the negative regulation of ZFP36L1 expression in GBM, suggesting new candidates for targeted therapy in GBM patients.

Bufalin Induces Apoptosis and Improves the Sensitivity of Human Glioma Stem-Like Cells to Temozolamide.

Glioma is the most common malignant tumor of the central nervous system, and it is characterized by high relapse and fatality rates and poor prognosis. Bufalin is one of the main ingredients of Chan-su, a traditional Chinese medicine (TCM) extracted from toad venom. Previous studies revealed that bufalin exerted inhibitory effects on a variety of tumor cells. To demonstrate the inhibitory effect of bufalin on glioma cells and glioma stem-like cells (GSCs) and discuss the underlying mechanism, the proliferation of glioma cells was detected by MTT and colony formation assays following treatment with bufalin. In addition, we investigated whether bufalin inhibits or kills GSCs using flow cytometry, Western blotting, and reverse transcription polymerase chain reaction analysis (RT-PCR). Finally, we investigated whether bufalin could improve the therapeutic effect of temozolomide (TMZ) and discussed the underlying mechanism. Taken together, our data demonstrated that bufalin inhibits glioma cell growth and proliferation, inhibits GSC proliferation, and kills GSCs. Bufalin was found to induce the apoptosis of GSCs by upregulating the expression of the apoptotic proteins cleaved caspase 3 and poly(ADP-ribose) polymerase (PARP) and by downregulating the expression of human telomerase reverse transcriptase, which is a marker of telomerase activity. Bufalin also improved the inhibitory effect of TMZ on GSCs by activating the mitochondrial apoptotic pathway. These results suggest that bufalin damages GSCs, induces apoptosis, and enhances the sensitivity of GSCs to TMZ.

Gliomatosis cerebri mimicking acute viral encephalitis and with malignant transformation of partial lesions: A case report.

Gliomatosis cerebri (GC) is a rare glial neoplasm, characterized by extensive diffuse brain infiltration and relative preservation of the underlying architecture. In the present case report, a patient with type 2 GC, which mimicked the clinicoradiological course of acute viral encephalitis, is presented. A 56-year-old male presented with fever, dizziness, headache and numbness in the right extremities three days prior to admission to hospital. The cerebrospinal fluid (CSF) showed mild pleocytosis. Brain magnetic resonance imaging (MRI) revealed hyperintensity on fluid-attenuated inversion recovery images in the left frontal, temporal, insular lobes and in the left thalamus. No signal enhancement was observed following gadolinium administration. The patient was diagnosed with acute viral encephalitis of unknown cause and received a 10-day course of acyclovir, intravenously. At the follow-up three months later, the patient had personality changes and memory deterioration. The results from the follow-up MRI revealed no remarkable changes. At the follow-up six months after presentation, the patient had expressive aphasia and severe headaches. Subsequently, the patient had two tonic-clonic seizure onsets. The results from the MRI showed an increase in lesion size, more edema around the lesion and irregular enhancement in the left frontal lobe. However, the lesions in the left temporal and insular lobes and in the left thalamus were nearly unchanged. Magnetic resonance spectroscopy (MRS) showed elevated choline (Cho)/creatine (Cr) and Cho/N-acetylaspartate (NAA) ratios, as well as decreased NAA/Cr ratios. Surgery was performed and the neuropathological diagnosis of WHO grade III astrocytoma was confirmed. Thus, it is important to pay attention to the differential diagnoses of GC and acute viral encephalitis in patients who have widespread MRI lesions. A brain biopsy is recommended for a diagnosis in this case.

Two new triterpenoid saponins from Caragana microphylla seeds.

Two new triterpenoid saponins, caraganins A and B (1 and 2), structurally characterized by a 22-oxo group, were isolated from the seeds of Caragana microphylla Lam., together with their n-butyl esters as artifacts (1a and 2a). Their structures and configurations were elucidated by detailed spectroscopic analyses on the basis of NMR, IR, and MS data. Compounds 1a and 2a exhibited potent antibacterial activity against Staphylococcus aureus and Bacillus subtilis with minimum inhibitory concentration values ranging from 3.125 to 6.25 µg/ml.

Action of db-cAMP on the bystander effect and chemosensitivity through connexin 43 and Bcl-2-mediated pathways in medulloblastoma cells.

Medulloblastoma (MB) is one of the most common malignant brain tumors of childhood and is associated with a poor prognosis. Gap-junctional intercellular communication (GJIC) is an important mode for cell-to-cell communication. Dysfunctional GJIC is exhibited in most cancer cells. There is significant evidence that GJIC is important in at least some prodrug/suicide gene systems by augmenting the bystander effect (BE). GJIC is made up of connexins (Cxs), among which Cx43 is present in most tissues. Bcl-2, an important apoptosis blocker, is closely associated with the sensitivity to anticancer drugs. Our study showed that dibutyryl cyclic adenosine monophosphate (db-cAMP) upregulated the Cx43 expression and GJIC function in Daoy medulloblastoma cells. It directly enhanced the BE using a herpes simplex virus thymidine kinase (HSV­tk)/ganciclovir (GCV) system, which was blocked by a Cx43 inhibitor. In addition, db-cAMP increased the cytotoxicity of temozolomide and teniposide, possibly by downregulating the Bcl-2 expression and inducing apoptosis. Taken together, we demonstrated the beneficial effect of db-cAMP in treating medulloblastoma depending on the upregulation of BE and chemosensitivity through Cx43 and Bcl-2-mediated pathways.

Triterpenoid saponins from the seeds of Caragana microphylla.

Two new triterpenoid saponins, namely caraganoside C (1) and caraganoside D (2), were isolated from the seeds of Caragana microphylla. Their structures were elucidated on the basis of spectroscopic analyses, including homo- and hetero-nuclear correlation NMR experiments (COSY, HSQC and HMBC). Both 1 and 2 exhibited moderate inhibitory activity against NO production in LPS-stimulated RAW264.7 cells with IC(50) values of 26.4 µM and 32.2 µM, respectively. In addition, 1 showed weak cytotoxicity against MCF-7, HL-60, HCT116, and A549 cell lines.

Sesquiterpenoids from Trichoderma atroviride, an endophytic fungus in Cephalotaxus fortunei.

Two new sesquiterpenoids, identified as (rel 1S, 3R, 4R, 7R)-3-[5-hydroxy-4-methylpent-3-enyl]-1, 3, 7-trimethyl-2-oxabicyclo [2, 2, 1] heptane (1) and (rel 1S, 3R, 4R, 7R)-3-[3, 4-dihydroxy-4-methylpentyl]-1, 3, 7-trimethyl-2-oxabicyclo [2, 2, 1] heptane (2), were isolated from cultures of Trichoderma atroviride (strain no. S361), an endophytic fungal strain residing in the bark of Cephalotaxus fortunei. The structures of compounds 1 and 2 were elucidated by detailed spectroscopic analyses on the basis of NMR, IR, and MS data. Both compounds 1 and 2 were potent inhibitors on NO production in LPS-stimulated RAW264.7 cells, with IC50 values of 15.3 and 9.1µM, respectively.

Trichodermanin A, a novel diterpenoid from endophytic fungus culture.

Trichodermanin A, a structurally unique diterpenoid with skeletal carbons arranged compactly in a fused 6-5-6-6 ring system, has been isolated from cultures of Trichoderma atroviride (strain no. S361), an endophytic fungus isolate in Cephalotaxus fortunei. The structure of this compound was elucidated based on extensive spectroscopic methods and confirmed by X-ray diffraction analysis.

Recent developments and future prospects of antimicrobial metabolites produced by endophytes.

Endophytes, found ubiquitous in all plant species in the world, contribute to their host plants by producing plenty of substances that provide protection and ultimately survival value to the plant. Many researches have proven that endophyte is a new and potential source of novel natural products for exploitation in modern medicine, agriculture and industry. So far, a great number of novel natural products possessing antimicrobial activities have been isolated from endophytes. It is believed that screening for antimicrobial compounds from endophytes is a promising way to overcome the increasing threat of drug resistant strains of human and plant pathogen. Antimicrobial metabolites isolated from endophytes belong to diverse structural classes, including: alkaloids, peptides, steroids, terpenoids, phenols, quinones, and flavonoids. In this review, many well-studied areas are presented and examples will be given to discuss the structure of compounds isolated from endophytes extracts with antimicrobial activities and show the wide variety of approaches taken within the field. These achievements would provide the opportunity to utilize endophytes as a new source for production of antibiotics.