Chemotherapy-induced peripheral neurotoxicity (CIPN) is a severe dose-limiting adverse event of chemotherapy. Presently, the mechanism underlying the induction of CIPN remains unclear, and no effective treatment is available. In this study, through metabolomics analyses, we found that nab-paclitaxel therapy markedly increased serum serotonin [5-hydroxtryptamine (5-HT)] levels in both cancer patients and mice compared to the respective controls. Furthermore, nab-paclitaxel-treated enterochromaffin (EC) cells showed increased 5-HT synthesis, and serotonin-treated Schwann cells showed damage, as indicated by the activation of CREB3L3/MMP3/FAS signaling. Venlafaxine, an inhibitor of serotonin and norepinephrine reuptake, was found to protect against nerve injury by suppressing the activation of CREB3L3/MMP3/FAS signaling in Schwann cells. Remarkably, venlafaxine was found to significantly alleviate nab-paclitaxel-induced CIPN in patients without affecting the clinical efficacy of chemotherapy. In summary, our study reveals that EC cell-derived 5-HT plays a critical role in nab-paclitaxel-related neurotoxic lesions, and venlafaxine co-administration represents a novel approach to treating chronic cumulative neurotoxicity commonly reported in nab-paclitaxel-based chemotherapy.
Paclitaxel/toxicity* ; Animals ; Albumins/adverse effects* ; Serotonin/metabolism* ; Mice ; Humans ; Male ; Female ; Venlafaxine Hydrochloride/therapeutic use* ; Neurotoxicity Syndromes/metabolism* ; Middle Aged ; Schwann Cells/metabolism* ; Peripheral Nervous System Diseases/drug therapy* ; Antineoplastic Agents

Curcumae Rhizoma, derived from the rhizome of Curcuma phaeocaulis, Curcuma kwangsiensis and Curcuma wenyujin, was called Ezhu in China. In the past, Curcumae Rhizoma extracts were obtained through water decoction or alternative methods, which showed significant anti-cancer effects. However, the mixed extracts contain various compound components of Curcumae Rhizoma, leading to an ambiguous mechanism of action for Curcumae Rhizoma extracts anti-cancer. Contemporary researchers have extracted the chemical components of Curcumae Rhizoma separately for experimental verification of its active ingredients in the anti-cancer field. Numerous studies demonstrated that curcumol, germacrone, β-elemene, and curcumin in Curcumae Rhizoma extracts have significant governing effects in anti-cancer activities. Pharmacological studies have shown that Curcumae Rhizoma suppresses cancer cell proliferation, invasion, and migration, triggering apoptosis and regulating cellular autophagy to achieve anticancer effects. Here, we summarized the research progress of Curcumae Rhizoma on anti-cancer effects from 2013 to 2022, aiming to explore the deeper molecular mechanisms of Curcumae Rhizoma's active components in cancer treatment.

This article summarizes the overview, occurrence, adverse effects, assessment tools, influencing factors and interventions of kinesiophobia in breast cancer survivors, with a view to providing basis for preventing and reducing the occurrence of kinesiophobia in breast cancer survivors, improving the rehabilitation effect and the quality of life.

Objective:To investigate the impact of exogenous lactate on the replication of dengue virus type 2 (DENV-2) in Raw264.7 cells, mouse bone marrow-derived macrophages (BMDMs) and THP-1 cells and explore its association with cell activation.Methods:BMDMs from BALB/c mouse bone marrow were prepared and evaluated by flow cytometry to detect the proportion of F4/80 + CD11b + cells. Glucose transporter type 1 (GLUT1), hexokinase 2 (HK2), and monocarboxylate transporters 4 (MCT4) expression at mRNA level in BMDMs at different time points after DENV-2 infection were measured by qRT-PCR. The content of lactate in the culture supernatants was quantified via colorimetric assay. CCK-8 assay was used to evaluate the impacts of different concentrations of lactate on the viability of Raw264.7 cells, BMDMs, and THP-1 cells. qRT-PCR was used to detect the expression of DENV-2 E gene, TGF-β, CD86, retinoic acid-inducible gene Ⅰ (RIG-Ⅰ), IFN-β, interferon-stimulated gene 15 (ISG15), and ISG56 at mRNA level in cells infected with DENV-2 at different MOIs in the presence of different concentrations of lactate. Meanwhile, flow cytometry was used to analyze the expression of CD86 and CD206. Results:The percentage of BMDMs was (87.53±1.66)%. GLUT1 expression at mRNA level exhibited a decrease in BMDMs at 24 h after DENV-2 (MOI=3) infection following a transient increase at 12 h ( P<0.05), while HK2 expression at mRNA level was higher that than in blank control and inactivated DENV-2 infection groups at 12, 24, and 36 h ( P<0.01). Besides, there was an increase in both MCT4 mRNA level and the content of lactate in culture supernatants at 24 h after DENV-2 (MOI=1.5) infection ( P<0.05). The viability of the three types of cells remained above 80% when the concentration of lactate was 31.25 mmol/L. Lactate at the concentration of 35 mmol/L increased the expression of the DENV E gene at mRNA level in DENV-2-infected BMDMs at MOI=1 or MOI=2 ( P<0.05). Besides, it promoted the expression of DENV E gene at mRNA level in Raw264.7 and THP-1 cells ( P<0.001) as well as the expression of CD163, TGF-β, RIG-Ⅰ, IFN-β, ISG15 and ISG56 at mRNA level in BMDMs at MOI=1.5, but inhibited the expression of CD86 at mRNA level in BMDMs ( P<0.05). It also up-regulated CD206 protein expression ( P<0.01) and down-regulated CD86 protein expression ( P>0.05) in BMDMs. Conclusions:Exogenous lactate enhances DENV-2 replication in both human- and murine-derived macrophages and that might correlate with M2 macrophage polarization.

OBJECTIVE We have previously shown that inhibition of phosphodiesterase-4(PDE4)protects against neuronal damage in models of Parkinson's dis-ease(PD).However,the mechanisms have not yet been completely revealed.Here we aimed to elucidate the pharmacological effects and mechanisms of action of rof-lupram(ROF),an novel PDE4 inhibitor,in experimen-tal models of PD.METHODS The survival rate,apopto-sis rate and toxicity level of SH-SY5Y cells were deter-mined by MTT,flow cytometry and lactate dehydroge-nase detection kit.At the same time,LYT staining was used to detect the changes of lysosome fluorescence intensity:Western blotting was used to detect the changes of lysosome associated proteins,Sirtuin1 and α-Syn;NAD/NADH assay kit was used to determine the change of NAD content.To explore whether SIRT1 inhibitor(EX527)and lysosomal inhibitor could block the effect of ROF.In addition,ROT was used to stimulate C57BL/6J mice to construct a mouse model of PD to verify the effect and mechanism of ROF.The changes of motor function were evaluated by behavioral experiments(pole climb-ing,bar rotating and balance beam experiments).Super-oxide dismutase kit and Western blotting were used to detect the changes of SOD activity and expression of related proteins in substantia nigra.RESULTS We showed that pretreatment with ROF significantly attenu-ated cell apoptosis in ROT-treated SH-SY5Y cells.Fur-thermore,ROF significantly enhanced the lysosomal function,as evidenced by the increased levels of mature cathepsin D(CTSD)and lysosomal-associated mem-brane protein 1(LAMP1)through increasing NAD+/NADH and the expression of sirtuin 1(SIRT1).Pretreatment with an SIRT1 inhibitor selisistat(SELI,10 μ mol·L-1)attenuated the neuroprotection of ROF,and ROF-increased expression levels of LAMP1 and mature CTSD.Moreover,inhibition of CTSD by pepstatin A(20 μmol·L-1)attenuated the protective effects of ROF.In vivo study was conducted in mice exposed to ROT(10 mg·kg-1·d-1,ig)for six weeks;then,ROT-treated mice received ROF(0.5,1 and 2 mg·kg-1·d-1,ig)for four weeks.ROF significantly ameliorated motor deficits,which was accompanied by increased expression levels of tyro-sine hydroxylase,SIRT1,mature CTSD,and LAMP1 in the substantia nigra pars compacta.CONCLUSION Taken together,these results demonstrate that ROF exerts a neuroprotective action in PD models.The mech-anisms underlying ROF neuroprotective effects appear to be associated with NAD+/SIRT1-dependent activation of lysosomal function.

The negative effects of low temperature can readily induce a variety of diseases. We sought to understand the reasons why cold stress induces disease by studying the mechanisms of fine-tuning in macrophages following cold exposure. We found that cold stress triggers increased macrophage activation accompanied by metabolic reprogramming of aerobic glycolysis. The discovery, by genome-wide RNA sequencing, of defective mitochondria in mice macrophages following cold exposure indicated that mitochondrial defects may contribute to this process. In addition, changes in metabolism drive the differentiation of macrophages by affecting histone modifications. Finally, we showed that histone acetylation and lactylation are modulators of macrophage differentiation following cold exposure. Collectively, metabolism-related epigenetic modifications are essential for the differentiation of macrophages in cold-stressed mice, and the regulation of metabolism may be crucial for alleviating the harm induced by cold stress.
Acetylation ; Animals ; Cold-Shock Response ; Epigenesis, Genetic ; Macrophages/metabolism* ; Mice ; Mitochondria/metabolism*

Overlap myoclonic epilepsy with ragged-red fibers (MERRF)-Leigh syndrome is a rare mitochondrial encephalomyopathy. A case of MERRF-Leigh syndrome associated with mitochondrial DNA 8344A>G (m.8344A>G) mutation was reported in this article. The patient has suffered from the disease since 15-year old with myoclonus, exercise intolerance, ataxia, limb weakness, dysphasia, dyspnea, blurred vision and hearing loss. Magnetic resonance imaging revealed lesions on right thalamus, bilateral medulla and lumbar spinal cord and atrophy of cervical spinal cord. Electromyography showed predominantly axonal damage of both sensory nerve and motor nerve. Histochemical analyses revealed ragged red fibers, ragged blue fibers, succinate dehydrogenase-stronghly reactive vessels and decreased cytochrome oxidase activity. Gene tests demonstrated a high level of m.8344A>G mutation and m. 14484T>C mutation. MERRF-Leigh overlap syndrome with m.8344A>G mutation was rare. Bulbar paralysis following myoclonus is the main clinical symptom.

The 30th International Symposium on Amyotrophic Lateral Sclerosis-Motor Neuron Disease was held in Perth, Australia from December 4 to 6, 2019. This article mainly introduces the clinical research of this meeting, including epidemiology, non-motor symptoms, auxiliary examinations and biomarkers, etc., while the basic research includes genomics and genetics, protein metabolism abnormalities, neuroimmunity and inflammation, synapse pathology and preclinical treatment strategies,

A female patient aged 42 years with deep burn on right lower limb was admitted to Affiliated Hospital of Jining Medical University on January 25, 2019. The patient previously had cerebral infarction, hypertension, and hysteria, with long-term use of aspirin and risperidone. After admission, the patient underwent tangential excision twice. On the third day after the second tangential excision and skin grafting, the muscle strength of the right limb gradually decreased, and the patient was treated with emergency craniocerebral magnetic resonance imaging, which suggested acute cerebral infarction. Improvement of cerebral circulation and vasodilatation were given immediately. The limb muscle strength of the patient gradually recovered on the fifth day after the operation, and no sequela was left when the patient was discharged. After the case was discussed, we think that postoperative decreased blood volume and blood concentration resulting from tangential excision bleeding of deep burn and wound exudate as well as inadequate fluid infusion are the main causes of hemodynamic change, the patient had the basis of multiple cerebral artery stenosis, and superposition of multiple factors led to the occurrence of postoperative acute cerebral infarction. Appropriate increase in the fluid infusion volume during and after surgery and transfusion if necessary to increase blood and oxygen supply to the brain can reduce the occurrence of cerebral infarction.

Limb girdle muscular dystrophy (LGMD) is characterized by progressive proximal muscle weakness with high genetic heterogeneity.LGMD is the fourth prevalent form of muscular dystrophies in the adult neurology department.Since most patients are juvenile-or adult-onset and present as limb muscle weakness,it would be easily misdiagnosed as myositis or metabolic myopathies.The final diagnosis depends on muscle immunohistochemical staining,Western blotting and genetic screening.In China,LGMD2B and LGMD2A are the most prevalent forms,accounting for 74.3％ in overall LGMD.Patients with LGMD2B usually have onset age between 19-27 years old.LGMD2B patients present as asymptomatic hyper creatine kinase emia (CK) at the early stage,and later develop to typical proximal muscle weakness with bilateral calf atrophy and extremely high serum CK.The onset age of LGMD2A patients is between 7-18 years old.LGMD2A patients presented as proximal muscle weakness with or without bilateral scapular winging and Achilles tendon contractures.Serum CK can be moderately or highly elevated.Current therapies are mainly supportive and the effective treatment is insufficient.The ongoing global elinical history study and gene therapy bring us new hope for treating LGMD in the coming future.