Biofabrication and biomanufacturing in Ireland and the UK

As we navigate the transition from the Fourth to the Fifth Industrial Revolution,the emerging fields of biomanufacturing and biofabrication are transforming life sciences and healthcare.These sectors are benefiting from a synergy of synthetic and engineering biology,sustainable manufacturing,and integrated design principles.Advanced techniques such as 3D bioprinting,tissue engineering,directed assembly,and self-assembly are instrumental in creating biomimetic scaffolds,tissues,organoids,medical devices,and biohybrid systems.The field of biofabrication in the United Kingdom and Ireland is emerging as a pivotal force in bioscience and healthcare,propelled by cutting-edge research and development.Concentrating on the production of biologically functional products for use in drug delivery,in vitro models,and tissue engineering,research institutions across these regions are dedicated to innovating healthcare solutions that adhere to ethical standards while prioritising sustainability,affordability,and healthcare system benefits.

3D printed tacrolimus suppositories for the treatment of ulcerative colitis

Ulcerative colitis is a global health problem,affecting millions of individuals worldwide.As an inflammatory condition localised in the large intestine,rectal delivery of immunosuppressive therapies such as tacrolimus is a promising strategy to maximise drug concentration at the site of action whilst minimising systemic side effects.Here,for the first time,self-supporting 3D-printed tacrolimus suppositories were prepared without the aid of moulds using a pharmaceutical semi-solid extrusion(SSE)3D printer.The suppositories were printed vertically in three different sizes using combinations of two lipid pharmaceutical excipients(Gelucire 44/14 or Gelucire 48/16)and coconut oil.Although both suppository formulations had the appropriate viscosity characteristics for printing,the Gel 44 formulation required less energy and force for extrusion compared to the Gel 48 system.The Gel 44 disintegrated more rapidly but released tacrolimus more slowly than the Gel 48 suppositories.Although the tacrolimus release profiles were significantly different,both suppository systems released more than 80% drug within 120 min.DSC and XRD analysis was inconclusive in determining the solid-state properties of the drug in the suppositories.In summary,this article reports on the fabrication of 3D printed selfsupporting suppositories to deliver personalised doses of a narrow therapeutic index drug,with potential benefits for patients with ulcerative colitis.

The engineering of doxorubicin-loaded liposome-quantum dot hybrids for cancer theranostics

Many studies have recently attempted to develop multifunctional nanoconstructs by integrating the superior fluores- cence properties of quantum dots （QD） with therapeutic capabilities into a single vesicle for cancer theranostics. Liposome- quantum dot （L-QD） hybrid vesicles have shown promising potential for the construction of multifunctional nanoconstructs for cancer imaging and therapy. To fulfil such a potential, we report here the further functionalization of L-QD hybrid vesi- cles with therapeutic capabilities by loading anticancer drug doxorubicin （Dox） into their aqueous core. L-QD hybrid vesi- cles are first engineered by the incorporation of TOPO-capped, CdSe/ZnS QD into the lipid bilayers of DSPC：Chol：DSPE- PEG2000, followed by Dox loading using the pH-gradient technique. The loading efficiency of Dox into L-QD hybrid vesicles is achieved up to 97%, comparable to liposome control. All these evidences prove that the incorporation of QD into the lipid bilayer does not affect Dox loading through the lipid membrane of liposomes using the pH-gradient technique. Moreover, the release study shows that Dox release profile can be modulated simply by changing lipid composition. In conclusion, the Dox-loaded L-QD hybrid vesicles presented here constitute a promising multifunctional nanoconstruct capable of transporting combinations of therapeutic and diagnostic modalities.

The molecular profile of nerve repair: humans mirror rodents

Peripheral nerve injuries(PNI)are common following blunt or penetrating trauma and can lead to disability and chronic pain in affected individuals,with limited options available to promote regeneration and functional recovery.From animal models,it is known that the regenerative capacity of the peripheral nervous system(PNS)is heavily dependent upon the remarkable ability of Schwann cells to undergo a phenotypic shift from a supportive/myelinating/maintaining phenotype to one that encourages neural regeneration.

Harnessing endothelial cells and vascularization strategies for nerve regeneration

Peripheral nerves are essential components of the human body’s communication system,transmitting signals between the central nervous system and various body parts.Damage resulting from trauma or disease can result in debilitating sensory and motor deficits.Nerve injuries,particularly those resulting in significant gaps in the nerve tissue,pose a formidable challenge for clinicians and researchers.Despite their limitations,including limited availability and donor site morbidity,nerve autografts remain the clinical gold standard for treating nerve injuries.

川芎嗪对脓毒症大鼠肝细胞线粒体体视学的影响

目的研究川芎嗪(TMP)对脓毒症大鼠肝细胞线粒体结构的保护作用及可能机制。方法实验大鼠被分成对照组、脓毒症组、治疗组和预防组;用盲肠结扎穿孔法制备大鼠脓毒症实验模型,在术后10 h,取肝脏标本用JEM-1230透射电子显微镜观察肝细胞的超微结构,选用Image-Pro Plus 6.0图像软件对线粒体进行测量;用Western blot技术检测肝细胞线粒体内膜水通道蛋白(AQP)8的表达。结果和对照组比较,其余3组单个肝细胞切面的线粒体总数和数密度均减少(P<0.01),但治疗组和预防组均多于脓毒症组(P<0.01);线粒体体积密度脓毒症组也较对照组低(P<0.01);线粒体内膜AQP8的相对表达量在脓毒症组、治疗组和预防组均较对照组明显减少(P<0.01);治疗组和预防组的AQP8相对表达量较脓毒症组增多(P<0.01)。结论在脓毒症状态下,TMP可保护肝细胞线粒体的结构,可能是通过增加线粒体内膜AQP8表达而起作用的。

Antibody fragments: Prolonging circulation half-life special issue-antibody research

Antibodies are currently the fastest growing class of therapeutic proteins. When antibody fragments are included, there are over thirty-five antibody-based medicines approved for human therapy. Many more antibody and antibody-like fragments are being evaluated clinically. Production of antibody fragments can be efficient and their compact size can allows for better tissue extravasation into solid tumors than full antibodies. Unfortunately, a key limitation of antibody fragments for systemic use is their short half-life in circulation. Prolonging their circulation half-life can be accomplished clinically by the covalent conjugation of the antibody fragment to the water-soluble polymer, poly(ethylene glycol) (PEG). Many polymers and strategies are also being pursued to increase antibody fragment half-life.

Monitoring film coalescence from aqueous polymeric dispersions using atomic force microscopy: Surface topographic and nano-adhesion studies

The aim of the investigation was to develop the use of topographic and nano-adhesion atomic force microscopy(AFM) studies as a means of monitoring the coalescence of latex particles within films produced from a pharmaceutically relevant aqueous dispersion(Eudragit~?NE30 D). Films were prepared via spin coating and analysed using AFM, initially via tapping mode for topographic assessment followed by force-distance measurements which allowed assessment of site-specific adhesion. The results showed that colloidal particles were clearly observed topographically in freshly prepared samples, with coalescence detected on curing via the disappearance of discernible surface features and a decrease in roughness indices. The effects of temperature and humidity on film curing were also studied, with the former having the most pronounced effect. AFM force measurements showed that the variation in adhesive force reduced with increasing curing time, suggesting a novel method of quantifying the rate of film formation upon curing. It was concluded that the AFM methods outlined in this study may be used as a means of qualitatively and quantitatively monitoring the curing of pharmaceutical films as a function of time and other variables, thereby facilitating rational design of curing protocols.

Genetic diversity of food-medicinal Lycium spp.in China:Insights from chloroplast genome

Objective:Goji(fruits of Lycium spp.)is commonly consumed as food and medicine.The increasing market demand for goji has led to its wide cultivation and broad breeding,which might cause loss of genetic diversity.This study aims to uncover the genetic diversity of the cultivated and wild Lycium.Methods:The chloroplast genome(CPG)of 34 accessions of Chinese food-medicinal Lycium spp.,including the popular cultivars and their wild relatives,was re-sequenced and assembled,based on which the genetic diversity was evaluated.Results:Sequence structural comparison shows that CPG is comparatively conserved within species.Phylogenetic analysis indicates that CPG is sufficient for the discrimination of Lycium species;combined with nuclear ribosomal internal transcribed spacer(Nr ITS)sequences,materials with mixed genetic backgrounds can be identified.Nucleotide diversity analysis reveals that the modern cultivars are probably with a common maternal parent,while the wild accessions are with higher level of genetic diversity.Conclusion:For the first time this study reveals the intraspecies genetic diversity of Lycium spp.using CPG,highlighting the urgent conservation demand of wild genetic resources of Lycium.Our study also demonstrates that CPG provides crucial evidence for identification of Lycium species with mixed genetic backgrounds and highlights the importance of the wild relatives in genetic diversity conservation.This CPG-based technology will contribute to the sustainable development of medicinal plants broadly.

nhe regulation and deregulation of Wnt signaling by PARK genes in health and disease

Wingless/Int （Wnt） signaling pathways are signal transduction mechanisms that have been widely studied In the field of embryogen- esis. Recent work has established a critical role for these pathways in brain development, especially of midbrain dopaminergic neu- rones, However, the fundamental importance of Wnt signaling for the normal function of mature neurones in the adult central nervous system has also lately been demonstrated by an increasing number of studies. Parkinson＇s disease （PD） is the second most prevalent neurodegenerative disease worldwide and is currently incurable. This debilitating disease is characterized by the progres- sive loss of a subset of midbrain dopaminergic neurones in the substontla nigm leadingto typical extrapyramidal motor symptoms. The aetiology of PD is poorly understood but work performed over the Last two decades has identified a growing number of genetic defects that underlie this condition. Herewe review a growing body of data connecting genes implicated in PD--most notablythe PARKgenes-- with Wnt signaling. These observations provide clues to the normal function of these proteins in healthy neurones and suggest that deregulated Wnt signaling might be a frequent pathomechanlsm leading to PD. These observations have implications for the patho- genesis and treatment of neurodegenerative diseases in general.

Fabrication of Electrospun Levodopa-Carbidopa Fixed-Dose Combinations

Introduction Parkinson’s disease(PD)is a disabling disorder that signifi-cantly affects a patient’s quality of life[1].Treatments are available,but only 10%of PD patients fully adhere to their treatment regimens[2].Non-adherence is a serious problem linked to worsening symptoms and increased motor fluc-tuations[3-5].Levodopa(LD)remains the most effective treatment for PD[6].However,a single dosing treatment is only effective in the early phase of the disease.In the severe phase,4-5 years after diagnosis,the therapeutic window of dopamine becomes narrow,and due to its short half-life of between 0.7 and 1.4 h dosing of LD will be required every 2 h[7-9].One way to ameliorate this issue is to co-admin-ister LD with carbidopa(CD),which can increase LD’s oral bioavailability to 40-70%[10].

Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases

The human gastrointestinal tract is populated with a diverse microbial community.The vast genetic and metabolic potential of the gut microbiome underpins its ubiquity in nearly every aspect of human biology,including health maintenance,development,aging,and disease.The advent of new sequencing technologies and culture-independent methods has allowed researchers to move beyond correlative studies toward mechanistic explorations to shed light on microbiome–host interactions.Evidence has unveiled the bidirectional communication between the gut microbiome and the central nervous system,referred to as the“microbiota–gut–brain axis”.The microbiota–gut–brain axis represents an important regulator of glial functions,making it an actionable target to ameliorate the development and progression of neurodegenerative diseases.In this review,we discuss the mechanisms of the microbiota–gut–brain axis in neurodegenerative diseases.As the gut microbiome provides essential cues to microglia,astrocytes,and oligodendrocytes,we examine the communications between gut microbiota and these glial cells during healthy states and neurodegenerative diseases.Subsequently,we discuss the mechanisms of the microbiota–gut–brain axis in neurodegenerative diseases using a metabolite-centric approach,while also examining the role of gut microbiota-related neurotransmitters and gut hormones.Next,we examine the potential of targeting the intestinal barrier,blood–brain barrier,meninges,and peripheral immune system to counteract glial dysfunction in neurodegeneration.Finally,we conclude by assessing the pre-clinical and clinical evidence of probiotics,prebiotics,and fecal microbiota transplantation in neurodegenerative diseases.A thorough comprehension of the microbiota–gut–brain axis will foster the development of effective therapeutic interventions for the management of neurodegenerative diseases.

Ternary NiCoTi-layered double hydroxide nanosheets as a pH-responsive nanoagent for photodynamic/chemodynamic synergistic therapy

Combining photodynamic therapy(PDT)with chemodynamic therapy(CDT)has been proven to be a promising strategy to improve the treatment efficiency of cancer,because of the synergistic therapeutic effect arising between the two modalities.Herein,we report an inorganic nanoagent based on ternary NiCoTi-layered double hydroxide(NiCoTi-LDH)nanosheets to realize highly efficient photodynamic/chemodynamic synergistic therapy.The NiCoTi-LDH nanosheets exhibit oxygen vacancy-promoted electron-hole separation and photogenerated holeinduced O_(2)-independent reactive oxygen species(ROS)generation under acidic circumstances,realizing in situ pH-responsive PDT.Moreover,due to the effective conversion between Co^(3+)and Co^(2+)caused by photogenerated electrons,the NiCoTi-LDH nanosheets catalyze the release of hydroxyl radicals(-OH)from H_(2)O_(2)through Fenton reactions,resulting in CDT.Laser irradiation enhances the catalyzed ability of the NiCoTi-LDH nanosheets to promote the ROS generation,resulting in a better performance than TiO_(2)nanoparticles at pH 6.5.In vitro and in vivo experimental results show conclusively that NiCoTi-LDH nanosheets plus irradiation lead to efficient cell apoptosis and significant inhibition of tumor growth.This study reports a new pH-responsive inorganic nanoagent with oxygen vacancy-promoted photodynamic/chemodynamic synergistic performance,offering a potentially appealing clinical strategy for selective tumor elimination.

川芎嗪对脓毒症致急性肝损伤大鼠肝细胞线粒体膜转运功能保护作用的实验研究

目的 探讨川芎嗪对脓毒症致急性肝损伤（SALI）大鼠肝细胞线粒体膜转运功能的保护作用.方法 按随机数字表法将SD大鼠分为假手术组、SALI模型组〔采用盲肠结扎穿孔术（CLP）制模〕、川芎嗪治疗组（CLP术后经尾静脉注入盐酸川芎嗪60 mg/kg）和川芎嗪预防组（CLP术前7 d,每日经尾静脉注射盐酸川芎嗪60 mg/kg）,每组12只.各组于术后10 h取腹主动脉血和肝脏,用酶耦联速率法测定血清丙氨酸转氨酶（ALT）、天冬氨酸转氨酶（AST）和线粒体型天冬氨酸转氨酶（m-AST）水平;用比色和化学荧光素法检测肝细胞三磷酸腺苷（ATP）含量;用磷定量化方法检测肝细胞线粒体ATP酶活性;用蛋白质免疫印迹试验（Western Blot）检测肝细胞线粒体膜水通道蛋白8（AQP8）、肉毒碱棕榈酰基转移酶（CPT）的表达.结果 与假手术组相比,SALI模型组、川芎嗪治疗组和川芎嗪预防组血清ALT、AST和m-AST水平显著升高,肝细胞ATP含量显著降低,肝细胞线粒体膜ATP酶活性、AQP8和CPT-1A的表达量明显下降.与SALI模型组相比,川芎嗪治疗组和川芎嗪预防组血清ALT、AST和m-AST水平显著降低〔ALT（U/L）：123.8±32.8、105.0±44.5比233.0±110.1,AST（U/L）：427.0±117.9、303.9±110.3比742.6±441.4,m-AST（U/L）：239.6±64.9、168.2±60.0比412.8±252.6,均P＜0.01〕,肝细胞ATP含量均显著升高（nmol/mg：29.5±10.3、34.6±11.2比19.3±8.8,均P＜0.01）,线粒体膜ATP酶活性也均显著升高〔Na＋-K＋-ATP酶（U/mg）：3.91±0.30、3.97±0.35比2.87±0.82,Mg2＋-ATP酶（U/mg）：3.75±0.38、3.88±0.35比2.64±1.06,Ca2＋-ATP酶（U/mg）：3.15±0.58、2.98±0.31比1.75±1.25,Ca2＋-Mg2＋-ATP酶（U/mg）：3.82±0.31、3.91±0.42比2.57±1.01,均P＜0.01〕,线粒体膜AQP8和CPT-1A的表达量明显升高〔以假手术组（100%）为参照,AQP8/COX-Ⅳ：（79.12±7.79）%、（88.40±9.22）%比（62.08±11.91）%,CPT-1A/COX-Ⅳ：（87.92±10.06）%、（84.91±17.48）%比（72.11±7.82）%,均P＜0.01〕,其中川芎嗪预防组较川芎嗪治疗组血清AST、m-AST水平降低更为显著〔AST（U/L）：303.9±110.3比427.0±117.9,m-AST（U/L）：168.2±60.0比239.6±64.9,均P＜0.05〕.4组间肝细胞线粒体膜CPT-2表达量差异无统计学意义.结论 川芎嗪可以保护SALI大鼠肝细胞线粒体膜转运水、离子和脂肪的功能;川芎嗪对脓毒症的预防作用要优于治疗作用.

Regulating Wnt signaling： a strategy to prevent neurodegeneration and induce regeneration

During the past three decades, Wingtess/Int （Wnt）signaling has emerged as an essential regu{ator crucial for neuronal development and maintenance （Inestrosa and Arenas, 201_0）. In addition, Wnt signal- ing was recently shown to be involved in the regula- tion of synaptic function and plasticity, which is critical for learning and memory （Oliva et aL, 2013）. Deregulation of Wnt signaling has been proposed as a key contributor to the pathogenesis of neurode- generative disorders including Alzheimer＇s disease （AD） and Parkinson＇s disease （PD）. This increasing knowledge of the specific roles of Wnt signaling cascades during different stages of life has suggested innovative therapeutic strategies for the treatment of neurodegenerative diseases.

‘Food and medicine continuum’–Why we should promote cross-cultural communication between the global East and West

It is estimated that by 2030 one sixth of the global population will be aged over 60(WHO,2021).Aging leads to functional decline,which triggers many chronic diseases and geriatrics.It is reported that the elderly often suffer from geriatric syndromes such as frailty,sarcopenia,weight loss and dementia(Sanford et al.,2020);for those aged over 85,conditions of hearing and vision loss,decline in immune function,cardiovascular diseases,osteoporosis and dementia are in high prevalence(Jaul&Barron,2017).Therefore,aging has been an important risk for chronic diseases and geriatrics globally.

2D antimonene-integrated composite nanomedicine for augmented low-temperature photonic tumor hyperthermia by reversing cell thermoresistance

The overexpression of heat shock proteins(HSPs)in tumor cells can activate inherent defense mechanisms during hyperthermia-based treatments,inducing thermoresistance and thus diminishing the treatment efficacy.Here,we report a distinct“non-inhibitor involvement”strategy to address this issue through engineering a calcium-based nanocatalyst(G/A@CaCO_(3)-PEG).The constructed nanocatalyst consists of calcium carbonate(CaCO_(3))-supported glucose oxidase(GOD)and 2D antimonene quantum dots(AQDs),with further surface modification by lipid bilayers and polyethylene glycol(PEG).The engineered G/A@CaCO_(3)-PEG nanocatalyst features prolonged blood circulation,which is stable at neutral pH but rapidly degrades under mildly acidic tumor microenvironment,resulting in rapid release of drug cargo in the tumor microenvironment.The integrated GOD effectively catalyzes the depletion of glucose for reducing the supplies of adenosine triphosphate(ATP)and subsequent down-regulation of HSP expression.This effect then augments the therapeutic efficacy of photothermal hyperthermia induced by 2D AQDs upon irradiation with near-infrared light as assisted by reversing the cancer cells’thermoresistance.Consequently,synergistic antineoplastic effects can be achieved via low-temperature photothermal therapy.Systematic in vitro and in vivo evaluations have demonstrated that G/A@CaCO_(3)-PEG nanocatalysts feature potent antitumor activity with a high tumor-inhibition rate(83.92%).This work thus paves an effective way for augmenting the hyperthermia-based tumor treatments via restriction of the ATP supply.