Recent advances in nanoformulation-based delivery for cancer immunotherapy.

Cancer is one of the leading causes of mortality worldwide, and its treatment faces several challenges. Phytoconstituents derived from recently discovered medicinal plants through nanotechnology potentially target cancer cells via PI3K/Akt/mTOR pathways and exert their effects selectively through the generation of reactive oxygen species through ß-catenin inhibition, DNA damage, and increasing caspase 3/9 and p53 expression. These nanocarriers act specifically against different cancer cell lines such as HT-29, MOLT-4 human leukemia cancer and MCF-7 cell lines SKOV-3, Caov-3, SW-626, HepG2, A-549, HeLa, and MCF-7. This review comprehensively elaborates on the cellular and molecular mechanisms, and therapeutic prospects of various plant-mediated nanoformulations to attain a revolutionary shift in cancer immunotherapy.

Undiagnosed rare disease clinic identifies a novel UBE3A variant in two sisters with Angelman syndrome: The end of a diagnostic odyssey.

Angelman syndrome (AS, MIM #105830) is a neurodevelopmental disorder characterized by severe intellectual disability, profound developmental delay, movement or balance problems, an excessively cheerful disposition, and seizures. AS results from inadequate expression of the maternal UBE3A gene (MIM #601623), which encodes an E3 ligase in the ubiquitin-proteasome pathway. Here we present the case of two sisters with features consistent with AS who had negative methylation analyses. An autism/intellectual disability expanded panel revealed a maternally inherited novel UBE3A (NM_001354506.2) variant c.2443C>T p.(Pro815Ser) in both patients that was initially classified as a variant of uncertain significance. The patients were enrolled in Indiana University's Undiagnosed Rare Disease Clinic (URDC) to further investigate the variant. Additional data, including deep phenotyping, familial segregation analysis, and in silico studies, suggest that the variant is likely pathogenic. 3D modeling studies based on the available crystal structure revealed that the Pro815Ser variant can introduce more flexibility into the protein and alter its enzymatic activity. Recent literature confirms the pathogenic nature of the variant. Reanalysis of the UBE3A variant has heightened existing knowledge of AS and has offered this family an end to their diagnostic odyssey.

Innovative technologies for removal of micro plastic: A review of recent advances.

Plastics are becoming a pervasive pollutant in every environmental matrix, particularly in the aquatic environment. Due to increased plastic usage and its impact on human and aquatic life, microplastic (MP) pollution has been studied extensively as a global issue. The production of MP has been linked to both consumer and commercial practices. There is a significant amount of MP's that must be removed by wastewater treatment plants before they can be bioaccumulated. Many researchers have recently become interested in the possibility of eliminating MPs in wastewater treatment plants (WWTP). Many studies have analyzed MP's environmental effects, including its emission sources, distribution, and impact on the surrounding environment. The effectiveness of their removal by various wastewater treatment technologies requires a critical review that accounts for all these methods. In this review, we have covered the most useful technologies for the removal of MP during WWTP. The findings of this review should help scientists and policymakers move forward with studies, prototypes, and proposals for significant remediation impact on water quality.

Biochemical characterization of bioinspired nanosuspensions from Swertia chirayita extract and their therapeutic effects through nanotechnology approach.

Swertia chirayita is used as a traditional medicinal plant due to its pharmacological activities, including antioxidant, antidiabetic, antimicrobial, and cytotoxic. This study was aimed to evaluate the therapeutic efficacy of newly synthesized nanosuspensions from Swertia chirayita through nanotechnology for enhanced bioactivities. Biochemical characterization was carried out through spectroscopic analyses of HPLC and FTIR. Results revealed that extract contained higher TPCs (569.6 ± 7.8 mg GAE/100 g)) and TFCs (368.5 ± 9.39 mg CE/100 g) than S. chirayita nanosuspension, TPCs (500.6 ± 7.8 500.6 ± 7.8 mg GAE/100 g) and TFCs (229.5± 3.85 mg CE/100 g). Antioxidant activity was evaluated through DPPH scavenging assay, and nanosuspension exhibited a lower DPPH free radical scavenging potential (06 ±3.61) than extract (28.9± 3.85). Anti-dabetic potential was assessed throughα-amylase inhibition and anti-glycation assays. Extract showed higher (41.4%) antiglycation potential than 35.85% nanosuspension and 19.5% α-amylase inhibitory potential than 5% nanosuspension. Biofilm inhibition activity against E. coli was higher in nanosuspension (69.12%) than extract (62.08%). The extract showed high cytotoxicity potential (51.86%) than nanosuspension (33.63%). These nanosuspensions possessed enhanced bioactivities for therapeutic applications could be explored further for the development of new drugs.

A case of stuck mechanical Tricuspid Valve.

A 34-year-old non hypertensive, non-diabetic and ill looking weak woman came to our emergency department with shortness of breath NYHA III-IV, severe bilateral pedal edema extending up to the thighs and gross ascites. Physical examination revealed 3mm pitting ankle and leg edema and hemodynamically was stable with raised jugular venous pressure. There was a closing and opening mechanical click on Cardiac auscultation. At the lower left sternal border, there was grade 2/6 holodiastolic rumble and a grade 2/6 systolic murmur. She had history of mitral valve replacement and tricuspid valve replacement in 2017 with mechanical valves then she had Redo tricuspid valve replacement with mechanical prosthesis again after four months. No known food or drug allergy and psychosocial issues. Her routine bloods Labs were normal and COVID-19 was negative. On chest X-ray P/A view images and echo showed markedly gross left sided pleural effusion. In Coronary angiogram showed normal coronaries and stuck tricuspid valve (Fig.1). Echocardiography report showed preserved LV systolic function (EF=57%), dilated left atrium and right atrium. Prosthetic mitral valve was seen at mitral position, well seated and well-functioning. The mechanical mitral valve was functioning well with normal disc motion with no thrombus formation. Prosthetic tricuspid valve was seen at tricuspid level with peak gradient of 22mmHg and shown stuck mechanical tricuspid discs stuck throughout the cardiac cycle, in a fully open position (Fig.2A and 2B). Atrial fibrillation was shown on ECG. The diagnosis was made as; pannus formation resulting in mechanical TV thrombosis.

Advances in nanotechnology-assisted photodynamic therapy for neurological disorders: a comprehensive review.

Neurological disorders such as neurodegenerative diseases and nervous system tumours affect more than one billion people throughout the globe. The physiological sensitivity of the nervous tissue limits the application of invasive therapies and leads to poor treatment and prognosis. One promising solution that has generated attention is Photodynamic therapy (PDT), which can potentially revolutionise the treatment landscape for neurological disorders. PDT attracted substantial recognition for anticancer efficacy and drug conjugation for targeted drug delivery. This review thoroughly explained the basic principles of PDT, scientific interventions and advances in PDT, and their complicated mechanism in treating brain-related pathologies. Furthermore, the merits and demerits of PDT in the context of neurological disorders offer a well-rounded perspective on its feasibility and challenges. In conclusion, this review encapsulates the significant potential of PDT in transforming the treatment landscape for neurological disorders, emphasising its role as a non-invasive, targeted therapeutic approach with multifaceted applications.

Photodynamic therapy is a promising tool to revolutionise the treatment landscape for neurological disorders.The nexus between photodynamic therapy and biological drug conjugation is best suited for non-invasive neurological disorder treatment.

Mitigation of sciatica injury-induced neuropathic pain through active metabolites derived from medicinal plants.

Sciatica characterized by irritation, inflammation, and compression of the lower back nerve, is considered one of the most common back ailments globally. Currently, the therapeutic regimens for sciatica are experiencing a paradigm shift from the conventional pharmacological approach toward exploring potent phytochemicals from medicinal plants. There is a dire need to identify novel phytochemicals with anti-neuropathic potential. This review aimed to identify the potent phytochemicals from diverse medicinal plants capable of alleviating neuropathic pain associated with sciatica. This review describes the pathophysiology of sciatic nerve pain, its cellular mechanisms, and the pharmacological potential of various plants and phytochemicals using animal-based models of sciatic nerve injury-induced pain. Extensive searches across databases such as Medline, PubMed, Web of Science, Scopus, ScienceDirect, and Google Scholar were conducted. The findings highlights 39 families including Lamiaceae, Asteraceae, Fabaceae, and Apocyanaceae and Cucurbitaceae, effectively treating sciatic nerve injury-induced pain. Flavonoids made up 53% constituents, phenols and terpenoids made up 15%, alkaloids made up 13%, and glycosides made up 6% to be used in neuorpathic pain. Phytochemicals derived from various medicinal plants can serve as potential therapeutic targets for both acute and chronic sciatic injury-induced neuropathic pain.

TET1-mediated epigenetic regulation of tumor necrosis factor-α in trigeminal ganglia contributes to chronic temporomandibular joint pain.

Chronic temporomandibular joint (TMJ) pain profoundly affects patients' quality of life. Trigeminal tumor necrosis factor-α (TNFα) plays a pivotal role in mediating TMJ pain in mice, yet the underlying epigenetic mechanisms remain enigmatic. To unravel these epigenetic intricacies, we employed a multifaceted approach. Hydroxymethylated DNA immunoprecipitation (hMeDIP) and chromatin immunoprecipitation (ChIP) followed by qPCR were employed to investigate the demethylation of TNFα gene (Tnfa) and its regulation by ten-eleven translocation methylcytosine dioxygenase 1 (TET1) in a chronic TMJ pain mouse model. The global levels of 5-hydroxymethylcytosine (5hmc) and percentage of 5hmc at the Tnfa promoter region were measured in the trigeminal ganglia (TG) and spinal trigeminal nucleus caudalis (Sp5C) following complete Freund's adjuvant (CFA) or saline treatment. TET1 knockdown and pain behavioral testing were conducted to ascertain the role of TET1-mediated epigenetic regulation of TNFα in the pathogenesis of chronic TMJ pain. Our finding revealed an increase in 5hmc at the Tnfa promoter region in both TG and Sp5C of CFA-treated mice. TET1 was upregulated in the mouse TG, and the ChIP result showed TET1 direct binding to the Tnfa promoter, with higher efficiency in the CFA-treated group. Immunofluorescence revealed the predominant expression of TET1 in trigeminal neurons. TET1 knockdown in the TG significantly reversed CFA-induced TNFα upregulation and alleviated chronic TMJ pain. In conclusion, our study implicates TET1 as a vital epigenetic regulator contributing to chronic inflammatory TMJ pain via trigeminal TNFα signaling. Targeting TET1 holds promise for epigenetic interventions in TMJ pain management.

A case of MBTPS1-related disorder due to compound heterozygous variants in MBTPS1 gene: Genotype-phenotype expansion and the emergence of a novel syndrome.

MBTPS1 (NM_003791.4) encodes Site-1 protease, a serine protease that functions sequentially with Site-2 protease regulating cholesterol homeostasis and endoplasmic reticulum stress response. MBTPS1 pathogenic variants are associated with spondyloepiphyseal dysplasia, Kondo-Fu type (MIM:618392; cataract, alopecia, oral mucosal disorder, and psoriasis-like syndrome, and Silver-Russell-like syndrome). In this report, we describe a 14-year-old female with a complex medical history including white matter volume loss, early-onset cataracts, retrognathia, laryngomalacia, inguinal hernia, joint hypermobility, feeding dysfunction, and speech delay. Additionally, features of ectodermal dysplasia that she has include decreased sweating, heat intolerance, dysplastic nails, chronically dry skin, and abnormal hair growth issues. Exome sequencing analysis identified compound heterozygous variants in the MBTPS1 gene: c.2255G > T p.(Gly752Val) predicted to affect important function of the protein, which was inherited from the mother, and a splice site variant c.2831 + 5G > T, which was inherited from the father. The RNA-seq analysis of the splice variant showed skipping of exon 21, predicted to result in frameshifting p.(Ser901fs28*) leading to non-sense mediated decay. To our knowledge, only eight studies have been published that described the MBPTS1-related disorders. Interestingly, we observed the features of ectodermal dysplasia in our patient that further expands the phenotypic spectrum of MBTPS1 gene-related disorders.

Omicron variant (B.1.1.529) challenge the integrity of blood brain barrier: Evidence from protein structural analysis.

Studies on nonhuman primates, wild-type and transgenic mice have shown the presence of SARS-CoV-2 RNA components in the brains. Despite the Blood-Brain Barrier (BBB) provides protection there are less evidences on how the SARS-CoV-2 crosses the BBB. Given that there is an increase of Omicron reinfection rates, transmissibility rate and involvement to cause neurological dysfunctions, we hypothesized to investigate how the Omicron variant (B.1.1.529) binds structurally to key BBB-maintaining proteins and thus can possibly challenge the integrity and transportation to the brain. By using molecular dynamics simulation approaches we examined the interaction of Omicron variant (B.1.1.529) with different structural and transporter proteins located at the BBB. Our results show that in Zona Ocludin 1-RBD complex, we observe a distinct pattern. Omicron demonstrates a docking score of -88.9 ± 6.8 kcal/mol and six interactions, while the wild type (WT) presents a higher score of -94.0 ± 2.3 kcal/mol, forming eight interactions. Comparing affinities, the WT-RBD displays a stronger preference for Claudin-5, boasting a docking score of -110.2 ± 3.0 and nine interactions, versus Omicron-RBD's slightly reduced engagement, with a docking score of -105.6 ± 0.2 and seven interactions. Interestingly, the Omicron variant exhibits heightened stability in interactions with Glucose Transporter and ABC transporters, registering docking scores of -110.6 ± 1.9 and -112.0 ± 3.6 kcal/mol, respectively. This surpasses the WT's respective scores of -95.2 ± 2.2 and -104.0 ± 6.2 kcal/mol, reflecting a unique interaction profile. Rigorous molecular dynamics simulations validate our findings. Our study emphasizes the Omicron variant's increased affinity towards transporter proteins, illuminating potential implications for BBB integrity and brain transportation. While these insights offer a valuable framework, comprehensive experimental validation is indispensable for a comprehensive understanding.

Correction: Mitochondria-targeting nanozyme alleviating temporomandibular joint pain by inhibiting the TNFα/NF-κB/NEAT1 pathway.

Correction for 'Mitochondria-targeting nanozyme alleviating temporomandibular joint pain by inhibiting the TNFα/NF-κB/NEAT1 pathway' by Qian Bai et al., J. Mater. Chem. B, 2023, https://doi.org/10.1039/d3tb00929g.

An exploratory study of knowledge, attitudes, and practices toward HPV associated anal cancer among Pakistani population.

Background: Anal cancer, mainly attributed to human papillomavirus (HPV) infection, is rising in prevalence among the general population in Pakistan. This study aimed to examine the knowledge, attitudes, and practices (KAP) towards anal cancer screening and HPV of the general population in Pakistan. Method: We surveyed anal cancer KAP using social media and snowball sampling from December 2022 to May 2023. The questionnaire had 16 knowledge, 12 attitudes, 6 practice questions, and socio-demographic variables. We applied validity criteria for inclusion and exclusion and used cutoffs ≥50% for each KAP category. We analyzed data in R with Guttman's λ2 for reliability, did univariate and bivariate analysis, and reported frequencies, percentages, p-values, coefficients, odds ratios, and 95% confidence intervals. Results: We surveyed 1620 people and discovered low awareness of HPV and anal cancer causes prevention, and screening (11%-24%), high stigma and embarrassment for screening (54%-70%), strong moral beliefs (89%), condom nonuse (91%), and low engagement in health services and programs (9.1%-14%). Knowledge (75.23%, OR = 1.0984, p = 0.05) was shaped by socio-demographic factors, attitude, and practice, with higher education enhancing knowledge (OR = 1.0984, p = 0.05). Attitude (78.45%, OR = 6.6052, p< 0.001) was influenced by socio-demographic factors, practice, and knowledge as well. Younger females, single, unemployed, students, living with more family members, earning more income, and residing in Islamabad had a more positive attitude (ORs from 1.0115 to 6.6052, p< 0.05), while religion did not affect attitude (p = 0.51). Practice (9.16%, OR = 0.1820, p< 0.001) was determined by socio-demographic factors, knowledge, and attitude. Older males, employed teachers, living with more family members, earning less income, and residing in Islamabad had better practice (ORs from 0.1323 to 3.8431, p< 0.05), but marital status and religion did not influence practice (p > 0.05). Conclusion: Pakistani young adults need more education, awareness, health services, and programs on HPV and anal cancer, as they have low awareness, high stigma, and socio-cultural challenges. In addition, it is recommended for more research and policy initiatives are needed to address socio-cultural factors and increase anal Pap to overcome anal cancer.

Transcriptome-wide analysis of trigeminal ganglion and subnucleus caudalis in a mouse model of chronic constriction injury-induced trigeminal neuralgia.

Trigeminal neuropathic pain (TNP) induces mechanical allodynia and hyperalgesia, which are known to alter gene expression in injured dorsal root ganglia primary sensory neurons. Non-coding RNAs (ncRNAs) have been linked to TNP. However, the functional mechanism underlying TNP and the expression profile of ncRNAs in the trigeminal ganglion (TG) and trigeminal subnucleus caudalis (Sp5C) are still unknown. We used RNA sequencing and bioinformatics analysis to examine the TG and Sp5C transcriptomes after infraorbital nerve chronic constrictive injury (IoN-CCI). The robust changes in the gene expression of lncRNAs, circRNAs, and mRNAs were observed within the TG and Sp5C from mice that underwent IoN-CCI and the sham-operated mice (day 7). In total, 111,003 lncRNAs were found in TG and 107,157 in Sp5C; 369 lncRNAs were differentially expressed in TG, and 279 lncRNAs were differentially expressed in Sp5C. In addition, 13,216 circRNAs in TG and 21,658 circRNAs in Sp5C were identified, with 1,155 circRNAs and 2,097 circRNAs differentially expressed in TG and Sp5C, respectively. Furthermore, 5,205 DE mRNAs in TG and 3,934 DE mRNAs in Sp5C were differentially expressed between IoN-CCI and sham groups. The study revealed a high correlation of pain-related differentially expressed genes in the TG and Sp5C to anxiety, depression, inflammation, neuroinflammation, and apoptosis. Gene Ontology analysis revealed that binding-related molecular functions and membrane-related cell components were significantly enriched. Kyoto Encyclopedia of Genes and Genomes analysis shows the most significant enrichments in neurogenesis, nervous system development, neuron differentiation, adrenergic signaling, cAMP signaling, MAPK signaling, and PI3K-Akt signaling pathways. Furthermore, protein-protein interaction analysis showed that hub genes were implicated in neuropeptide signaling pathways. Functional analysis of DE ncRNA-targeting genes was mostly enriched with nociception-related signaling pathways underpinning TNP. Our findings suggest that ncRNAs are involved in TNP development and open new avenues for research and treatment.

Mitochondria-targeting nanozyme alleviating temporomandibular joint pain by inhibiting the TNFα/NF-κB/NEAT1 pathway.

Inflammatory cytokines that are secreted into the spinal trigeminal nucleus caudalis (Sp5C) may augment inflammation and cause pain associated with temporomandibular joint disorders (TMD). In a two-step process, we attached triphenylphosphonium (TPP) to the surface of a cubic liposome metal-organic framework (MOF) loaded with ruthenium (Ru) nanozyme. The design targeted mitochondria and was designated Mito-Ru MOF. This structure scavenges free radicals and reactive oxygen species (ROS) and alleviates oxidative stress. The present study aimed to investigate the effects and mechanisms by which Mito-Ru MOF ameliorates TMD pain. Intra-temporomandibular joint (TMJ) injections of complete Freund's adjuvant (CFA) induced inflammatory pain for ≥10 d in the skin areas innervated by the trigeminal nerve. Tumor necrosis factor-alpha (TNF-α), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), long non-coding RNA nuclear paraspeckle assembly transcript 1 (lncRNA NEAT1), and ROS also have been proved to be significantly upregulated in the Sp5C of TMD mice. Moreover, a single Mito-Ru MOF treatment alleviated TMD pain for 3 d and downregulated TNF-α, NF-κB, lncRNA NEAT1, and ROS. NF-κB knockdown downregulated NEAT1 in the TMD mice. Hence, Mito-Ru MOF inhibited the production of ROS and alleviated CFA-induced TMD pain via the TNF-α/NF-κB/NEAT1 pathway. Therefore, Mito-Ru MOF could effectively treat the pain related to TMD and other conditions associated with severe acute inflammatory activation.

Nonsense variant in a consanguineous family expands the phenotype of KPTN gene-related syndrome to include hearing impairment.

A short report with two affected siblings from consanguineous family born with intellectual disability, motor disability, language deficit, and hearing impairment and found to carry biallelic nonsense variant in KPTN gene known to be associated with KPTN gene related syndrome.

Biochemical, structural characterization and in-vitro evaluation of antioxidant, antibacterial, cytotoxic, and antidiabetic activities of nanosuspensions of Cinnamomum zeylanicum bark extract.

Cinnamomum zeylanicum is a traditional medicinal plant known for its anti-inflammatory, antidiabetic, antimicrobial, anticancer, and antioxidant properties. Its therapeutic efficacy using nanosuspensions is still unclear for treating infectious diseases. This study was designed to evaluate the bioactivities, biochemical characterization, and bioavailability of freshly prepared nanosuspensions of C. zeylanicum. Structural and biochemical characterization of C. zeylanicum and its biological activities, such as antioxidants, antimicrobials, antiglycation, α-amylase inhibition, and cytotoxicity was performed using Fourier-transform infrared (FTIR) spectroscopy and High-Performance Liquid Chromatography (HPLC). C. zeylanicum extract and nanosuspensions showed TPCs values of 341.88 and 39.51 mg GAE/100 g while showing TFCs as 429.19 and 239.26 mg CE/100g, respectively. DPPH inhibition potential of C. zeylanicum extract and nanosuspension was 27.3% and 10.6%, respectively. Biofilm inhibition activity revealed that bark extract and nanosuspension showed excessive growth restraint against Escherichia coli, reaching 67.11% and 66.09%, respectively. The α-amylase inhibition assay of extract and nanosuspension was 39.3% and 6.3%, while the antiglycation activity of nanosuspension and extract was 42.14% and 53.76%, respectively. Extracts and nanosuspensions showed maximum hemolysis at 54.78% and 19.89%, respectively. Results indicated that nanosuspensions possessed antidiabetic, antimicrobial, anticancer, and antioxidant properties. Further study, however, is needed to assess the clinical studies for the therapeutic use of nanosuspensions.