Evidence mapping and quality assessment of systematic reviews on exercise intervention for Alzheimer's disease.

BACKGROUND: A significant body of literature suggests that exercise can reverse cognitive impairment and ameliorate somatic function in patients with Alzheimer's disease (AD). Systematic reviews (SRs), a common approach of evidence-based medicine, concentrate on a specific issue of a research area. The objective of this work is to provide an overview of existing evidence on the effects of exercise intervention in AD patients and report related health outcomes by reviewing SRs. METHODS: SRs on exercise intervention in AD patients were retrieved from the PubMed, the Cochrane Library, CBMdisc, Scopus, Web of Science, Embase (via Ovid), China National Knowledge Infrastructure, and WanFang databases from the time of inception to February 2023. The quality of the SRs was evaluated utilizing the A Measurement Tool to Assess Systematic Review 2 (AMSTAR 2) checklist. The results were reported according to the population-intervention-comparison-outcome (PICO) framework and the corresponding evidence mapping was illustrated in tables and bubble plots. RESULTS: A total of 26 SRs met the eligibility criteria. In terms of methodological quality, 10 SRs were rated as "critically low", 13 SRs were rated as "low", and 3 SRs were rated as "moderate". Exercise was found to exert a beneficial effect on cognitive function, functional independence, physical function, and neuropsychiatric symptoms in patients with AD. CONCLUSION: Exercise intervention benefits AD patients mainly by improving cognitive function, physical function, functional independence, and neuropsychiatric symptoms. However, due to the low-to-moderate methodology of most SRs included in this analysis, further investigations are required to support our current findings.

Analyzing Immune Cell Infiltration and Copper Metabolism in Diabetic Foot Ulcers.

Background: Diabetes impairs wound healing, notably in diabetic foot ulcers (DFU). Stress, marked by the accumulation of lipoylated mitochondrial enzymes and the depletion of Fe-S cluster proteins, triggers cuproptosis-a distinct form of cell death. The involvement of copper in the pathophysiology of DFU has been recognized, and currently, a copper-based therapeutic strategy is emerging as a viable option for enhancing ulcer healing. This study investigates genes linked to copper metabolism in DFU, aiming to uncover potential targets for therapeutic intervention. Methods: Two diabetic wound Gene Expression Omnibus (GEO) datasets were analyzed to study immune cell dysregulation in diabetic wounds. Differentially expressed genes related to copper metabolism were identified and analyzed using machine learning methods. Gene ontology, pathway enrichment, and immune infiltration analyses were performed using DFU samples. The expression of identified genes was validated using qRT-PCR and single-cell RNA sequencing. Results: Ten genes associated with copper metabolism were identified. Among these, SLC31A1 and ADNP were found to be significantly differentially expressed in DFU. Notably, SLC31A1 exhibited higher expression in macrophages, whereas ADNP was found to be highly expressed in fibroblasts and chondrocytes. Conclusion: The study indicates a close link between copper metabolism, the infiltration of immune cells, and DFU. It proposes that copper metabolism could influence the progression of DFU through the activation of immune responses. These observations offer fresh perspectives on the underlying mechanisms of DFU and identify potential targets for therapeutic intervention.

Platelet Biorheology and Mechanobiology in Thrombosis and Hemostasis: Perspectives from Multiscale Computation.

Thrombosis is the pathological clot formation under abnormal hemodynamic conditions, which can result in vascular obstruction, causing ischemic strokes and myocardial infarction. Thrombus growth under moderate to low shear (<1000 s-1) relies on platelet activation and coagulation. Thrombosis at elevated high shear rates (>10,000 s-1) is predominantly driven by unactivated platelet binding and aggregating mediated by von Willebrand factor (VWF), while platelet activation and coagulation are secondary in supporting and reinforcing the thrombus. Given the molecular and cellular level information it can access, multiscale computational modeling informed by biology can provide new pathophysiological mechanisms that are otherwise not accessible experimentally, holding promise for novel first-principle-based therapeutics. In this review, we summarize the key aspects of platelet biorheology and mechanobiology, focusing on the molecular and cellular scale events and how they build up to thrombosis through platelet adhesion and aggregation in the presence or absence of platelet activation. In particular, we highlight recent advancements in multiscale modeling of platelet biorheology and mechanobiology and how they can lead to the better prediction and quantification of thrombus formation, exemplifying the exciting paradigm of digital medicine.

Inhibition of P21-activated Kinase 1 Promotes Vascular Smooth Muscle Cells Apoptosis Through Reduction of Phosphorylation of Bad.

BACKGROUND: P21-activated kinase 1 (Pak1) has an effect on cell apoptosis and has recently been reported to play an important role in various cardiovascular diseases, in which vascular smooth muscle cell (VSMC) apoptosis is a key process. Thus, we hypothesized that Pak1 may be a novel target to regulate VSMC behaviors. METHODS AND RESULTS: In the present study, we found that the expression of Pak1 was dramatically upregulated in vascular smooth muscle cells (VSMCs) on H2O2 administration and was dependent on stimulation time. Through a loss-of-function approach, Pak1 knockdown increased apoptosis of VSMCs, as tested by TUNEL (TdT-mediated dUTP Nick-End Labeling) immunofluorescence staining, whereas it inhibited the proliferation of VSMCs examined by EdU staining. Moreover, we also noticed that Pak1 silencing promoted the mRNA and protein levels of pro-apoptosis genes but decreased anti-apoptosis marker expression. Importantly, we showed that Pak1 knockdown reduced the phosphorylation of Bad. Moreover, increased Pak1 expression was also noticed in carotid arteries on the wire jury. CONCLUSIONS: Our study identified that Pak1 acted as a novel regulator of apoptosis of VSMCs partially through phosphorylation of Bad.

N-Acetylcysteine Alleviates Phenylephrine-Induced Cardiomyocyte Dysfunction via Engaging PI3K/AKT Signaling Pathway.

BACKGROUND: Increased reactive oxygen species (ROS) and oxidative stress response lead to cardiomyocyte hypertrophy and apoptosis, which play crucial roles in the pathogenesis of heart failure. The purpose of current research was to explore the role of antioxidant N-acetylcysteine (NAC) on cardiomyocyte dysfunction and the underlying molecular mechanisms. METHODS AND RESULTS: Compared with control group without NAC treatment, NAC dramatically inhibited the cell size of primary cultured neonatal rat cardiomyocytes (NRCMs) tested by immunofluorescence staining and reduced the expression of representative markers associated with hypertrophic, fibrosis and apoptosis subjected to phenylephrine administration examined by reverse transcription-polymerase chain reaction (RT-PCR) and western blot. Moreover, enhanced ROS expression was attenuated, whereas activities of makers related to oxidative stress response examined by individual assay Kits, including total antioxidation capacity (T-AOC), glutathione peroxidase (GSH-Px), and primary antioxidant enzyme Superoxide dismutase (SOD) were induced by NAC treatment in NRCMs previously treated with phenylephrine. Mechanistically, we noticed that the protein expression levels of phosphorylated phosphatidylinositol 3-kinase (PI3K) and AKT were increased by NAC stimulation. More importantly, we identified that the negative regulation of NAC in cardiomyocyte dysfunction was contributed by PI3K/AKT signaling pathway through further utilization of PI3K/AKT inhibitor (LY294002) or agonist (SC79). CONCLUSIONS: Collected, NAC could attenuate cardiomyocyte dysfunction subjected to phenylephrine, partially by regulating the ROS-induced PI3K/AKT-dependent signaling pathway.

Increased NMDARs in neurons and glutamine synthetase in astrocytes underlying autistic-like behaviors of Gabrb1-/- mice.

Mutations of the GABA-A receptor subunit ß1 (GABRB1) gene are found in autism patients. However, it remains unclear how mutations in Gabrb1 may lead to autism. We generated Gabrb1-/- mouse model, which showed autistic-like behaviors. We carried out RNA-seq on the hippocampus and found glutamatergic pathway may be involved. We further carried out single-cell RNA sequencing on the whole brain followed by qRT-PCR, immunofluorescence, electrophysiology, and metabolite detection on specific cell types. We identified the up-regulated Glul/Slc38a3 in astrocytes, Grin1/Grin2b in neurons, glutamate, and the ratio of Glu/GABA in the hippocampus. Consistent with these results, increased NMDAR-currents and reduced GABAAR-currents in the CA1 neurons were detected in Gabrb1-/- mice. NMDAR antagonist memantine or Glul inhibitor methionine sulfoximine could rescue the abnormal behaviors in Gabrb1-/- mice. Our data reveal that upregulation of the glutamatergic synapse pathway, including NMDARs at neuronal synapses and glutamine exported by astrocytes, may lead to autistic-like behaviors.

Panaxynol ameliorates cardiac ischemia/reperfusion injury by suppressing NLRP3-induced pyroptosis and apoptosis via HMGB1/TLR4/NF-κB axis.

BACKGROUND AND PURPOSE: Panaxynol (PNN) is a common natural minor component in Umbelliferae plants. Many clinical studies have shown that PNN exhibits nutritional value and anti-inflammatory and other pharmacological activities. However, whether PNN can mediate cardiac ischemia/reperfusion injury (IRI) remains unclear. Here, we aimed to determine the potential effects of PNN on myocardial IRI. METHODS: Myocardial IRI was stimulated in a mouse IRI model, and neonatal rat ventricle myocytes (NRVMs) were exposed to hypoxia/reoxygenation to construct in an vitro model. Myocardial infarction size, myocardial tissue injury, myocardial apoptotic index, hemodynamic monitoring, pyroptosis-related proteins, cardiac enzyme activities and inflammatory responses were examined to assess myocardial injury. RESULTS: It was found that PNN administration markedly reduced myocardial infarct size and apoptosis, suppressed myocardial damage and cell pyroptosis, attenuated pro-inflammatory cytokines and neutrophil infiltration via NLRP3 inhibitor. More importantly, PNN treatment remarkably decreased the expression of TLR4/NF-κB pathway-associated proteins and NLRP3-related pyroptosis proteins by HMGB1 inhibitor. PNN also enhanced cell viability, reduced cardiac enzyme activities, suppressed apoptosis and attenuated inflammation in the isolated NRVMs. Furthermore, vitro studies indicated that MCC950 (a NLRP3 inhibitor) increased the anti-inflammatory and anti-apoptotic effects of PNN on NRVMs via HMGB1/TLR4 pathway. CONCLUSION: To sum up, our results demonstrate that PNN exhibits a cardioprotective effect by modulating heart IRI-induced apoptosis and pyroptosis via HMGB1/TLR4/NF-κB pathway, thereby inhibiting NLRP3 inflammasome stimulation.

Reply to Chan et al.

We agree that smoking might be a risk factor for the severity of COVID-19, but in our previous study, smoking was not so robust compared with our conclusion. Also, we strongly agreed that COVID-19 patients with diabetes or other chronic diseases might worsen the situation of the disease. But these factors were out of the scope of our study and we had published other research on this topic related to diabetes. Because of the limited sample size and original medical records, our study could not cover many factors. But we wish our study will be a useful and meaningful pilot study for future studies.

Acute effects of ballistic versus heavy-resistance exercises on countermovement jump and rear-hand straight punch performance in amateur boxers.

BACKGROUND: Ballistic and heavy-resistance exercises may potentially enhance lower body power, which is paramount for the punching performance of amateur boxers. This study aimed to determine the acute effects of ballistic exercise (BE) and heavy-resistance exercise (HRE) on countermovement jump (CMJ) and rear-hand straight punch performance in amateur boxers. METHODS: Ten amateur boxers performed two conditioning exercises in a randomized and counterbalanced order as follows: squat jump with 4 sets × 8 repetitions at 30% one-repetition maximum (1RM) for BE and squat with 3 sets × 5 repetitions at 80% 1RM for HRE. The jump height (JH), relative maximal force (RMF), relative maximal power (RMP) of the CMJ, punch force (PF), and punch speed (PS) of a rear-hand straight punch were measured before and 3, 6, 9, and 12 min after either BE or HRE. RESULTS: No significant condition × time interaction was found for JH (p = 0.303), RMF (p = 0.875), RMP (p = 0.480), PF (p = 0.939), and PS (p = 0.939). In addition, no main effect of the condition for JH (p = 0.924), RMF (p = 0.750), RMP (p = 0.631), PF (p = 0.678), and PS (p = 0.712). A significant main effect of time was observed for PF (p = 0.001) and PS (p = 0.001), whereas JH (p = 0.081), RMF (p = 0.141), and RMP (p = 0.430) were not. Pairwise comparison identified that PF (p = 0.031) and PS (p = 0.005) significantly increased at 9 min compared with those at baseline. CONCLUSIONS: The findings of this study demonstrated that BE and HRE protocols can potentiate the rear-hand straight punch performance at 9 min but bring less favorable improvements for JH, RMF, or RMP of CMJ.

Lower extremity isokinetic strength characteristics of amateur boxers.

Aim: Sufficient strength and dynamic stability of the lower limbs are essential for improving punching force and preventing injury in amateur boxers. However, there are still no comprehensive reports on the isokinetic knee strength of boxers with different performance levels. The current study aimed to profile the isokinetic muscle strength of flexion and extension of the knee in boxers, as well as bilateral, unilateral, and functional ratios, and investigate the variation in these muscle strength characteristics associated with different performance levels. Methods: Boxers were divided in two performance groups, elite (five males and four females) and non-elite groups (five males and four females). Muscle strength of the knee was determined via an IsoMed2000 device. Parameters examined included peak torque of the hamstring (H) and quadriceps (Q) during concentric (con) and eccentric (ecc) contractions at low (60°/S), medium (180°/S), and high (240°/S) speed and bilateral ratios (BLs), unilateral ratios (ULs), and functional ratios of dominant (D) and non-dominant limbs. Results: In all angular velocities, the peak torque of H and Q was stronger in the elite group than in the non-elite group. ULs were lower in the elite group than in the non-elite group in Hcon/Qcon at 180D (p < 0.01) and 180ND (p < 0.05) and in Hecc/Qecc at 60D, 180D (p < 0.05) and 240D (p < 0.01). The elite group had higher BLs than the non-elite group in Hcon at 60°/S (p < 0.05) and Qcon at 180°/S (p < 0.05). The non-elite group had a higher functional ratio than elite boxers in Hecc/Qcon at 180D and 240D (p < 0.01). Conclusion: Elite boxers had stronger knee strength in con and ecc contractions. All boxers had normal Hecc/Qecc and Hcon/Qecc. Hcon/Qcon and Hecc/Qcon were abnormal at lower angular velocity. Elite boxers had higher BLs and lower ULs, indicating that they are at a higher risk of injury.

The clinical and bioinformatics analysis for the role of antihypertension drugs on mortality among patients with hypertension hospitalized with COVID-19.

Comorbidities such as hypertension could exacerbate symptoms of coronaviral disease 2019 (COVID)-19 infection. Patients with hypertension may receive both anti-COVID-19 and antihypertension therapies when infected with COVID-19. However, it is not clear how different classes of anti-hypertension drugs impact the outcome of COVID-19 treatment. Herein, we explore the association between the inpatient use of different classes of anti-hypertension drugs and mortality among patients with hypertension hospitalized with COVID-19. We totally collected data from 278 patients with hypertension diagnosed with COVID-19 admitted to hospitals in Wuhan from February 1 to April 1, 2020. A retrospective study was conducted and single-cell RNA-sequencing (RNA-Seq) analysis of treatment-related genes was performed. The results showed that Angiotensin II receptor blocker (ARB) and calcium channel blocker (CCB) drugs significantly increased the survival rate but the use of angiotensin-converting enzyme inhibitor/ß-block/diuretic drugs did not affect the mortality caused by COVID-19. Based on the analysis of four public data sets of single-cell RNA-Seq on COVID-19 patients, we concluded that JUN, LST1 genes may play a role in the effect of ARB on COVID-19-related mortality, whereas CALM1 gene may contribute to the effect of CCB on COVID-19-related mortality. Our results provide guidance on the selection of antihypertension drugs for hypertensive patients infected with COVID-19.

Empirical Support for the Pattern of Competitive Exclusion between Insect Parasitic Fungi.

Fungal entomopathogens are largely facultative parasites and play an important role in controlling the density of insect populations in nature. A few species of these fungi have been used for biocontrol of insect pests. The pattern of the entomopathogen competition for insect individuals is still elusive. Here, we report the empirical competition for hosts or niches between the inter- and intra-species of the entomopathogens Metarhizium robertsii and Beauveria bassiana. It was found that the synergistic effect of coinfection on virulence increase was not evident, and the insects were largely killed and mycosed by M. robertsii independent of its initial co-inoculation dosage and infection order. For example, >90% dead insects were mycosed by M. robertsii even after immersion in a spore suspension with a mixture ratio of 9:1 for B. bassiana versus M. robertsii. The results thus support the pattern of competitive exclusion between insect pathogenic fungi that occurred from outside to inside the insect hosts. Even being inferior to compete for insects, B. bassiana could outcompete M. robertsii during co-culturing in liquid medium. It was also found that the one-sided mycosis of insects occurred during coinfection with different genotypic strains of either fungi. However, parasexual recombination was evident to take place between the compatible strains after coinfection. The data of this study can help explain the phenomena of the exclusive mycosis of insect individuals, but co-occurrence of entomopathogens in the fields, and suggest that the synergistic effect is questionable regarding the mixed use of fungal parasites for insect pest control.

Neutrophil Extracellular Traps Serve as Key Effector Molecules in the Protection Against Phialophora verrucosa.

Phialophora verrucosa (P. verrucosa) is a pathogen that can cause chromoblastomycosis and phaeohyphomycosis. Recent evidence suggests that neutrophils can produce neutrophil extracellular traps (NETs) that can protect against invasive pathogens. As such, we herein explored the in vitro functional importance of P. verrucosa-induced NET formation. By assessing the co-localization of neutrophil elastase and DNA, we were able to confirm the formation of classical NETs entrapping P. verrucosa specimens. Sytox Green was then used to stain these NETs following neutrophil infection with P. verrucosa in order to quantify the formation of these extracellular structures. NET formation was induced upon neutrophil exposure to both live, UV-inactivated, and dead P. verrucosa fungi. The ability of these NETs to kill fungal hyphae and conidia was demonstrated through MTT and pouring plate assays, respectively. Overall, our results confirmed that P. verrucosa was able to trigger the production of NETs, suggesting that these extracellular structures may represent an important innate immune effector mechanism controlling physiological responses to P. verrucosa infection, thereby aiding in pathogen control during the acute phases of infection.

Degraded melanocores are incompetent to protect epidermal keratinocytes against UV damage.

Melanosomes are membrane-bound intracellular organelles that are uniquely generated by melanocytes (MCs) in the basal layer of human epidermis. Highly pigmented mature melanosomes are transferred from MCs to keratinocytes (KCs), and then positioned in the supra-nuclear region to ensure protection against ultraviolet radiation (UVR). However, the molecular mechanism underlying melanosome (or melanin pigment) transfer remains enigmatic. Emerging evidence shows that exo-/endo-cytosis of the melanosome core (termed melanocore) has been considered as the main transfer manner between MCs and KCs. As KCs in the skin migrate up from the basal layer and undergo terminal differentiation, the melanocores they have taken up from MCs are subjected to degradation. In this study, we isolated individual melanocores from human MCs in culture and then induced their destruction/disruption using a physical approach. The results demonstrate that the ultrastructural integrity of melanocores is essential for their antioxidant and photoprotective properties. In addition, we also show that cathepsin V (CTSV), a lysosomal acid protease, is involved in melanocore degradation in calcium-induced differentiated KCs and is also suppressed in KCs following exposure to UVA or UVB radiation. Thus, our study demonstrates that change in the proportion of melanocores in the intact/undegraded state by CTSV-related degradation in KCs affects photoprotection of the skin.

Baicalin increases hair follicle development by increasing canonical Wnt/ß­catenin signaling and activating dermal papillar cells in mice.

Baicalin is a traditional Chinese herbal medicine commonly used for hair loss, the precise molecular mechanism of which is unknown. In the present study, the mechanism of baicalin was investigated via the topical application of baicalin to reconstituted hair follicles on mice dorsa and evaluating the effect on canonical Wnt/ß­catenin signaling in the hair follicles and the activity of dermal papillar cells. The results indicate that baicalin stimulates the expression of Wnt3a, Wnt5a, frizzled 7 and disheveled 2 whilst inhibiting the Axin/casein kinase 1α/adenomatous polyposis coli/glycogen synthase kinase 3ß degradation complex, leading to accumulation of ß­catenin and activation of Wnt/ß­catenin signaling. In addition, baicalin was observed to increase the alkaline phosphatase levels in dermal papillar cells, a process which was dependent on Wnt pathway activation. Given its non­toxicity and ease of topical application, baicalin represents a promising treatment for alopecia and other forms of hair loss. Further studies of baicalin using human hair follicle transplants are warranted in preparation for future clinical use.

Distribution of Chlamydia Trachomatis Genotypes in Infective Diseases of the Female Lower Genital Tract.

The purpose of this study was to investigate the distribution of Chlamydia trachomatis (CT) genotypes in infective diseases of the female lower genital tract, especially in cervical diseases. This study included 128 CT-positive women. DNA was extracted from cervical swabs. Omp1 gene PCR-RFLP and sequencing were used to confirm the subtypes of CT. The association of subtypes with age, clinical symptoms, cervical cytology, and biopsy results was further analyzed. Omp1 gene PCR-RFLP and sequencing showed that the order of prevalent CT genotypes in the female lower genital tract was D (n=38, 29.69%), followed by E (n=28, 21.88%), G (n=21, 16.41%), and F (n=16,12.50%). Genotypes J, H, and K were comparatively rare. Genotype I was not identified in our samples. Further analysis showed that patients with genotype G were more frequently co-infected with other bacteria. Genotype G was also associated with mucopurulent cervicitis (MPC) and cervical intraepithelial neoplasia (CIN). Patients with genotype E were commonly co-infected with HR-HPV. Although genotype D was the most prevalent, it was a relatively low-risk type. These results provide information on distribution of CT genotypes in infective diseases of the female lower genital tract, which is instrumental to developing a vaccine for CT.

Induction of retinal-dependent calcium influx in human melanocytes by UVA or UVB radiation contributes to the stimulation of melanosome transfer.

OBJECTIVES: The transfer of melanosomes from melanocytes to neighbouring keratinocytes is critical to protect the skin from the deleterious effects of ultraviolet A (UVA) and ultraviolet B (UVB) irradiation; however, the initial factor(s) that stimulates melanosome transfer remains unclear. In this study, we investigated the induction of retinal-dependent calcium (Ca2+ ) influx in melanocytes (MCs) by UVA or UVB irradiation and the effect of transient receptor potential cation channel subfamily M member 1 (TRPM1) (melastatin1)-related Ca2+ influx on melanosome transfer. MATERIALS AND METHODS: Primary human epidermal MCs were exposed to physiological doses of UVB or UVA light and loaded with a calcium indicator Fluo-4 dye. The change of intracellular calcium of MCs was monitored using a two-photon confocal fluorescence microscopy. MCs were co-cultured with human epidermal keratinocytes (KCs) in the absence or presence of voriconazole (a TRPM1 blocker) or calcium chelators. MCs were also transfected with TRPM1 siRNA for silencing the expression of TRPM1 gene. The melanosome transfer in the co-cultured cells was quantitatively analysed using flow cytometry and was further confirmed by immunofluorescent double-staining. The protein levels and distributions of TRPM1, OPN3 and OPN5 in MCs were measured by Western blotting or immunofluorescent staining. RESULTS: The retinal-dependent Ca2+ influx of UVA-exposed melanocytes differed greatly from that of UVB-exposed melanocytes in the timing-phase. The protein expression of TRPM1 in mono- and co-cultured MCs was dose-dependently up-regulated by UVA and UVB. TRPM1 siRNA-mediated knockdown and the blockage of TRPM1 channel using a putative antagonist (voriconazole) significantly inhibited melanosome transfer in co-cultures following UVA or UVB exposure. CONCLUSIONS: The distinct time-phases of Ca2+ influx in MCs induced by UVA or UVB contribute to the consecutive stimulation of melanosome transfer, thereby providing a potent photoprotection against harmful UV radiation.